spina bifida and anencephalus in greater london · journalofmedicalgenetics (1973). 10, 209. spina...

Journal of Medical Genetics (1973). 10, 209.

Spina Bifida and Anencephalus in Greater LondonC. 0. CARTER and KATHLEEN EVANS

MRC Clinical Genetics Unit, Institute of Child Health, 30 Guilford St, London WC1N 1EH

Summary. In order to make comparisons with the findings in a high fre-quency area, South Wales, with those in a low frequency area, south-east England,a birth frequency and family study was made of all births with neural tube mal-formations (spina bifida cystica, encephalocele, anencephaly, and iniencephaly) in32 of the 33 London Boroughs over a 3-year period from 1 April 1965 to 31 March1968. The births were ascertained through local authority registers, stillbirth andinfant death certificates, and hospital records. The frequencies found were 1-54for spina bifida (including encephalocele) and 1 41 for anencephaly (includinginiencephaly). This was less than four tenths of the South Wales frequency.Evidence of an excess of winter births was found for both types of malformation,with a peak for conceptions in February, March, and April.The parents of 870 of the original 1209 index patients were traced and visited for

the family survey. The usual social class effect was seen, a deficit of fathers insocial class I and II. The birth order distribution of legitimately born patientsstandardized for maternal age showed only a small excess of firstborn and a deficitrather than an excess of lateborn. For maternal age, however, standardized forbirth order, there was an excess of patients born to mothers under 20 and over 35years of age. The whole family study sample showed a striking excess of patientsborn to parents from India and Pakistan compared to parents born in the WestIndies in relation to households of immigrant parents in the 1966 sample Census.A small sample of 164 patients with matched controls had more parents born inIreland and India and Pakistan and fewer born in south-east England and the WestIndies than the controls.The proportions ofsibs affected with spina bifida and anencephaly were 3 42% for

spina bifida index patients and 5 44% for anencephaly. For patients born after theindex patient the proportions were 5-17 and 4-17%, respectively. The overallrisk to sibs was lower than that shown in the South Wales survey, but substantiallyhigher relative to the population birth frequency. The risk to sibs was not ap-parently influenced by father's social class but there was an indication of an effect ofmother's father's social class, with a lower risk where mother had grown up in aclass I, II, or IIIa home. There was no apparent influence of grandparental birthplace. There was no apparent effect ofa relative affected other than a sib. Amongcousins a significant increase over the population birth frequency was seen only inmother's sisters' children.The findings, like those of earlier surveys, suggest a multifactorial aetiology of

the neural tube malformations, depending both on genetic predisposition and en-vironmental triggers.

Received 31 May 1973.209

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Data on the frequency of anencephalic still birthspublished by the Registrar General for England andWales since 1962 show a marked regional variationwith a steady fall as one passes from the North-West to the South-East of the country (Carter,1969; Elwood, 1970a). For spina bifida less in-formation is available, but local studies (Williamson,1965; Carter, David, and Laurence, 1968; Lecket al, 1968; Elwood, 1972) indicate that the birthfrequency parallels that of anencephaly.

Following a large scale birth frequency andfamily study in a high incidence area, South Wales,based on births from 1956 to 1962 inclusive (Carteret al, 1968; Laurence, Carter, and David, 1968aand b), a similar study has been carried out in a lowincidence area, Greater London, in order to comparefamily risks. Data were also collected on maternalage and birth order, social class and parental birthplace.

BIRTH FREQUENCY STUDYMaterial and Methods

Together with Miss B. Spain of the Greater LondonCouncil who was studying incidence and survival ratesfor neural tube defects within Greater London for a 4-year period beginning 1 April 1965, an attempt was madeto identify all mothers domiciled in the London area whohad had a child (live or still born) with a malformationof the central nervous system between 1 April 1965 and31 March 1968. (The frequency over the longer periodwill be published separately, Spain-in preparation.) Itwas on 1 April 1965 that the Borough boundaries wereredefined at the setting up of the Greater LondonCouncil. Not all children are born in hospital so it wasnecessary to search for births outside as well as insidehospitals.The statutory procedure at the birth of a child (live or

still) is that the medical attendant notifies the localMedical Officer of Health, who collects informationabout malformed children from this notification andother sources and sends it, without identification details,to the Office of Population Censuses and Surveys; if achild is stillborn or dies soon after birth the medicalattendant gives the parent a certificate which he takesto the local Registrar when registering the birth. TheRegistrar makes returns to the Registrar General. TheRegistrar General's figure for malformations in thosestillborn or dying soon after birth for any area shouldagree with that from the Medical Officer of Health forthe area.Our main source of names was the local authority,

since it was through the kind help oftheir medical officersof health that we had an introduction to the families.The staff of one borough only out of the 33 were unableto help and that borough was excluded. Londonboroughs have various systems of record keeping, but itis usual for them to make registers of abnormalitiesfrom birth notification cards and other sources, under

such headings as congenital abnormalities, infant deaths,still births, at risk, and others. It was these registersand any other source of a record of an abnormalitywhich were scrutinized to compile the list for the series.In this way 1002 names were collected.Although the local authority totals for stillborn

and dead babies should agree with those which theRegistrar General receives from the local Registrar, itis well known that there is usually a deficit in the localauthority figure (Weatherall, 1969; Elwood, 1970b).Accordingly, our list of names from the local authorityregisters was checked against the neonatal death certi-ficates (up to 3 months) and still-birth certificates for thesame area and period which the Registrar General kindlyallowed us to see. There were 189 births found fromthe Registrar General's certificates which had notappeared in the local Health Department registers. Oncethename was knownfrom the still-birth or death certificateit was usually possible to confirm the diagnosis from theindividual birth notification at the local authority and toobtain an introduction to the family. Failing this, thediagnosis was confirmed with the hospital. The namesof five patients were found first from the records ofmaternity hospitals or those specializing in the treatmentof spina bifida.

All babies born in London whose mothers weredomiciled elsewhere were excluded, but babies bornoutside London whose mothers were domiciled inLondon are included. The criterion for inclusion was adiagnosis of spina bifida cystica, anencephaly, inien-cephaly, or encephalocele; hydrocephalus was includedonly when secondary to spina bifida. For the analysisencephalocele is included with spina bifida and inien-cephaly with anencephaly. Any death or still-birthcertificate which recorded hydrocephalus without men-tion of spina bifida or 'congenital abnormalities' waschecked at the maternity hospital and if anencephaly orspina bifida was recorded they are included (13 nameswere found in this way). Where a baby was born athome a similar check was made with the attendingdoctor or midwife. Cases of spina bifida occulta areexcluded. There were altogether 1209 cases.

Virtually all children born affected in the area willhave been ascertained in one way or another. The firstsource of ascertainment is shown in Table I.

ResultsOverall Birth Frequency. The total births

for the 32 cooperating London Boroughs for theperiod and the numbers and proportions affectedare shown in Table II.The overall frequency of spina bifida was 1-54

and of anencephaly 1 41 per 1000 total births. Thecombined frequency was 2-95 per 1000 live andstill births. There was no significant variation inbirth frequency of either condition over the periodsurveyed. The rates per 1000 for the years are asfollows: April to December 1965, 2-92; January toDecember 1966, 2-88; January to December 1967,

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Spina Bifida and Anencephalus in Greater London

TABLE ISOURCE OF ASCERTAINMENT OF INDEX PATIENTS*

Spina Bifida Anencephaly

Male Female Male Female Total

Initial search in LAregisters 245 319 119 319 1002

Further cases from1. RG's certificates 22 30 47 90 1892. RG's certificates,

stated hydrocephalusor congenitalmalformation butspina bifida oranencephaly found onhospital records 7 4 1 1 13

3. Searching hospitalrecords 4 - 1 - 5

Total 278 353 168 410 1209

* LA = Local Authority; RG =Registrar General.

TABLE IIIOBSERVED AND EXPECTED SPINA BIFIDA ANDANENCEPHALY BIRTHS IN GREATER LONDONAPRIL 1965-MARCH 1968 SHOWING MONTHS OF

OCCURRENCE(Registrar General's unpublished data)


Observed Expected Observed Expected

Jan. 53 52-59 49 48-18Feb. 52 50 22 53 46-01Mar. 53 57 20 48 52-39Apr. 55 53-77 52 49-26MavJuneJulyAug.Sept.Oct.Nov.Dec.

Total

61 55-2355 52-7144 53.9944 52-6659 52 5036 51 3754 48 1165 50-65

631 631o00

4739534346514552

578

50 5948-2849-4648-2348-0947 0544 0746 40

578 00

3-13, and January to March 1968 (only 3 months),2-62. The total of 631 spina bifida births included278 males and 353 females, a sex ratio of 0 79.The total of 578 anencephalic births included 168males and 410 females, a sex ratio of 0-41.

Seasonal Variation. The number of patientsborn in each month is shown in Table III togetherwith the expected numbers related to the monthlyfrequency of total births in the Greater London area

(Registrar General's table 1967 TT a, unpublished).For spina bifida the summer quarter (June, July,

and August) has a relatively low incidence and thewinter quarter (November, December, and January)a relatively high incidence. For anencephaly, thereis a noticeable low incidence in April, May, andJune and a relatively high incidence in December,January, and February. None of the differencesare significant.

However, if one allows for a one month shorter

gestation period for anencephaly, then for both mal-formations combined the highest incidence is forconceptions in February, March, and April andlowest incidence for conceptions in September,October, and November. The observed distribu-tion by estimated season of conception for spinabifida and anencephaly are shown in Table IV to-gether with the expected distribution; also the ratioof observed and expected by month and the three-monthly running average. The latter is shown inFigure 1.

FAMILY STUDYMethods

To collect the family information an attempt was madeto visit every mother of an index patient to find outabout her other children, nieces and nephews of herhusband and herself, husband's occupation, parental ageand birth places, birth places of the grandparents, andsome information about the pregnancy. Altogether 771

TABLE IITOTAL BIRTHS AND SPINA BIFIDA AND ANENCEPHALY IN 32 LONDON BOROUGHS

Total Births Spina Bifida* Anencephaly* Total (spinabifida and

Live Still Male Female Male Female anencephaly)*

Apr.-Dec. 1965 103,963 1553 72 87 47 102105,516 159 (1 507) 149 (1 412) 308 (2-919)

Jan.-Dec. 1966 137,162 1984 96 115 57 133139,146 211 (1-516) 190 (1-366) 401 (2 882)

Jan.-Dec. 1967 130,620 1753 95 123 54 143132,373 218 (1-647) 197 (1-488) 415 (3-135)

Jan.-Mar. 1968 31,980 451 15 28 10 3232,431 43 (1-326) 42 (1-295) 85 (2-621)

Total 278 353 168 410409,466 631 (1-541) 578 (1-412) 1209 (2 953)

* The rate per 1000 births is given in parentheses.

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TABLE IVOBSERVED AND EXPECTED SPINA BIFIDA ANDANENCEPHALY BIRTHS BY ESTIMATED MONTH

OF CONCEPTION

Observed Expected Obs/Exp

Jan. 82 98-42 0-83Feb. 105 92-18 1-14Mar. 110 97 05 1-13Apr. 105 100-77 1-04May 101 96-23 105June 106 109-59 0 97July 103 103-03 1 00Aug. 113 105-82 1-07Sept. 102 100-99 1-01Oct. 183 103-45 0-80Nov. 97 100-89 0-96Dec. 102 100-59 1-01

.2

I *1

1-0

0-9

0@8

0.7

(3= O/E by monthx = three-monthly run

x%x

,x @\ x

ining average

,,w'~ ~~~~~\ X) i)\x (

x-

x@, ,-

I~~~~~

J F M A M J J A S O N DMonth

FIG. 1. Distribution ratio of observed (0) spina bifida and anen-cephaly births over expected (E) births by month of conception.

families were visited in this way by one of the threesocial workers taking part in the study. These families,the main series, for which full information was obtainedare called group 1 (Appendix I).

For a subsidiary series of 99, called group 2 (AppendixII) more limited information, always including the detailsof the mother's other births, was available. Includedin this group were 64 patients already being visited athome by Miss Spain, the psychologist working for theGreater London Council who collaborated in collectingfamily information; 22 patients born in one boroughwhere the Medical Officer of Health preferred that hisHealth Visitors carried out the interview; 13 where theUnit social workers were able to collect limited familyinformation only.The family survey is therefore based on 870 patients,

72% of the total sample.The 339 patients whose families were not interviewed

included 43 whose parents refused to take part; 35

where the family doctor or Medical Officer of Healththought a visit to the family inadvisable, and 261 whosefamilies were never traced. The rather high proportionuntraced is related to the fact that about half the patientswere still born. The reasons for failure to trace in-cluded: inadequate initial address, frequent change ofaddress, migration out of the United Kingdom, andadoption.Where a sib or cousin of the patient was reported to be

affected, confirmation was obtained from hospital re-cords, still-birth or death certificates. Miscarriagesare not included in the analysis (or Appendices I and II),although it is stated in the text where it is known that amiscarriage had a neural tube malformation.

ResultsSocial Class. The patient's father's occupation

was recorded for the 771 patients in the main seriesand the 64 visited by the GLC psychologist. Themothers of 10 patients (mostly illegitimate) did notknow the occupation of the father.The social class distribution of fathers of index

patients was compared (Table V) with that for alladult males in Greater London in the 1961 Census(Table 27). There is a significant deficit of ob-served cases (127) compared with expected cases(170-52) in social classes I and II. This deficitwould almost certainly have been larger if it hadbeen possible to include the families which werenot traced. There is also a small and nonsignificantdeficit in classes IV and V, but this may well be dueto the omission of those families not traced.

TABLE VDISTRIBUTION OF FATHERS' SOCIAL CLASS (0)COMPARED WITH THAT FOR ALL MEN INGREATER LONDON (E). FROM 1961 CENSUS

Maternal Age and Birth Order. The mater-nal age and birth order distribution of the legitimateindex patients was compared with the expectednumber estimated from the distribution of all legiti-mate births in Greater London in 1967 (RegistrarGeneral, unpublished). The comparison is shownin Table VI. The distribution by maternal agestandardized for birth order, and birth orderstandardized for maternal age is shown in TableVII. It will be seen from Table VI that the moststriking excess of observed over expected, 75 ascompared with 48-95, is for first born children to

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TABLE VIDISTRIBUTION BY MATERNAL AGE AND NUMBER OF PREVIOUS

LIVE BORN SIBS OF LEGITIMATE INDEX PATIENTSCOMPARED WITH EXPECTED DISTRIBUTION (E) FOR ALL

LEGITIMATE BIRTHS IN GREATER LONDON(Registrar General's figures 1967, unpublished)

Birth OrderMaternal Age (yr) Total

0 1 2 3 4 5

15-19O 75 9 0 0 0 0 84E 48-95 10 43 118 0-07 0 01 0 00 60 64

20-24O 170 80 22 6 1 0 279E 163-45 88-11 25-48 7-11 1-64 0-52 286 31

25-29O 81 93 53 19 6 1 253E 90-02 92.41 48-07 19-30 7-69 4-41 261-89

30-34 IO 41 31 25 18 5 4 124E 32-50 42-68 32-89 18 09 8-84 8-84 143-85

35-39O 15 10 21 9 9 8 72E 12-05 14 64 15 09 10-54 6-67 8 55 67-54

40+0 6 3 8 3 4 3 27E 2-94 2-88 3-56 3-24 2-00 4-16 18-77

Total 388 226 129 55 25 16 839349-91 251-13 126-27 58-35 26-85 26-49

mothers under the age of 20 years. The birth orderdistribution standardized for maternal age (TableVIIa) shows no significant deviation from the ex-

pected figures; it is noteworthy that though there isa small excess of first born, and a deficit of late born,it is possible that a higher proportion of first bornwere present among the legitimately born patientswho were not traced. The observed maternal agedistribution (Table VIIb), however, deviates fromthe expected at the 1 in 100 level of significance; the

TABLE VIIaDISTRIBUTION BY NUMBER OF PREVIOUS LIVEBORN SIBS STANDARDIZED FOR MATERNAL AGE

TABLE VIIbDISTRIBUTION BY MATERNAL AGE STANDARDIZED

FOR BIRTH ORDER

Maternal AgeTotal

15-19 20-24 25-29 30-34 35-39 40+

O 84 279 253 124 72 27 839E 6416 293-10 260-26 139-83 64-32 17-34 I

excess of observed over expected is for mothers ofindex patients both under the age of 20 and over theage of 35 years.Place of Birth of Parents and Grandparents.

No figure for all Greater London births was avail-able with which to compare the distribution ofparental birth places of our index patients. How-ever in the 1966 sample Census a table (Common-wealth Immigrant Tables, Table 18) is givenshowing the distribution for Greater London ofhouseholds with children by birthplace of headand spouse where this was in the old or the newCommonwealth. The two large groups are parentsborn in India and Pakistan and those born in theWest Indies. The comparison for those two areasfor the parents of index patients is shown in TableVIII. This shows a significant deficit of parents of

TABLE VIIIRELATIVE FREQUENCY WITH WHICH BOTH

PARENTS OF PATIENTS WERE BORN IN INDIAAND PAKISTAN AND THE WEST INDIES,

COMPARED WITH THAT FOR ALL HOUSEHOLDSWITH CHILDREN IN GREATER LONDON (SAMPLE

CENSUS 1966)

India and West Indies India/Pakistan West Indies

Parents of patients 25 23 1109All households 695 2706 0-26

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index patients born in the West Indies and an excessborn in India and Pakistan.A separate smaller scale, but better controlled,

comparison may be made for 164 index patientswho were matched with an equal number of controlbirths (those immediately following in the samematernity unit). The homes of these controls werealso visited. The findings for parents are shown inTable IX. The differences are not significant.However, more parents of patients than of controlswere born in India and Pakistan and fewer inSouth-East England and the West Indies.The grandparental birth places gave no additional

information.

TABLE IXPARENTAL BIRTHPLACES OF INDEX PATIENTSAND CONTROLS WHEN BOTH PARENTS WERE

BORN IN THE SAME REGION

Birthplace Index Patients Controls

Ireland 15 10India and Pakistan 6 3North and West Britain, Scotland,and Wales 5 5

South-East England 82 108West Indies 5 8Others 51 30

Consanguinity of Parents. In the wholeseries only five index patients were born to con-sanguineous parents, and in no case were the parentsnative born. In three instances (two first cousinsand one first cousin once removed) the parents wereborn in India, in one instance (first cousin) parentswere born in Ireland, and in one instance (secondcousin) the parents were born in Aden. In thesefive families none of the 11 sibs of the index patientshad a neural tube malformation.

Twins. The information on twins is summarizedin Table X; this includes two twin born indexpatients whose families were not visited. Of fourtwin born index patients with spina bifida, one male(No. 31) had a normal female twin, two females (No.360 and an unvisited encephalocele) had normalmale twins, and one female (No. 327) had a normalfemale twin. Of 11 twin born index patients withanencephaly, one male (No. 491) had a female twinwith anencephaly (No. 755) and one male (un-visited) had a normal male twin; one female (No.755) had a male twin with anencephaly (No. 491),three females (Nos. 733, 701, and 702) had maletwins without central nervous system malformation,but two of these died neonatally, one with atresia ofthe aorta and one from prematurity; five otherfemales (Nos. 670, 605, 576, 499, and 500) had

TABLE XTWIN BORN INDEX PATIENTS

Spina bifida Anencephaly(total births 498) (total births 425)

No. 31 M* F No. 491 M* F* No. 755No visit M* M

No. 360 F* MNo visit F*e M No. 733 F* MNo. 327 F F No. 701 F* Mnnd

No. 702 F Mnnd

No. 670 F* FNo. 605 F* FNo. 576 F* FNo. 499 F* FsbNo. 500 F* Fsb

M, male; F, female (italics indicate affected relative); *, indexpatient; e, encephalocele; sb, still born; nnd, neonatal death.

female twins of whom three were normal and twowere still born but without malformation.The proportion of twins born among the visited

index patients, 13 in 870 is less, though not signifi-cantly so, than the approximately 1 in 50 expected ina random sample of the general population.

Sibs. The findings in the sibs do not differappreciably between group 1 and 2 so the results inthe two groups are combined and summarized inTable XI distinguishing spina bifida and anence-phaly in index patients and distinguishing the sex ofindex patients and sibs. Only sibs for whom it waspossible to get documentary confirmation of themalformation are shown as affected, with two excep-tions described below.

Spina Bifida Index Patients. Of 389 brothers,three had spina bifida and one a nasopharyngealencephalocele which is entered in Table XI as'spina bifida', and five anencephaly (including oneiniencephaly). Of 341 sisters, nine had spina bifidaand seven anencephaly including one still born girl(No. 364) with anencephaly born in Eire where theaccount given by the mother (who is a nurse) is ac-cepted. Thus 2-31% of brothers and 469% ofsisters and 3 42% of sibs of both sexes were affectedwith a neural tube malformation. Subdividing bysex of index patients shows no appreciable dif-ference (12/316 = 3 80% for sibs of male and 13/414=3-14% for sibs of female). The proportionaffected of sibs born after the index patients (14/271=5-17%) was higher though not significantly sothan of sibs born before the index patient (11/459=2A40%).

Included among the index patients with spinabifida there were 11 male and 40 female patients withencephalocele. These had 82 sibs, of whom onlyone was affected (with anencephaly).

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TABLE XISIBS OF INDEX PATIENTS WITH SPINA BIFIDA (S) AND ANENCEPHALY (A) DISTINGUISHING THOSE BORN

BEFORE AND AFTER THE INDEX PATIENTS

Brothers Sisters

Index Patients Older (total Younger Older (total Younger Grand Total C",affected) (total Total affected) (total Total affected

afce) affected) affected

Spina bifidaMale (n = 217) 108 (2S) 70 (1 S, 2A) 178 (3S, 2A) 83 (3S) 55 (2S, 2A) 138 (5S, 2A) 316 (85, 4A) 3 80Female (n=261) 142(2A) 69(1S, 1A) 211 (1S,3A) 126(3S, 1A) 77(1S,4A) 203(4S,5A) 414(5S,8A) 3 14

Total (n = 478) 250 (2S, 2A) 139 (2S, 3A) 389 (4S, 5A) 209 (6S, 1A) 132 (3S, 6A) 341 (9S, 7A) 730 (13S, 12A) 3 42

A nenzcephalv 1Male (n=110) 67(2A) 54 121(2A) 61(2S,1A) 47(2A) 108(2S,3A) 229(2S,5A) 3 17Female (n= 282) 154 (4S, 5A) 127 (4S, 2A) 281 (8S, 7A) 136 (6S, 7A) i 108(1S,5A) 244(7S, 12A) 525(15S, 19A) 6-48

Total (n=392) 221 (45,7A) 181 (45,2A) 402(85,9A) 197(85,8A) 155(1S,7A) 352(9S,15A) 754(175,24A) 544

Grand total(n= 870) 471 (6S,9A) 320 (6S, 5A) 791(12S, 14A) 406 (14S, 9A) 287(4S, 13A) 693(18S,22A) 1484(30S,36A) 4-45

Anencephaly Index Patients. Of 402 brothers,eight had spina bifida and nine anencephaly. Of352 sisters, nine had spina bifida and 15 anencephaly(including one unconfirmed still born girl [No. 660]born in India where the parents' story was acceptedas reliable and one encephalocele). Thus, 4-23%of brothers and 6&820% of sisters were affected and5-440o of sibs of both sexes were affected by neuraltube malformations. In addition (and not shownin Table XI) two male abortuses, families Nos. 419and 454, had documented anencephaly. Subdivid-ing by sex of index patient shows fewer sibs of maleindex patients affected than of female, 7/229 =3-170o and 34/525=6 480%, respectively. Thedifferences are not significant. The proportion ofsibs born after the index patient (14/336=4-17%o)was lower than that of sibs born before the indexpatient (27/418 = 6-460'); but again the difference isnot significant.Combining spina bifida and anencephalic index

patients 4-45% of sibs were affected, including4-33O' of older and 4-65°' of younger sibs.

Subdividing by father's occupation (RegistrarGeneral's social classes I-V) there are no significantdifferences in the proportion of sibs affected. Sub-dividing by mother's father's occupation there was a

relatively low risk of recurrence when mother grew

up in a social class I, II, or IIIa home and a highrisk when mother's father's occupation was notknown. This is shown in Table XII.

Subdividing by grandparental birthplaces, theproportion of sibs affected are shown in Table XIIIfor index patients where all four grandparents were

from South-East England, Ireland, India withPakistan, and the West Indies. There is no indica-tion of any lower recurrence risk for couples bothoriginating in South-East England or of a higherrecurrence risk for those both of Irish origin.The series presents little information on the effect

of the proportion of sibs affected where there isanother relative affected in the family. There were

12 children born after an index patient where themother had another child with a neural tube mal-formation born before the index patient; one had

TABLE XIIPROPORTION OF SIBS AFFECTED BY FATHER'S SOCIAL CLASS AND BY

MOTHER'S FATHER'S SOCIAL CLASS (GROUP 1 ONLY)

Social Class Father's Social Class Mother's Father's Social Class

Total Affected* Affected 0o Total Affected Affected 0

I, II, IIIa, and 0 366 8S; 10A 4-92 316 1S; 5A 1 90

* S, spina bifida; A, anencephaly.

IIIb 710 12S; 18A 4-22 419 13S; 9A 5-25

IV, V 404 lOS; 8A 4-46 478 lOS; 12A 4-60

Not known 4 0 0 00 152 3S; 7A 6-58

Total I 1484 30S; 36A 4-45 1365 27S; 33A 4 40_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

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TABLE XIIIPROPORTION OF SIBS AFFECTED BY BIRTH PLACEOF ALL FOUR GRANDPARENTS OF INDEX PATIENTS

No. of GadaetlProportionIndex Grandparental Sibs AffectedPatients BrhPae(oi%)258 South-East England 409 5-62

(15S, 8A)

76 Ireland 163 3-68(1S, 5A)

28 India with Pakistan 75 6-67(1S, 4A)

20 West Indies 50 0 00

anencephaly. There were also 11 children bornafter the mother had had another child with a neuraltube malformation after the index patient; one hadanencephaly. Where an aunt or uncle of an indexpatient had a neural tube malformation (eight fami-lies) one of six sibs had anencephaly. Where acousin of the index patient (28 families) had a neuraltube malformation, of 65 sibs one had spina bifidaand one anencephaly; in seven of these 28 families,two cousins were affected but none of 13 sibs wasaffected.

TABLE XIVSIBS AFFECTED WHEN ANOTHER RELATIVE

AFFECTED

Affected Relative

Sibs Aunt/Uncle Cousin

No. of sibs 23 5 65(2A) (1A) (IS, IA)

Sibs with Other Malformations. The sibswith malformations other than those of the neuraltube are shown in Appendix III (p. 234). Amonga total of 1484 sibs 31 had a major malformation.These include seven patients with congenital heartdefects, four with congenital dislocation of the hip,three with pyloric stenosis, two with imperforateanus, one with cleft lip, one with cleft palate, twowith talipes equinovarus, one with Hirschsprung'sdisease, two with Down's syndrome, one with ace-

phalus and holocardius, one with Klippel Feil cervi-cal vertebral malformation, examphalos and aorticatresia, one with a sacrococcygeal tumour, and twowith hydrocephalus (both perforated before de-livery) without spina bifida. Both the total numberof malformations, other than neural tube malforma-tions, and the individual malformations do not differfrom those that might be found in any random seriesof births. Only the Klippel Feil anomaly, the

sacrococcygeal tumour and, less plausibly, the ace-phalus and holocardius might be regarded aspossibly related to spina bifida and anencephaly.

Parents. No parent had a meningocele ormeningomyelocele. One mother (family 526) had alarge mole over the lumbar spine and bilateraltalipes, and another (family 293) had a hairy moleremoved and was recorded as having spina bifidaocculta.

Half Sibs. Of 74 maternal half sibs of spinabifida cases one had spina bifida and one anence-phaly; of 42 paternal half sibs, one had spina bifida.For anencephaly cases there were 41 maternal halfsibs of whom one had spina bifida and 42 paternalhalf sibs who were all unaffected. The details aresummarized in Table XV. Of the 84 paternal halfsibs one was affected and of the 115 maternal halfsibs three (2-61%) were affected. In sum, four of199, or 2 0%, were affected.

TABLE XVHALF SIBS OF INDEX PATIENTS SHOWING THOSEWHO HAVE SPINA BIFIDA (S) OR ANENCEPHALY (A)

Index Patient Paternal Maternalwith a Half Sib

Sisters Brother SistersBrothers Sisters Brothers Sisters

Spina bifida 28 14 46 28(n=53) (iS) (1S, 1A)

Anencephaly 20 22 16 25(n = 33) (iS)

Total 48 36 62 53(n=86) (1S) (2S, 1A)

Cousins. Though the attempt was made tocheck the cause of death in all reported still birthsand infant deaths in cousins, information on thefirst cousins of index patients is inevitably less com-plete than for sibs as the information is supplied bythe index patients' parents. A positive report that acousin was affected was usually found to be correct,but the parents may well not know of all the still-born children of their brothers and sisters andwhen they do they may not know the cause of thestill birth. The information on cousins is sum-marized in Table XVI. The report that a cousinwas affected was confirmed in all but three cases, allbom in Ireland, two with a convincing history. Insummary, 4-32 per 1000 cousins were found affected,the individual risks being 1-21, 4 94, 3-01, and 6-77per 1000 for the children offather's brothers, father'ssisters, mother's brothers, and mother's sisters,respectively. Only in the latter group is the num-ber affected (14) significantly more (8 72) than

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Spina Bifida and Anencephalus in Greater LondonTABLE XVI

COUSINS OF INDEX PATIENTS, SHOWING THOSE HAVING SPINA BIFIDA OR ANENCEPHALY

Father's Brothers Father's Sisters Mother's Brothers Mother's SistersTotal

Sons Daughters Sons Daughters Sons Daughters Sons DaughtersSpina bifida 440 (1S)1 412 518 (2S, 2A) 485 (1S, 3A) 487 433(2S,lA)| 514 (2S, 2A) 495(3S,3A) 3784 (l1S, llA)

Anencephaly 1418 389 (1S) 544 (1S) 479 (1S) 381 358 (2S) 581 (1S, 1A) 479(1S,1A)t 3629(7S,2A)

Total |858 (1S) 801 (1S) 1062(3S, 2A)l 964(2S, 3A)l 868 791 (4S, lA)i 1095 (3S, 3A) 974(4S,4A)1 7413(18S, 13A)

Grand total 1659 (2S) 2026 (5S, 5A) 1659 (4S, IA) 2069 (7S, 7A)

Percentage 1210 494% 301%Xo 677°o

would be expected in a random sample of the samesize from the general population.

DiscussionBirth Frequency. The birth frequency of

both malformations shows the expected relativelylow figure for South-East England. The birthfrequency in South Wales (Carter et al, 1968) wasapproximately 2- times higher for each malformationthan in this London study. The comparison isshown in Table XVII.

TABLE XVIIBIRTH FREQUENCY OF SPINA BIFIDA AND

ANENCEPHALY (PER 1000 BIRTHS). A COMPARISONOF GREATER LONDON AND SOUTH WALES

Spina Bifida Anencephaly Total

Greater London, 1965-68 1-54 141 2-95South Wales, 1956-62 4 13 3-54 7-67

Ratio (South Wales/Greater London) 2-7 2-5 2-6

A more recent series (1962-66) from South Wales(Richards and Lowe, 1971) gave frequencies of3'9 and 3-1 for spina bifida and anencephaly, re-

spectively. The South Wales frequency is ex-

ceeded perhaps only in Northern Ireland whereElwood (1972) reported 3-6 and 3-5 for the years1964-68; the spina bifida figure in this series isprobably an underestimate because of the classifica-tion of some cases as hydrocephalus. Liverpoolwith 3-4 and 3-1 in 1960-64 (Smithells, 1968)approaches the South Wales figures. Birminghamwith 3-1 and 2-8 for 1955-59 (Leck et al, 1968),Glasgow with 2-80 and 2-83 (Wilson, 1970), andSouthampton with 3-2 and 1-9 for 1958-62 (William-son, 1965) have figures intermediate between thosefor South Wales and London.These detailed surveys confirm the overall pic-

ture of a cline of increasing frequency from South-East to North-West Britain shown by the RegistrarGeneral's anencephaly still-birth data (Carter, 1969).They also indicate that the frequency of spina bifidacystica (with or without hydrocephalus and includ-ing encephalocele) follows the same cline.

Season of Birth. Still-birth registration datahave tended to show an excess of anencephaly amongwinter births. This was noted early in the Scottishdata (Edwards, 1958) with peaks in December andJanuary and also may be seen in the data for Eng-land and Wales since the introduction of the regis-stration of the causes of still birth. Of the 10calendar years 1961-70, the October rates werehigher than the average for the year in 7 out of the 10calendar years, for November in 9, for December in9, for January in 9, and for February in 7. Incontrast the rates were low in March, April, May,June, July, August, and September for 7, 6, 8, 9,8, 7,and 8 out of the 10 calendar years, respectively. Nocomparable national data are available for spinabifida, but the data for Birmingham (Leck, 1972)agree with the present series in showing arelationship of the birth frequency with month ofbirth similar to that of anencephaly, if the anen-cephaly rates for one month are related to those forspina bifida one or two months later.

Maternal Age and Birth Order. A U-shaped relationship of birth order and maternal agewas shown early in the Scottish registration data foranencephaly (Record, 1961). More recently thelarger scale data for England and Wales have be-come available and the same relationship holds forthe years 1962-66 (Carter, 1969); there is an excessof first born and late born, and an excess at maternalages under 20 years and over 35 years. The re-lationship has persisted in the years 1967-70. Theeffects of birth order and maternal age cannot beseparated for this data as published. However,

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independent U-shaped birth order and maternalage effects for anencephaly and spina bifida havebeen shown for Birmingham (Record andMcKeown, 1949; Leck, 1972) and on a specialtabulation of the Scottish anencephaly data (Record,1961).In the South Wales series approximate standard-

ization (using a comparison with the births in Eng-land and Wales) for birth order left little late birthorder effect, but a primiparity and early and latematernal age effect (Carter et al, 1969). In thisLondon series the availability of a simultaneoustabulation for maternal age and birth order forGreater London (Registrar General, unpublished)makes accurate standardization possible and it isinteresting (see Table VII) that in the presentseries there is again no excess (rather a deficit)among late births and also no significant excessamong firstborn. Only a U-shaped maternal ageeffect remains with an excess among mothers under20 and over 35 years. The excess for youngmothers may in part be associated with social classsince only five in 90 were in social class I and II, butthere was no such association for mothers over theage of 35 years, of whom 12 in 97 were in classes Iand II.

Parental Birth Places. It is of considerableinterest to know whether the marked ethnic dif-ferences in birth frequency of central nervous sys-tem malformations persist after migration. Leck(1969) has demonstrated that in Birmingham thebirth frequency of spina bifida and anencephaly formothers of different ethnic origin parallels that inthe countries of origin, the descending order offrequency being Ireland, India, England, and theWest Indies. He (Leck, 1972) notes that the birthfrequency in Negroes tends to be low in a widevariety of environments, England, South Africa,and North America. In contrast the frequency forthe Irish tends to be high in Birmingham andBoston, though not so high as in Northern Ireland.The findings in this study (see Tables IX and XIII)though less direct than those from Birminghamagain suggest a descending order of birth frequencyfor those born in Ireland, India and Pakistan,North-West Britain, South-East England, and theWest Indies. The low frequency in those from theWest Indies is the more remarkable because mostof the fathers are manual workers and thus in socialclasses IIIb, IV, and V.

Relatives.Twins. The smaller proportion than expected of

twin-born in the London series was also seen in the

South Wales series where there were 13 twin-bornamong 784 index patients. Such a deficit has beenseen in most, though not all, other reported series(listed in Czeizel and Revesz, 1970). If a realphenomenon, this deficit may be associated with thesmall proportion affected of co-twins of patients withspina bifida and anencephaly. Both malformationsprobably occur at a higher frequency early in preg-nancy than in live and still births and therefore bothprobably predispose to abortion. A twin preg-nancy in which both fetuses were affected might beexpected to have a still higher risk of abortion.

Sibs with Neural Tube Malformations. Theproportion of sibs found affected is in good agree-ment with that found in other studies. The SouthWales findings were compared with those of earliersurveys (Carter et al, 1968), and this London seriesis compared with the South Wales and a recentlyreported series from Glasgow (Richards, McIntosh,and Sweenie, 1972) in Table XVIII. The latterseries is comparable though substantially fewerfamilies were traced. The proportion ofsibs affectedis actually higher, though not significantly so, in theGlasgow than the South Wales series, but the Lon-don series shows a lower proportion affected, asmight be expected from the lower birth frequency inLondon, though again the difference is not signifi-cant.The London series shows a higher proportion of

affected sibs of anencephalic than of spina bifidaindex patients. This difference is not significantand in the other two series the difference is reversed.There is no real indication of a difference in the pro-portion of sibs affected according to whether theindex patient had spina bifida or anencephaly.There is a consistent, though not very strong,

tendency in all three series for an affected sib to havethe same type of malformation as the index patient.This is shown in Table XIX. This tendency ismost marked in the Glasgow series.The absence of any increase in malformations

other than those of the spina bifida-anencephalygroup in the sibs is consistent with the findings inother series, including the South Wales and Glas-gow series. In earlier studies (for example, Recordand McKeown, 1949) it was considered that hydro-cephalus was aetiologically related to spina bifidaand anencephaly. This however was probablydue to the classification of cases of hydrocephalussecondary to spina bifida as hydrocephalus. Oneexample of hydrocephalus was recorded as occurringamong the sibs in the South Wales study, none inthe Glasgow survey and only two in this study.

Half Sibs. It is unfortunate that so few half

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TABLE XVIIIPROPORTION OF SIBS AFFECTED IN THREE LARGE RECENT FAMILY STUDIESWITH A COMPARISON WITH THE PROPORTION AFFECTED IN THE GENERAL

POPULATION

Malformation Proportion of Sibs Malformations Relative Proportionin Population (%) Malformed in Sibs (%) Sibs/Population

South WalesSpina bifida 0-413 52/854 6-09)s.18 056 x 6-8Anencephaly 0-354 29/709 4 101

GlasgowSpina bifida 0-280 25/450 5-56 5*64 + 085 x 10 1Anencephaly 0-283 26/454 5-735

LondonSpina bifida 0-154 25/730 3-42 4.4 +054 x 15-8Anencephaly 0-141 41/754 5-44 4

TABLE XIXTENDENCY FOR AFFECTED SIBS TO HAVE THESAME MALFORMATION AS THE INDEX PATIENT

SibIndex Patient Same: Different


South WalesSpina bifida 32 20 48:33Anencephaly 13 16

GlasgowSpina bifida 14 5 24:11Anencephaly 6 10

LondonSpina bifida 13 12 37:29Anencephaly 17 24

sibs were found in either South Wales or the Londonsurvey, since the comparison of the proportionaffected of maternal and paternal half sibs would bea valuable pointer as to whether the father's geno-type contributes to the risk of his children havingspina bifida or anencephaly. A larger series of halfsibs would be valuable, though the point may beclarified first from information on the proportionaffected of children of male and female patients.

Cousins. As in the South Wales and other series,only among the mother's sisters' children is theproportion with affected spina bifida and anen-cephaly greater than in the general population. Themost likely explanation is that information is mostcomplete for this class of cousins.

Social Class. The importance of social class wasshown clearly in the Scottish registration data(Edwards, 1958). It was strikingly confirmed in thenational sample reported by Butler and Alberman(1969). The effect was less marked but still presentin more local surveys in Birmingham (Leck, 1972),South Wales (Laurence et al, 1968b), and in thispresent London survey.

Genetics. The findings in this family survey,as in earlier surveys, are suggestive of a multi-factorial aetiology for spina bifida and anencephaly,with a genetic predisposition depending on variationat several gene loci and additional environmentalfactors. However, much further study is needed toprove this and to identify the mechanism. Thereare no indications of any single gene-determinedcomponent among this group of malformations.The proportion of sibs affected is not increasedwhere there is parental consanguinity, nor is it in-creased where a relative other than a sib is affected(though there is no information yet on the riskwhere the parent is also affected).Assuming polygenic inheritance, the ratio of pro-

portion of sibs affected to birth frequency in SouthWales and London is much as expected. Theheritability estimates, using Falconer's method(1965/66) on the relative proportions affected of sibsof patients and of the general population, are about60, 65, and 70% for the South Wales, Glasgow,and London series, respectively. This estimate ofheritability includes common family environment.If, however, the proportion of mother's sister'schildren affected is representative of all cousins, thisgroup with a lesser degree of common family en-vironment gives a similar estimate of heritability.It should be remembered however that this estimateof heritability refers to the proportion of variancewithin the community studied, for example SouthWales or London, which is due to genetic variance,and that 100% heritability within each com-munity is compatible with all the difference in thefrequency between South Wales and London beingenvironmental. It is however difficult to visualizeother than a genetic basis for the low incidence ofneural tube malformations among Negroes in a widevariety of environments.

We are much indebted to Miss B. Spain of the Greater

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London Council for her collaboration throughout thestudy. We gratefully acknowledge the help of theAssociation of London Borough Medical Officers ofHealth and the staffs of their departments; the staffs ofthe maternity hospitals in Greater London who gave us

an introduction to controls; Mr D. Smale and the staffat the National Health Service Central Register at South-port; and particularly Miss P. K. Heath and Mrs A. V.Hickman who shared the family visiting of the mainseries with K.A.E. The Department of Health andSocial Security generously paid for the copies of thedeath and still-birth certificates.

REFERENCESButler, N. R. and Alberman, E. D. (eds.) (1969). Perinatal Pro-

blems. (The Second Report of the 1958 British Perinatal Mor-tality Survey.) Churchill Livingstone, Edinburgh.

Carter, C. 0. (1959). Spina bifida and anencephaly: a problem ingenetic-environmental interaction. J7ournal of Biosocial Science, 1,71-83.

Carter, C. O., David, P. A., and Laurence, K. M. (1968). A familystudy of major central nervous system malformations in SouthWales. Journal of Medical Genetics, 5, 81-106.

Czeizel, A. and Revesz, C. (1970). Major malformations of thecentral nervous system in Hungary. British Journal of Preventiveand Social Medicine, 24, 205-222.

Edwards, J. H. (1958). Congenital malformations of the centralnervous system in Scotland. British Journal of Preventive andSocial Medicine, 12, 115-130.

Elwood, J. H. (1970a). Anencephalus in the British Isles. De-velopmental Medicine and Child Neurology, 12, 582-591.

Elwood, J. H. (1970b). Notification of congenital malformationsin Northern Ireland 1964-66. Medical Officer, 123, 33-36.

Elwood, J. H. (1972). Major central nervous system malformationsnotified in Northern Ireland (1964-1968). Developmental Medi-cine and Child Neurology, 14, 731-739.

Falconer, D. S. (1965/66). The inheritance of liability to certaindiseases, estimated from the incidence among relatives. Annals ofHuman Genetics, 29, 51-76.

Laurence, K. M., Carter, C. O., and David, P. A. (1968a). Majorcentral nervous system malformations in South Wales. I. Inci-dence, local variations and geographical factors. British Journalof Preventive and Social Medicine, 22,146-160.

Laurence, K. M., Carter, C. O., and David, P. A. (1968b). Majorcentral nervous system malformations in South Wales. II. Preg-nancy factors, seasonal variation, and social class effects. BritishJournal of Preventive and Social Medicine, 22, 212-222.

Leck, I. (1969). Ethnic differences in the incidence of malformationsfollowing migration. British Journal of Preventive and SocialMedicine, 23, 166-173.

Leck, I. (1972). The etiology of human malformations: insightsfrom epidemiology. Teratology, 5, 303-314.

Leck, I., Record, R. G., McKeown, T., and Edwards, J. H. (1968).The incidence of malformations in Birmingham. Teratology, 1,263-279.

Record, R. G. (1961). Anencephalics in Scotland. British Journalof Preventive and Social Medicine, 15, 93-105.

Record, R. G. and McKeown, T. (1949). Congenital malformationsof the central nervous system. 1. A survey of 930 cases. BritishJournal ofPreventive and Social Medicine, 3, 183-219.

Richards, I. D. G. and Lowe, C. R. (1971). Incidence of congenitaldefects in South Wales 1964-6. British Journal of Preventive andSocial Medicine, 25, 59-64.

Richards, I. D. G., McIntosh, H. T., and Sweenie, S. (1972). Agenetic study of anencephaly and spina bifida in Glasgow. De-velopmental Medicine and Child Neurology, 14, 626-639.

Smithells, R. W. (1968). Incidence of congenital abnormalities inLiverpool, 1960-64. British Journal of Preventive and SocialMedicine, 22, 36-37.

Weatherall, J. A. C. (1969). A notification of congenital malforma-Medical Officer, 121, no. 6, 65-68.

Williamson, E. H. (1965). Incidence and family aggregation ofmajor congenital malformations of central nervous system.Journal of Medical Genetics, 2, 161-172.

Wilson, T. S. (1970). Congenital malformations of the central ner-vous system among Glasgow births 1964-68. Health Bulletin, 28,32-38.

Appendix IMain Series

M, male; F, female; *, index patient; italics indicate affected relative; [ ], twins; sb, stillbirth; A, anencephalus;S, spina bifida; e, encephalocele.

Serial 1 Half Sibs Date of BirthNo. Sibship Paternal Maternal Father Mother

SPINA BIFIDA-MALESOne-child families

3 M 4/656 M* 4/65

22 M* 8/6524 M*e 8/6527 M 8/6528 M 9/6531 M9 9/65;F9165]36 M 10/6546 M* 12/6558 Ms 2/6659 Ms64 Ms 2/66

65 M* 2/6669 M* 3/6672 Me 3/6688 M 6/6695 Ms 8/66101 Ms 9/66102 Ms 9/66108 Ms 9/66112 M* 10/66119 M 12/66

M -/52; M(S) 7/53

M -/42; M -/44

M 12/61

M 1/67; F 8/68

F 10/67; F 12/68

M 2/48; F 12/51M 10/68lF(A) 1/69

F 5/49; F 8/50F 9/51; M 11/56M 11/59; M 6/63F(S) 9/64

-/302/353/289/26-/404/404/4111/40-/36-/428/469/206/456/384/3512/15NK6/40-/399/42-/42-/38

1/419/3611/295/316/488/4012/434/413/3210/417/443/335/44

5/3811/375/239/421/459/4312/4310/441/28

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Appendix I Continued

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Serial Half Sibs Date of BirthNo. Sibship

Paternal Maternal Father Mother

123 M* 12/66 12/43 5/44130 M* 1/67 1/42 11/45136 M* 2/67 2/45 6/45142 M* 3/67 2/45 4/47147 M* 4/67 -/47 4/48157 M* 6/67 3/38 12/44159 M* 7/67 9/39 4/43161 M* 7/67 5/43 5/42164 M* 9/67 6/45 4/46165 M* 9/67 F 12/60 4/40 1/48168 M* 9/67 9/46 2/49170 M* 10/67 11/37 7/39173 M* 11/67 M -/67 8/42 5/50178 M* 1/68 7/48 5/49181 M*e 2/68 M 12/69 2/49 4/50

Two-child families4 M* 4/65; M 8/677 M 6/63;M* 4/659 M* 4/65; F 12/6810 M* 4/65; F 3/6715 M 5/60; M* 6/65

17 F 5/62; M* 6!6523 M 7/62; M* 8/6529 M* 9/65; M 8/6732 M 10/63; M* 9/6533 M* 10/65; M 10/6734 F 2/64; M* 10/6535 M 1/58; M* 10/6538 F 1/59; M* 11/6539 F 4/61; M* 11/65

42 F 12/47; M* 12/6543 M 6/52; M* 12/6544 F 10/63; M* 12/6547 M 1/65; M* 12/6553 F 11/62; M* 1/6654 F 7/61; M* 1/6655 M* 1/66; M 1/6756 F 2/63; M* 1/6657 M* 1/66; M 5/6860 M* 2/66; F 7/6861 M* 2/66; M 10/6766 F 9/62; M* 3/6667 M* 3/66; M 4/7070 M 12/64; M* 3/6673 M* 3/66; F 7/6774 M* 4/66; M 1/7176 F 10/61; M* 4/6680 M* 4/66; M 7/6882 F 11/63; M* 5/6684 F 10/64; M* 5/6686 F 9/63; M* 5/6690 M* 6/66; M 7/6791 M* 6/66; M 12/6792 M* 6/66; F 2/6993 M* 7/66; F 5/6896 M* 8/66; F 11/67106 M* 9/66; F 2/70109 M* 9/66; F 7/68118 M* 12/66; M 2/68120 M 6/65; M* 12/66122 M* 12/66; M(S) 5/68124 M*e 12/66; F 6/68128 M* 1/67; F 5/68131 M 10/62; M* 1/67134 F 12/64; M* 2/67138 M* 3/67; M 6/69145 M* 4/67; F 8/68148 M* 5/67; M 6/69149 M* 5/67; M 11/68151 M* 5/67; F 1/69153 M* 5/67; M 3/69154 M(Se) 8/65; M* 5/67

155 M* 5/67; M 11/68158 M* 7/67; F(S) 8/69162 M* 7/67; F 4/69166 F(S) 4/59; M* 9/67169 M 6/65; M* 10/67172 M* 11/67;M 11/68175 M 3/66; M* 11/67

M -/46; F -/48F -/50

M -/37; M -/43F -/46

M -/67

F -/62; M -/65

M -/53

F 3/59

M 7/50; M 6/53

M 5/64

M -/56; M -/59 M -/58; F -/60F -/61 M-/63

4/425/398/3110/402/27

8/376/353/382/33-/294/416/371/277/12

6/249/2811/388/3811/4112/291/369/297/411/29

10/338/408/434/369/415/42-/383/44-/366/395/355/429/342/4310/442/436/436/4310/441/447/377/321/28

12/268/426/444/434/431/39

12/478/4310/30

10/452/387/453/305/357/456/36

11/421/411/381/469/36

2/413/389/405/393/321/437/378/339/3010/255/305/447/40

10/417/305/405/443/363/366/388!379/445/3712/411/422/438/464/383/395/354/382/304/427/484/4411/465/436/478/468/407/396/345/366/4212/428/445/476/442/4911/457/39

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Serial Half Sibs Date of BirthNo. SibshipNoSishipPaternal Maternal Father Mother1~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~176 F 7/65; M*e 12/67 10/38 7/43177 F 12/66; M* 12/67 12/42 7/45180 M 1/68; M(A) 6/70 5/40 9/48

Three-child families1 M 4/64; M* 4/65; F 8/698 M* 4/65; F 3/67; M 2/6812 M 5/63; M* 5/65; M 8/7013 M 4/62; M* 5/65; M 10/6714 M* 5/65; M 5/67; M 4/6916 M 7/62; M* 6/65; F 9/6818 M* 6/65; M 9/66; M 10/6720 M* 6/65; F(A) 12/66; F 9/6826 F 5/61; F 8/62; M* 8/6530 M* 9/65; F 12/68; M 2/7037 F 9/60; M 8/64; M* 11/6540 M*e 11/65; M 3/67; M 11/6949 F 4/59; M 1/61; M* 12/6551 M 4/54 sb; M* 1/66; M 2/6752 M* 1/66; F 6/68; M 10/7162 F 12/60; F 3/64; M* 2/6663 M 1/55; F 3/61; M* 2/6671 F 11/63; F 5/65; M* 3/6675 M 7/63; F 9/64; M* 4/6683 M* 5/66; F 7/67; F 3/6987 M* 6/66; M 7/67; M 5/6989 M 2/60; M 9/62; M* 6/6694 M* 7/66; M 12/67; F 5/7098 F 5/62; M 11/63; M* 8!6699 F 10/64; M* 8/66; M 6/68100 M* 8/66; F 1/69; M 3/71107 M* 9/66; F 10/67; M 1/69110 F 8/58; F(S) 2/65; M* 10/66111 M 8/63; F 12/64; M* 10/66113 M 11/65 sb; M* 11/66; M 6/68115 M 3/64; F 4/65 sb; M* 11/66116 M 2/63; M 2/64; M* 11/66121 M* 12/66; F 1/68; F 4/70125 M 1/67; M 1/68; F 5/69127 F 11/63; M* 1/67; M 5/68132 F 6/65; M*e 1/67; M 3/68133 M 4/64; M* 2/67; F 3/68135 M* 2/67; M 2/68; F 9/70139 M 1/60; M* 3/67; F 3/69140 M 10/60; M 10/61; M* 3/67141 M 7/62; M 9/64; M* 3/67

143 M*e 3/67; F 5/68; F 5/69146 F 10/64; M* 4/67; M 9/68150 M* 5/67; F 8/68; M 7/70152 M 5/62; F 10/63; M* 5/67163 M 11/63; M 6/66; M* 8/67167 M 9/66 sb; M 9/67; F(Se) 6/70

179 M 1/64; F 2/67; M* 1/68182 F(S) 7/65 No. 204; M 2/68; F 1/71183 M* 3/68; M(A) 11/69; M 9/71

M -168

M -/62; M -/64M -/65

M -/65

F 7/63

M 12/46; F 12/50; F 10/52;M 3/56; M 2/58

Four-child families5 M 10/61; M* 4/65; F 9/67; M 7/68 10/37 1/4211 F 8/62; M* 4/65; M 4/67; F 11/68 12/39 10/4419 M* 6/65; M 8/66; M 11/67; M 7/69 2/39 8/4021 F 2/63; M* 7/65; M 8/66; F 6/68 3/40 2/4341 F 2/58; M 8/61; M*e 11/65; M 10/67 9/34 11/3545 F 9/64; M* 12/65; F 12/66; F 11/68 4/37 4/3750 M 3/54; M 10/59; F 5/61; M* 1/66 10/28 8/3181 M 9/62; M 11/63; M* 5/66; M 10/67 M -/52; F NTK; F NK 1/31 6/4385 M 8/63; M 7/64; M* 5/66; M 8/68 3/38 11/4197 F 11/59; F 10/61; M 2/64; M* 8/66 2/31 9/40105 M 12/60; M 3/63; M 5/64; M* 9/66 9/39 1/40126 F 12/57; M 9/60; M*e 1/67; F 8/68 8/32 7/39129 F 1/57; F 1/61; M 1/64; M* 1/67 3/21 11/28137 F 2/62; M 11/65; M* 2/67; M 8/69 -/35 7/38156 M* 6/67; M 7/68; F 8/69; F 1/71 7/46 3/49184 M 5/64; M 3/67; M 3/68; M 4/69 3/43 10/46

Five-childfamilies2 M 2/61; M 3163; M* 4/65; F(A) 7/66 No. 619; M 5/68

25 M 3/55; M 11/59;M 9/61; M* 8/65; F 6/7068 F 12/57; F 12/62; M 6/64; M* 3/66; M 6/68

1/38 7/429/30 2/3310/08 8/31

222

1/386/414/245/303/399/3411/375/447/33-/426/352/407/406/3111/392/383/238/419/385/426/373/384/433/429/447/4112/4311/326/385/392/394/3212/337/474/359/39-/455/435/29-/274/30

2/4210/294/3912/321/434/38

12/4010/387/44

6/358/408/335/319/389/3610/394/4711/3210/422/365/425/375/323/441/41

11/273/418/324/415/331/424/454/385/443/444/466/323/376/428/458/384/457/473/379/419/4612/415/383/296/30

5/444/374/479/348/299/47

5/381/477/48

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Spina Bifida and Anencephalus in Greater London 223


Serial Half Sibs Date of BirthNo. |Sibship


77 M 4/56; M 6/57; [M 9/58; F 9/58]; M* 4/66 M 11/46; M 9/53 4/23 12/2478 I F 2/50; M 9/51; M 1/55; F 7/60; M* 4/66 I M 9/44; M 12/45; M 8/48 3/17 2/23144 F 8/60; M 11/61; M* 4/67; F 8/68; M 1/70 2/29 5/32160 M 4/61; M 2/63; F 5/64; M* 7/67; M 8/69 2/41 10/43171 F 4/61; F 6/63; M 7/64; M* 11/67;M 6/70 12/35 1/32174 M 3/51; M 7/55; F 8/59; M 2/65; M* 11/67 NK 6/29

Six-child families48 F 6/48; M 12/52; F 3/54; F 3/58; M 1/60; 9/28 9/26

M* 12/6579 F 2/56; M 6/57; M 7/58; F 11/59; M* 4/66; 10/33 1/35

F 9/68103 M 8/47; F 7/51; F 12/53; M 12/55; M 7/58; 4/16 8/24

M* 9/66104 M 12/61; M 5/63; F 9/64; M* 9/66; F -/54 10/36 5/44

[M 10/68; M 10/68]114 M 10/53; M 9/55 sb; F 12/56; M 8/64; 5/31 3/34

M* 11/66; M 3/69

Seven-child families117 M 6/54; M 7/59; M 11/60; M 10/61; -/16 -/30

F 3/63; M 3/65; M* 11/66

SPINA BIFIDA-FEMALESOne-child families

185 F* 4/65 6/42 3/45195 F* 5/65 F 4/70 -/37 5/38203 F* 7/65 M -/45; F -/49; F -/53 7/23 4/44206 F*e 7/65 M 9/66; F 10/67 -/39 11/46229 F* 11/65 -/27 6/38238 F* 12/65 M 11/51 10/18 2/28242 F* 12/65 3/35 8/44255 F* 2/66 10/39 4/39265 F* 3/66 8/31 4/34268 F* 4/66 9/30 2/41274 F* 5/66 F 8/46; M -/51 9/09 7/25275 F*e 5/66 5/46 4/47277 F* 5/66 6/32 8/33281 F* 5/66 12/43 7/45284 F* 6/66 4/46 4/48292 F* 7/66 F 1/63 12/39 4/45297 F* 9/66 M 12/68 10/40 3/44298 F*e 9/66 10/33 8/33306 F* 11/66 4/42 5/42310 F* 12/66 9/38 4/37315 F* 12/66 -/45 9/46316 F* 1/67 F NK; F NK; M NK; M NK F 9/51; M 6/53; F 10/55; -/34 8/31

M 8/63343 F* 4/67 NK 1/48346 F* 5/67 12/37 8/44348 F*e 5/67 3/38 5/44349 F* 6/67 M NK -/46 11/46351 F* 6/67 10/45 6/46357 F* 7/67 9/24 2/29358 F* 8/67 8/40 -/41363 F* 10/67 -/44 11/46373 F* 12/67 7/40 6/43376 F*e 12/67 2/37 12/41378 F*e 12/67 6/29 8/44383 F* 1/68 M 11/68; M 10/69 -/29 2/43391 F* 2/68 NK 1/50

~~~~22

Two-child families190 F* 5/65; F 6/67194 M 9/62; F* 5/65199 F 11/59; F* 6/65200 F* 6/65; M 1/67201 F* 6/65; F 3/69205 F* 7/65; M 2/67207 F* 7/65; M 4/67208 F 12/63; F*e 8/65212 F* 8/65; M 2/68216 F 3/63; F*e 9/65219 F* 9/65; M 2/67 F -/51 sb; [M -/53; M -/53]221 F* 10/65; F(A) 10/66 No. 631223 F* 11/65; F 5/68224 F* 11/65; F 6/67

6/40 6/421/30 3/33

10/36 11/3811/42 12/442/37 9/382/36 7/415/38 5/43-/36 6/406/38 3/3912/36 8/407/25 1/374/35 2/4012(32 9/448/43 6/44

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Carter and Evans



Paternal Maternal Father |Mother

F 2/64; F*e 12/65F 4/63; F* 12/65F* 12/65; F 12/68M 3/59; F* 1/66F 7/64; F* 2/66M 3/63; F* 2/66F* 2/66; F 10/67F 7/64; F* 2/66M 2/64; F* 2/66M 11/63; F* 3/66F 3/58; F*e 3/66F* 4/66; F 12/69F* 4/66; F 3/69F* 5/66; M 8/67F* 5/66; F 3/68F* 5/66; F 4/67F 8/64; F* 6/66F* 9/66; M 9/67F* 9/66; M 6/71F*e 10/66; F 5/69F 9/63; F* 10/66F 7/64; F* 11/66F* 12/66; M 9/68F* 12/66; F 10/68M 4/61; F* 12/66F* 1/67; M 2/70F*e 1/67; F 12/67F* 1/67; F 3/68M 1/64; F*e 2/67F* 2/67; F 3/70F* 2/67; M 3/69F* 2/67; F 3/69M 1/60; [F* 2/67; F 2/67]M 5/61; F* 3/67F* 3/67; M 10/68F* 3/67; M 9/69F*e 4/67; M 4/69F* 4/67; F 5/68M 2/65; F* 4/67F 10/63; F* 4/67F* 4/67; F 7/68M 1/65; F* 6/67F 1/66; F* 9/67[F* 9/67; M 9/67]; F 5/70F* 9/67; M 12/68F*e 11/67; M 12/68F 10/64; F* 11/67F* 11/67; F 2/69F* 12/67; F 12/69F* 12/67; F 12/70M 9/66; F* 12/67F* 1/68; M 11/68F* 1/68; F 12/68F(S) 9/61; F* 1/68F*e 1/68; F 9/69F* 2/68; F 5/69

IF 3/52 sb; M 8/57; F 11/58

M 4/65

11/295/174/414/3611/391/221/385/389/3511/322/318/274/4612/268/413/382/376/461/369/438/393/477/418/41

10/314/35

12/415/45-/364/432/32

12/46-/311/353/4012/375/454/4512/368/429/463/327/371/459/465/43

10/334/371/40

12/4510/254/419/409/3610/392/41

11/436/334/437/391/37

10/324/416/403/385/446/364/287/451/35

11/451/457/374/485/409/464/408/475/421/418/2710/403/4310/4711/3811/429/416/4811/338/415/396/3912/465/46

10/411/473/493/318/325/499/486/464/393/422/465/47-/286/4612/457/409/446/46

Three-child families186 F 7/49; M 9/55; F* 4/65187 M 6/63; F* 4/65; F(S) 5/66 No. 278188 F* 5/65; F 3/66; F 4/68191 M 5/62; F* 5/65; M 12/67198 F*e 6/65; F 8/66; M 10/67202 F* 7/65; F(A) 11/66 No. 640; F 11/68204 F* 7/65; M(S) 2/68 No. 182; F 1/71210 M 10/60; M 10/62; F* 8/65211 M 5/61; F 2/63; F* 8/65213 F* 8/65; F 1/67; M 7/69215 M 4/64; F* 8/65; M 7/67222 M 11/63; F* 10/65; F 8/70225 F 10/62; F 12/64; F* 11/65228 F* 11/65; M 3/67; M 4/70231 F* 11/65; M 6/67; M 8/69234 F 6/62; M 11/64; F* 12/65240 F 7/48; F 5/53; F* 12/65241 F* 12/65; M(A) 12/67; F(A) 4/69244 F 1/63; F* 1/66; F 7/68246 F 4/65; F* 1/66; M 1/68253 F 9/64; F* 2/66; M 3/68257 F* 2/66; M 10/67; M 3/69260 F*e 3/66; M 6/67; F 7/68261 F 11/63; F*e 3/66; F 8/67263 F 10/63; F* 3/66; F 5/67

224

232236237247249250251252258259262267269273279282283299300303304305307308314317318319321322323326327330334335337338340341342353359360361366369370371374375380381382388389

M -/65

M 7/69

7/2512/404/3812/354/453/40

10/387/291/40

11/4210/3112/431/433/431/3311/374/259/351/397/384/4712/465/40

10/397/37

1/254/4410/381/414/462/391/472/322/373!4711/255/466/442/419/3911/366/268/394/433/405/441/474/391/424/41

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Serial Half Sibs Date of BirthNo. Sibahip ~~~~~~~~ ~~~~PatemnalMaternal Father TMother

264 M 10/59; F 10/62; F* 3/66 7/33 7/36266 F* 4/66; M 7/67; F 3/69 6/35 9/35270 F 9/60; F* 4/66; F 7/67 6/40 1/44272 F*e 5/66; M 5/67; F 3/69 1/44 6/45276 M 1/60; F 1/62; Fle 5/66 7/37 9/38278 M 6/63; F(S) 4/65 No. 187; F* 5/66 12/40 4/44280 F 5/64; F* 5/66; M 5/67 -/37 2/35285 M 6/61; M 5/63; F* 6/66 1 I953287 M 11/58; M 7/60; F* 7/66 -/18 8/35288 F 5/65; F* 7/66; F 12/68 4/43 7/42290 M 9/64; F* 7/66; F 8/68 7/35 12/33291 M 9/59; M 9/62; F* 7/66 11/32 5/34293 F 1/64; F* 8/66; M 2/68 7/40 2/40301 F* 10/66; F 7/68; F 8/69 F 1/63; M 2/64 3/43 11/41302 F 2/60; M 9/61; F*e 10/66 1/37 2/39309 F*e 12/66; M 3/68; M 6/70 2/44 3/48311 F* 12/66; M 12/67; F 1/70 11/42 2/46320 F 10/65; F* 1/67; M 3/69 1/44 1/45324 F* 2/67; M 5/68; M 7/70 2/43 3/44325 M 12/65; F* 2/67; F 7/69 6/44 1/45328 F 5/65; F* 2/67; F 7/70 4/32 7/42329 F 10/64; F* 3/67; F 9/68 11/42 1/43331 M 12/59; F 5/61; F*e 3/67 9/32 2/35332 M 3/66; F* 3/67; F 6/69 8/42 6/44333 F 12/62; F* 3/67; F 9/69 9/33 10/32339 F 12/63; F* 4/67; M 11/68 5/32 7/35344 F*e 5/67; M 4/68; M 12/69 6/25 5/42352 F 12/63; F*e 6/67; F 7/68 7/39 11/40355 F 2/59; M 5/63; F* 6/67 1/32 6/38362 M 10/59; F 3/62; F* 9/67 2/29 9/38367 M -/66; F*e 11/67; M 6/69 -/46 -/48377 M 8/64; M 2/66; F* 12/67 3/37 1/42384 F 3/66; F* 1/68; F 12/69 2/37 1/41387 M 1/66; F* 1/68; F 6/69 9/43 9/42390 M 8/65; F* 2/68; M 7/69 8/30 6/36392 M 9/62; M 6/65; F* 3/68 -/35 1/36393 F 6/64; M 8/66; F*e 3/68 5/45 10/45

Four-child families193 M -/49; M 7/59; F*e 5/65; F 9/69 12/22 10/31196 F* 6/65; M 7/66; F 12/67; M 12/69 10/44 12/46197 M 7/62; F 7/63; F* 6/65; M 10/66 M 3/68 6/40 12/41209 F 11/54; F 8/57; M 3/59; F*e 8/65 4/29 9/32214 F 2/58; M 2/59; M 4/61; F* 8/65 5/37 10/37217 M 2/64; F* 9/65; M 12/66; F 4/68 11/42 3/44218 FS5/61; M8/62; F* 9/65;F 11/66 3/24 7/26220 F 9/54; F 11/55; M 5/60; F* 10/65 11/29 7/32226 F 5/59; F 6/63; M 12/64; F* 11/65 1/27 11/37227 F 11/63; M 12/64; F*e 11/65; F 12/66 5/24 2/26230 F 4/53; F 7/55; F 1/58; F* 11/65 11/23 7/30235 F 11/57; F 3/60; M 3/62; F* 12/65 12/33 11/34245 M 12/54; M 9/59; M 2/63; F* 1/66 4/31 2/33248 F* 1/66; F 2/67; M 1/68; M 6/69 4/45 2/44254 M 7/51; F 5/53; M 1/61; F* 2/66 1/27 12/25256 F 2/56; F 8/62; F* 2/66; M 7/67 7/28 11/34271 M 12/62; F* 4/66; F 5/67; F 9/68 10/38 -/43294 M 6/46; M 4/48; M(A) 6/52; F* 6/66 4/21 2/24296 F 1/60; F 5/61; M 4/63; F* 9/66 -/38 3/42313 F 10/56; F 8/64; F* 12/66; F 5/68 9/31 3/31336 F 7/54; M 3/57; M 6/58; F* 3/67 6/30 8/32347 M 5/61; M 1/65; F* 5/67; M 12/70 4/34 7/30356 M 5/59; F 3/61; M 9/65; F* 7/67 4/36 1/38368 M 10/66; F* 11/67; M 8/69; M 6/71 6/46 7/45386 F 5/61; F 3/63; F 12/63; F* 1/68 2/40 1/43

Five-child families192 F* 5/65; F 8/66; M 7/67; F 7/68; F 6/70 2/44 10/45233 F 9/59; M 12/60; F 10/62; M 2/64; F* 12/65 1/40 3/38239 M 6/59; M 7/60; F 7/62; M 6/63; F* 12/65 -/34 8/27243 [M 12/55; M 12/55]; M 2/57; F* 1/66; 6/28 11/35

F 10/69286 F 10/59; M 4/61; M 6/62; F 9/63; F* 6/66 11/28 6/29295 M 10/63; M 9/64; F* 8/66; F 8/67; M 12/68 9/33 8/38312 F 4/58; M 8/59; F 9/62; M 11/64; F* 12/66 4/34 11/34345 M 1/60; M 4/62; M 4/64; F 5/65; F* 5/67 4/36 9/41350 M 7/62; F 9/64; M 12/65; F* 6/67; F 9/69 F 9/58 -/39 11/41379 F 10/50; F 1/53; M 5/54; M 3/64; F*e 12/67 7/29 9/24394 -F -/50; M -/52; F -/54; F 12/64; F* 3/68 -/30 -/30

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226 Carter and Evans


Serial Half Sibs Date of BirthNo. SibshipSix-child families Paternal Maternal Father Mother

Six-child families189 M -/49 sb; M 3/62; F -/56; F(S) 3/62; 12/32 8/32

F 4/63; F* 5/65354 F 10/57; F 12/58 sb; M 3/60; M 12/61 sb; M 12/54 sb; M 1/56 3/34 10/35

M 1/64; F* 6/67365 M 9/54; F 7/56; M 11/58; F 10!63; M 9/66; 10/33 7/32

F 10/67385 F 12/54; M 9/57; F 10/59; F 6/62; 2/28 2/27

M 9/64 sb; F* 1/68

Nine-child families364 M 5/57; F 12/58; F 6/61; M 11/62; F 7/64; 7/35 10/35

F(A) 6/66; F* 10/67; F 11/68; F 11/69

Ten-child families289 F 3/53; M 4/54; F 10/55; M 12/57; M 3/59; 6/27 3/30

F 11/60; M 1/62; M(A) 1/63; M 6/64;F*e 7/66

Eleven-child families372 F -/41; F -/43; M 10/45; M 9/48; F 10/51; 3/20 3/23

F -/53; M 10/54; F 5/55; M 10/56;M -/58 sb; F* 12/67

ANENCEPHALUS-MALESOne-child families

402 M* 7/65 M -/40 2/30 4/17408 M* 8/65 F 2/71 -/45 9/46415 M* 11/65 NK 9/39454 M* 1/67 12/40 10/42455 M* 1/67 M -/49; M -/59 -/22 9/23471 M* 6/67 7/48 1/47476 M* 8/67 F -/50; M -/52 3/20 1/46

Two-child families398 M* 5/65; M 9/66 8/39 5/40406 M(A) 8/64; M* 7/65 5/26 1/41409 M* 8/65; M 6/66 7/34 11/38410 M* 8/65; F 9/66 7/43 7/45412 M* 11/65; M 4/67 M -/60; M -/64 -/21 5/42413 M 10/64 sb; M* 11/65 M -/46; M -/49; M -155 F -/52; F -/54 11/19 5/30420 M* 12/65; F 2/67 9/36 12/38422 M* 1/66; M 5/67 5/37 4/42423 F -/63; M* 1/66 -/31 -/44431 F -/63 sb; M* 7/66 8/09 5/37443 M 7/65; M* 11/66 8/26 5/45444 M* 11/66; F 5/68 10/38 4/40448 F 1/62; M* 12/66 9/34 4/36452 M* 1/67; F 12/68 4/41 1/44462 M* 4/67; F 3/68 11/35 9/37465 M* 4/67; M 3/68 1/48 8/50467 M* 5/67; F 8/68 8/42 1/48468 M* 5/67; F 6/68 12/42 3/44474 F 11/65; M* 7/67 6/36 6/34478 M 7/65;M* 8/67 7/36 1/44481 M 8/67; M 11/68 5/27 7/37482 F 1/65 sb; M* 9/67 6/28 3/37484 M 4/64; M* 9/67 3/39 5/39488 M* 12/67; M 1/69 8/44 9/47492 M* 2/68; F 2/71 4/40 3/39494 M* 2/68; F 11/69 7/45 9/48

Three-child families396 Me 4/65; F 5/66; M 2/68399 M 5/65; F 8/67; M 12/69400 M 3/64 sb; M* 5/65; F 3/68401 M 5/65; M 4/66; F 5167403 M* 7/65; M 3/67; F 5/69407 F -/64; M 8/65; M -/66411 M* 10/65; M 1/67; M 6/71414 M* 11/65; M 12/66; M 12/68419 M 11/63; M* 12/65; M 8/67

3/34 1/3810/38 1/43-/40 6/3911/35 9/463/42 8/45-/39 11/425/33 1/36-/39 3/4412/33 9/35

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424 M* 1/66; F 5/68; F 2/70 7/39 2/44427 F 7/64; M* 4/66; M 2/68 6/38 1/41428 F(A) 5/65 No. 503; M* 5/66; M 3/70 3/26 3/35429 F 10/64; M* 6/66; M 9/69 2/41 2/44432 M* 7/66; M 6/67; M 1/69 -/39 7/42433 M 7/65; M* 8/66; M 4/69 7/42 8/46434 F 3/64; M* 8/66; F 7/67 8/41 10/40435 M 2/65; M* 8/66; F 10/68 3/39 5/40436 M* 8/66; F 12/67; M 4/70 8/42 4/45437 M* 9/66; [M 8/67; M 8/67] 8/46 4/45438 F 7/64; M* 9/66; M 10/69 10/40 7/42442 M* 10/66; F 9/67; M 12/68 8/39 10/42447 F 9/63; M* 12/66; M 3/69 9/36 4/38449 M 2/64; F 3/65; M* 12/66 3/39 3/42450 M* 12/66; F(A) 9/67 No. 721; F 10/69 7/47 3/49457 M 7/65; M* 1/67; M 9/68 4/40 6/39458 F 5/58; F 7/63; M* 1/67 M 2/53 4/31 7/33459 F 8/49; F 11/54; M* 2/67 5/24 5/26460 M 1/62; M 10/64; M* 2/67 2/41 10/42461 F 9/64; M* 3/67; M 3/69 NK 9/39463 M 4/64 sb; F 8/65; M* 4/67 10/32 3/36466 M 11/62; M* 4/67; F 12/68 11/35 7/38469 F 1/66; M* 5/67; F 11/68 10/39 5/45470 F(S) 11/64; M 3/66; M* 6/67 6/45 11/45472 M* 7/67; F 10/68; M 2/70 10/31 7/41473 M* 7/67; F 10/68; M 8/70 -/44 8/42477 M 8/66; M* 8/67; F 9/68 7/43 4/43479 M* 8/67; M 1/69; F 7/71 9/46 10/44480 F 4/66; M* 8/67; F 10/69 4/45 9/48483 M 10/65; M* 9/67; M 11/68 6/41 12/42487 M 11/59; M 2/61; M* 11/67 11/32 2/36489 F 10/66; M* 1/68; M 7/70 1/43 10/39490 M 10/64; F 9/66 sb; M* 1/68 1/32 9/33493 M 8/65; M* 2/68; F 6/69 F(S) 7/53 10/39 12/40496 M 4/65; M* 2/68; M 4/69 5/28 4/31

Four-child families397 F 8/61; M 12/63; M* 4/65; F 10/67 5/28 4/31416 M -/61 sb; M 2/64; M* 11/65; M 9/67 9/37 8/41417 M* 12/65; F 2/67; [F 11/68; F 11/68] 11/36 10/43418 F(S) 5/58; M* 12/65; F 12/66; F 11/69 9/33 5/35421 F 5/55; F 11/56; F 12/63; M* 1/66 8/26 3/27426 M 2/62; M 1/64; M* 3/66; M 2/68 2/38 3/39430 M* 6/66; M 5/67; F 10/68; M 9/70 8/44 4/45439 M* 9/66; M 8/67; M 2/70 sb; F 1/71 5/39 1/43440 M* 10/66; F 10/67; M 10/69; F 8/71 5/42 2/47441 F 10/63; M 8/65; M* 10/66; M 1/67 1/42 9/41446 F -/65; M* 12/66; F(A) 3/68 No. 770; -/42 4/43

M 7/69451 F 12/55; F 3/58; F 2/60; M* 12/66 -/25 7/30456 M 8/63; M* 1/67; M 1/69 sb; M 11/70 -/36 8/38486 M 5/55; M 3/57; M 9/58; M* 10/67 3/30 8/30495 F 1/56; F 6/57; M 1/60; M* 2/68 5/31 6/35497 M 12/66; M* 3/68; F 5/69; M 8/70 9/39 4/46

Five-child families404 F 8/55; F 12/57; M 9/59; M 8/61; M* 7/65 8/29 4/39405 M 5/59; M 8/60; M 3/64; M* 7/65; M 9/66 6/27 5/36453 F 12/58; M 12/59; F 1/61; M* 1/67; F 1/68 8/33 12/40475 M -/58; F -/59; M 2/60; M* 8/67; M 9/69 -/36 -/40491 M 1/54; M 12/60; M 1/65; F 6/66; 11/28 7/32

[M* 1/68; F(A) 1/68 No. 7551

Six-child families395 M 7/55; F 4517; M 8/59; F 12/61; M 12/63; 1/31 7/33

M* 4/65425 M 1/57; M 8/58; M 11/59; M 2/64; F 2/65; 5/30 7/33

M* 2/66445 F 9/61; M 5/63; M 1/65; M* 11/66; 2/36 3/42

M 12/68; F 3/70464 F -/61; M -/62; F 3/63; M 4/64; F 11/66; 8/32 6/41

M 4/67

Thirteen-child families455 M 3/49; M 9/50; F 12/51; F 1/53; M 2/54; 5/25 8/30

F 8/55; M 2/57; M 3/58; F 3/60; M 4/61;M 8/62; M* 10/67; F 1/69

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ANENCEPHALUS-FEMALESOne-child families499 tF 4/65; F 4/65] F 11/68; M 5/70 NK 11/43501 F* 5/65 7/32 3/34504 F* 5/65 5/30 6/33512 F* 6/65 M-/46 M 11/47; F 11/57 5/20 5/26528 F* 8/65 M -/50; F -/56 9/23 6/33532 F* 8/65 9/40 1/41536 F* 9/65 NK 5/41539 F* 10/65 5/43 2/45546 F* 11/65 12/36 5/43563 F* 1/66 6/14 7/25565 F* 1/66 F 3/60; M 4/63; M 3/67 -/44 9/39576 [F 3/66; F* 3/66] F -/47; F -/49; F -/52; F 9/54; F 6/64 12/36 7/34

M-/54; F-/58577 F* 3/66 F 2/67 NK 12/46591 F* 4/66 12/48 12/48593 F* 4/66 10/21 8/41599 F* 5/66 9/39 8/43605 [F* 6/66; F 6/66] 7/45 8/46612 F* 6/66 2/44 9/44647 F* 12/66 M -/60; M -/62 8/38 10/44648 F* 12/66 F -/56; F -/57; M -/59 F 2/65 2/36 6/44655 F* 1/67 3/46 8/47659 F* 1/67 11/32 3/34663 F* 2/67 5/38 1/36669 F* 3/67 -/47 11/49671 F* 3/67 7/43 5/45685 F* 4/67 6/46 5/47686 F* 5/67 NK 4/50687 F* 5/67 12/46 7/47688 F* 5/67 9/30 11/27690 F* 5/67 10/21 12/44700 F* 7/67 F 2/71 -/45 10/46703 F* 7/67 3/40 3/44710 F* 8/67 1/43 5/44714 F* 9/67 4/30 7/32720 F* 9/67 3/32 2/33723 [F* 10/67; M 10/67] F -/39; F -/50; F -/52 7/20 6/37738 F* 11/67 7/49 1/49743 F* 12/67 4/43 7/42764 F* 3/68 10/37 1/42766 F* 3/68 -/32 1/34

Two-child families

498 F* 4/65; F 6/66506 F* 5/65; F 6/67513 F* 6/65; F 5/66526 F 3/62; F* 8/65541 F* 10/65; M(S) 6/69544 F* 10/65; M 12/66548 M 11/64; F* 11/65552 F* 12/65; M 4/68559 F* 1/66; M 2/68561 M 10/63; F* 1/66562 F 7/63; F* 1/66569 F* 2/66; F 9/67573 F* 2/66; M 10/67574 F* 3/66; F 5/68584 F* 3/66; F 10/67587 F* 3/66; F 6/68594 F* 4/66; F 6/67596 F* 4/66; M 1/68600 F* 5/66; M 10/67601 F 3/64; F* 5/66610 F* 6/66; M 6/67613 F* 6/66;M 5/70615 F* 7/66; M 3/69616 F 1/58; F* 7/66618 F* 7/66; F 2/69624 F* 8/66; M 10/67628 F* 9/66; M 4/69630 F* 9/66; F 2/68631 F(S) 10/65 No. 221; F* 10/66634 F* 10/66; F 5/68635 F 2/64; F* 10/66637 F* 11/66; F 7/69638 M-/63; F* 11/66642 F* 11/66; F 12/67649 F* 12/66; F 8/68

F -/58

F 9/52

M 2/57; F 6/58; M 11/60

M -/61

F 8/56

2/406/372/164/263/37NK2/355/4211/35NK3/323/2811/381/331/44

11/4312/3512/438/404/373/3611/395/315/359/4310/3812/4311/374/3510/489/271/403/439/30-/35

2/431/382/465/312/436/273/4012/4612/413/3511/383/3612/393/333/456/4512/343/42

10/351/443/454/427/298/373/477/385/461/472/4011/4712/323/2912/429/371/37

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Serial Half Sibs Date of BirthNo. Sibship Paternal Maternal Father Mother

650 F* 12/66; M 1/68 6/37 5/42651 F* 1/67; F 9/63 12/37 9/34654 M -/50; F* 1/67 5/13 11/20668 M 1/66; F* 3/67 F 7/71 7/42 5/44670 [F 3/67; F* 3/67]; F 9/69 9/41 10/42672 F* 3/67; M 2/68 10/43 2/49676 F 9/59; F* 4/67 11/35 10/36689 F* 5/67; F 4/69 10/43 4/46691 F* 5/67; F 8/68 4/47 2/48692 M 1/65; F* 5/67 2/40 6/45693 F* 5/67; M 2/69 -/23 3/49696 F* 6/67; F(A) 6/68 12/36 8/38699 F* 6/67; F 10/69 5/45 12/46709 F* 8/67; M 11/68 9/41 9/44723 M 6/64; F* 9/67 -/27 11/38728 F* 10/67; F 10/68 7/44 6/44730 F* 10/67; M 10/68 9/45 10/48732 F* 10/67; M 4/69 12/36 2/31734 F 5/65; F* 11/67 6/44 7/46736 F 12/62; F* 11/67 7/37 3/41737 F* 11/67; M 11/69 4/45 8/44740 M-/64; F* 11/67 M-156; F-/57 3/31 1/43744 F* 12/67; F 2/69 9/44 6/47749 M 9/65; F* 12/67 9/41 8/47750 F* 12/67; M 11/70 9/47 2/48752 F* 1/68; F 2/69 12/46 7/49758 M 9/65; F* 2/68 -/28 7/36760 M 12/50; F* 2/68 8/18 9/24767 F* 3/68; F(A) 2/69 6/45 8/49

Three-child families502 M 7/63; F* 5/65; F 4/66503 F* 5/65; M(A) 5/66 No. 428; M 3/70505 M 5/60; F 7/61; F* 5/65508 F* 5/65; F 12/67; M(A) 11/69510 M 3/63; F* 6/65; M 4/67515 F* 7/65; F 4/67; F 1/70518 F' 7/65; M 1/67; M 5/68520 M 3/62; F* 7/65; M 3/67524 F 9/64; F* 8/65; M 7/66529 M 9/63; F* 8/65; F(A) 3/67 No. 667530 F* 8/65; M 11/66; M 9/70531 F* 8/65; F 3/67; F 12/68533 F 2/59; M 2/63; F* 8/65537 [F 1/61; M 1/611; F' 9/65540 F* 10/65; M 9/66; M 12/69542 M 9/61; F* 10/65; F 7/67543 F* 10/65; F 11/66; M 9/68545 F* 10/65; M 2/67; M 1/68549 F 1/55; F 12/56; F* 11/65550 F* 12/65; F 10/66; F 5/68553 F* 12/65; F 6/67; F 7/69554 F 11/58; F* 12/65; F 1/67556 F* 12/65; F 12/68; F 12/69557 F* 12/65; F 6/67; M 3/70564 M 5/61; M 12/63; F* 1/66566 F* 2/66; F 9/67; M 1/69567 M 7/51; M 2/53; F* 2/66568 F 11/61; F* 2/66; M 8/67570 M 11/51; M 7/56; F* 2/66572 M 6/64; P* 2/66; M 2/67575 F 7/64; F* 3/66; M 1/70579 M 4/61; F 3/63; F* 3/66

580585586589592595597602603604606607608609614621622

F' 3/66; M 2/67; M 1/69F* 3/66; F 5/67; M 5/68F* 3/66; M 6/67; F 5/69F 2/62; F* 4/66; M 7/67F* 4/66; M 3/67; M 6/69F 1/60; M 9/63; F* 4/66F 4/60; M 3/63; F* 6/66F* 6/66; M 7/67; M 1/70F* 6/66; F 5/67; M 8/69F 10/61; F 5/64; F* 6/66F* 6/66; F6/67; M 2/70F* 6/66; M 7/67; M 6/69F 8/65; F* 6/66; M 11/68F* 6/66; F 5/68; M 5/69F 1/65; F* 6/66; M 5/68M 6/62; M 3/65; F* 7/66F* 7/66; M 4/67; M 2/70

M -/32; F -/33; M -/56;M NK; F-/61;M NK;F NK; M NK; F -/63;M NK

F -164

F 2/48; F 5/53; M 8/57

5/423/268/393/347/191/476/366/40-/382/385/428/4012/251/369/424/398/456/373/2912/438/452/273/426/3212/2711/447/215/232/201/376/4012/13

6/453/356/421/431/29

10/473/413/4211/4410/387/426/429/295/379/4211/379/455/3810/312/476/4710/293/4412/432/3010/4410/2411/384/276/436/363/35

8/46 1/4712/42 10/4312/43 12/4710/34 7/388/42 9/453/18 5/304/29 4/392/37 12/408/45 5/441/33 10/27

10/42 4/426/42 3/445/38 7/41

11/31 8/32-/39 1/405/39 4/378/37 3/41

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Carter and Evans


Serial Half Sibs IPete of Pirth

Paternal Maternal Father Mother_- 1-~~~~~~~~~~~~~------Ii _

M 7/62; F* 7/66; M 10/67M 2/55; F 7/64; F* 8/66F 12/63; F 7/65; F* 9/66F 10/64; F* 10/66; F 1/70[M -/54; F -/54]; F* 10/66M 12/53; M 8/57; F* 11/66F(S) 7/65 No. 202; F* 11/66; F 11/68M(A) -/58; M 10/60; F* 11/66M(S) 1/62; M 3/63; F* 12/66F* 12/66; M 8/68; M 10!70F* 12/66; M 3/63; M 5/70F 7/64; F 12/65; F* 1/67M 12/64; F* 1/67; M 11/68F 9/61; F* 1/67; F 1/70F 11/63 sb; M 6/65; F* 1/67F* 3/67; F 5/68; M 8/69M 9/63; F(A) 8/65; No. 529 F* 3/67M 3/66; F* 4/67; M 8/70F 7/65; F* 4/67; M 3/68M 12/60; F 1/65; F* 4/67F 1/66; F* 4/67; F 11/68M 3/64; F* 4/67; M 5/68F* 4/67; F(A) 5/68; F(A) 12/70F 3/61; M 3/62; F* 4/67F 7/63; F 12/65; F* 4/67F 12/61; M 3/64; F* 4/67F* 6/67; F 5/69; F 10/71F* 6/67; F 9/68; F 8/70F 11/63; M 2/66; F* 6/67[M 7/67; F* 7/67]; F 9/68; M 2/70F* 8/67; F 11/68; F 5/71M 8/59; M 9/61; F* 9/67M 5/65; F* 9/67; M 5/70F* 9/67; M 8/68; F 10/69M 5/65; F* 9/67; F 11/68F 1/64; F 2/65; F* 9/67M(A) 12/66 No. 450; F* 9/67; F 10/69F* 9/67; [M 10/68; M 10/68]F* 9/67; F 11/68; M 6/71F 4/65; F* 9/67; M(S) 11/68F* 10/67; M 9/68; F 4/70F* 10/67; F 12/68; M 2/71M 2/62; F* 11/67; M 6/69F* 11/67; M 3/69; F 1/72M 8/62; F 1/64; F* 12/67[M 3/65; M 3/65]; F* 12/67F 9/61; M 5/65; F* 12/67M 3/65; F* 1/68; M 2/69M 7/64; F* 1/68; M 2/70F 5/66; F* 2/68; M(S) 3/69F* 2/68; F 2/69; F 8/70F 10/64; F* 2/68; F 12/70M 2/63; F 2/64; F* 3/68M 4/62; M 5/63; F* 3/68M 7/63; M 3/65; F* 3/68F 9/65; F* 3/68; F 1/70

M 5/65; F* 3/68; M 5/70

M -/45; F -/49; M -/53;F NK; F -/57

Four-child families507 M 11/62; F* 5/65; F 2/67; M(S) 12/69509 F* 5/65; M 7/66; (M 2/69; M 2/69]517 M 2/64; F* 7/65; M 2/67; M 12/70519 F 2/60; F 12/61; F* 7/65; F 9/67523 M 10/59; M 8/61; F* 8/65; M 4/69525 M 8/63; F* 8/65; M 10/66; F 8/69527 F* 8/65; M 11/66; (M 3/68; M 3/68]560 F 7/64; F* 1/66; F 9/67; F 1/70578 M 4/65; F* 3/66; F 6/67; M 7/68581 [F 10/61; M 10/61]; F* 3/66; F 2/68588 F 9/61; M 9/63; F 12/64; F* 4/66598 F 3/61; F 11/64; F* 5/66; F 1/68611 F 8/64; F* 6/66; F 8/68; M 8/69617 F 8/58; M 2/61; F* 7/66; F 9/68620 M 8/58; M 11/60; M 8/62; F* 7/66627 F* 9/66; F 1/68; [F 5/69; F 5/69]636 F 2/61; M 7/62; M 12/63; F* 10/66643 F 2/55; M(A) 8/56; M 6/58; F* 11/66657 F 9/64; F* 1/67; M 3/69; M 3/70660 F(A) -/65; F* 2/67; M 1/68; F 5/69662 M 9/64; F 8/65; F* 2/67; M 12/68665 F* 2/67; M 4/68; M 10/69; F 3/72

230

623625629632633639640641644645646652653656658666667674675677678679630632683684694695697701707711712713716718721722724726729730739742746747748753754756757759762765768769

771

7/353/386/344/45-/289/213/401/13

12/364/3611/4211/402/401/36

11/367/402/383/4310/399/3612/368/3910/407/333/404/401/478/475/305/414/406/347/4012/4311/29-/377/471/353/471/387/417/472/364/379/363/373/336/441/394/366/332/429/406/336/3910/23

12/41

7/4111/361/432/46-/2910/252/399/2412/397/407/4612/4610/409/415/412/4210/382/4810/3711/3910/473/422/456/379/396/425/492/491/376/459/417/407/394/446/397/403/495/479/473/422/437/347/349/459/416/386/384/408/421/42

12/369/396/405/329/439/42

12/43

F 12/62

6/3711/326/45-/3510/394/35-/368/363/462/3.74/391/303/444/3611/312/348/344/2812/436/303/3311/45

F NK; M -/56

8/429/451/455/386/366/404/391/41

12/443/41

12/391/321 45

10/3512/351/435/334/332/464/336/361/45

,1----.I-

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702 M 1/66; [F* 7/67; M 7/671; M 6,68; M 12/69 6/45 6j47705 F 2/66; F* 7/67; F 11/69; F 6/71 8/38 1/42715 F 7/61; F 1/63; F* 9/67; F 10/68 F-/59 3/36 11/41719 M 11/65; F* 9/67; F 8/68; M 1/70 F 2/56; F 4/60; M 5/62 -/30 3/31725 M 4/61; M 4/63; F(A) 7/64; F* 9/67 6/32 1/39741 M 12/64; F 10/66; F* 11/67; M 4/70 F 8/61 11/37 3/41745 M 2/62; F 11/64; M 7/66; F* 12/67 8/33 6/43751 M 8/64; M 7/66; F* 12/67; M 5/69 2/39 12/39761 F 9/62; F 6/64; F* 3/68; M 3/69 3/41 12/41763 M 10/59; F 1/61; F 1/64; F* 3/68 M 2/55; F 9/56 4/32 10/27770 F 6/65; M'A) 12/65 No. 446; F* 3/68; -/42 4/43_ M 7/69

Five-childfamilies511 M -/45; M -/47; M -/51; F(A) 4/56; 1/17 3/22

F* 6/65514 M 11/59; M 6/61; F 1/63; F* 7/65; F 10/66 -/37 6/39516 M 8/55; F 3/54; F 10/63; F* 7/65; M 3/67 10/32 12/31534 F 6/160; M(S) 7/61; F 7/63; F* 9/65; 11/36 7/39

F 9/67535 F(A) 9/60; [M 9/61 sb; M 9/61 sb]; F 11/64; 12/31 3/37

F* 9/65538 M 4/53; F 11/57; F 11/61; M 4/63; 8/25 8/29

F* 10/65547 M 3/55; M 6/57; M 4/59; M 5/61; F* 11/65 6/28 4/36551 M 6/62; F* 12/65; Ai 4/67; F 3/68 sb; 1/37 6/36

M 1/70571 M 5/58; F 3/60; F 2/62; F* 2/66; M 10/67 3/34 11/39582 M 10/61; F 3/63; F* 3/66; F 2/67; F 4/69 7/36 8/41583 M 6/61; M(A) 8/64; F* 3/66; F 5/67; 5/39 10/37

F 11/69590 F 3/63; F* 4/66; F 8/68; F 1/70; F 3/71 1/43 7/43619 M 2/61; M 3/63; M(S) 4/65; F* 7/66; 1/38 7/42

M 5/68626 F 7/57; F 1/60; M 10/63; F* 9/66; M 4/69 12/30 1/37661 F 5/59; F 5/60; F 11/62; F 11/64; F* 2/67 11/27 8/35664 [F 11/61; M 11/61]; M 12/62; F 4/64; F* 2/67 -/32 1/29673 F 3/64; F* 3/67; F 3/68; [M 6/69; M 6/69] 5/38 9/40681 F 11/62; M 10/63; M 12/64; M 4/66; 7/39 9/42

F* 4/67698 [F 8/64 sb; F 8/64]; M 3/66; F* 6/67; 3/37 7/37

F(S) 12/68706 M 7/64; M 8/66; F* 8/67; M 4/69; M 11/71 1/43 8/44708 F -/56; M -/62; F 1/66 sb; F* 8/67; M 11/69 9/36 2/38717 M 6/59; F 5/61; F 10/63; M 2/65; F* 9/67 11/34 12/37735 F(S) 10/60; M 1/62; F(S) 5/64; M 4/65; 11/33 8/35

F* 11/67755 M 1/54; M 12/60; M 1/65; F 6/66; 11/28 7/32

[M(A) 1/68 No. 491; F* 1/68]

Six-child families500 M 3/58 sb; M 6/59; F(A) 2/61; F 2/62; 3/27 11/29

[F 4/65 sb; F* 4/65]; M 9/66522 F 12/57; F 2/59; F(S) 4/61; F* 7/65; 7/21 11/37

F 1/68; F 1/69555 M 7/56; M 11/58; M 5/67; F* 12/65; 2/35 9/36

F 2/69; F 7/70

Seven-child families521 M 7/51; F 4/54; M 3/55; M 3/56; M 4/59; 12/25 2/32

M 1/61; F* 7/65558 F -/51; M -/52; F -/54; M -/58; F-/63; 1/23 8/29

F* 12/65; M -/67704 F 1/50; F 11/51; M 11/52; M 10/54; F 4/60; 10/30 6/30

F 9/63; F* 7/67727 M 3/52; M 2/53; F 3/57; F 4/59; M 2/61; 9/26 11/28

F 6/62; F* 9/67

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Appendix IISubsidiary Series

M, male; F, female; *, index patient; italics indicate affected relative; [],twins; sb, stillbirth; A, anencephalus;S, spina bifida; e, encephalocele.

Serial Half Sibs Date of BirthNo. SibshipNo.Sibahip


SPINA BIFIDA-MALESOne-child families772 M* 5/65 M 6/56; M 6/62 NK -/27778 M* 5/67 4/37 2/43780 M* 6/67 M -/64 10/40 3/45783 M* 7/67 M 3/61; M 7/62 3/37 11/41786 M* 7/67 4/45 12/45788 M* 8/67 2/42 6/41792 M* 10/67 12/40 9/42799 M* 1/68 1/46 1/47800 M* 1/68 6/42 2/45801 M* 2/68 9/46 3/50802 M* 3/68 7/46 1/47803 M* 3/68 9/39 6/41804 M* 3/68 8/48 3/48

Two-child families773 M* 6/66; F 7/67 3/38 5/38775 M 12/63; M* 4/67 7/46 8/46779 M* 5/67; M 3/69 1/41 5/42781 F 3/64; M* 6/67 11/35 7/41782 F 4/65; M* 6/67 8/29 9/33784 F 7/65; M* 7/67 2/43 10/41789 M 8/66; M* 9/67 M 1/56 10/31 12/35794 M 9/64; M* 11/67 2/33 4/40795 F 3/66; M* 11/67 5/41 4/44798 M 12/63; M* 1/68 5/40 12/42

Three-child families776 M 8/59; M 11/64; M* 4/67 12/36 6/36785 M 1/56; M 1/63; M* 7/67 6/28 12/33791 F 10/60; M 10/62; M* 10/67 -/29 7/43793 M* 10/67; M 4/69; F 6/70 1/47 8/48796 M NK; F NK; M* 12/67 M NK -/33 5/40

Four-child families774 M 5/63; M* 8/66; F 1/68; F 6/69 10/37 -/45777 F 8/60; F 6/62; M* 5/67; M 3/69 8/30 10/36787 M 8/64 sb; F 8/66; M*e 8/67; F 11/68 3/38 9/40790 [F 12/62; F 12/62]; M 1/65; M* 9/67 8/37 10/40797 F NK; M(S) 6/57; M 12/61; M* 12/67 F 9/52 1/27 3/31

SPINA BIFIDA-FEMALESOne-child families

808 F* 2/66 M 11/58; D 11/60; F 3/62 5/21 12/34812 F* 7/66 M 6/70 NK /47814 F* 3/67 5/31 9/35818 F* 5/67 M 3/56; M 1/58; M 10/59 2/38 4/37822 F* 6/67 1/47 6/48828 F* 7/67 8/36 1/42829 F* 7/67 11/45 11/45833 F* 8/67 2/45 6/46837 F* 9/67 3/45 4/47838 F* 9/67 4/50 5/51839 F* 9/67 5/41 2/44840 F* 10/67 8/38 10/46842 F* 11/67 3/42 12/41844 F* 12/67 12/30 5/35846 F*e 1/68 F 10/64 9/48 1/49849 F* 2/68 -/49 2/50850 F* 2/68 NK 1/52852 F* 3/68 10/35 7/36854 F* 3/68 8/44 11/45

Two-child families805 F* 7/65; M 1/69809 F* 4/66; M 1/68

9/43 11/466/27 12/34

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Appendix II Continued



810 F* 5/66; F(A) 2/68 No. 869 9/38 4/41811 M 1/65; F* 7/66 12/34 10/44815 M 12/62; F* 4/67 2/40 3/42816 F*e 4/67; M 8/68 NK NK819 M 2/66; F* 5/67 10/30 2/34820 F 2/65; F*e 5/67 10/26 7/37823 F* 6/67; F 7/68 7/47 9/47827 F*e 7/67; M 4/69 7/36 3/39830 F 6/66; F* 8/67 1/40 3/43834 M 8/66; F* 8/67 12/45 4/48835 M 2/64; F* 8/67 3/42 11/41836 F* 9/67; F 12/68 1/48 12/48841 F 4/65; F* 11/67 1/41 3/42847 F*e 1/68; M 12/70 111/48 3/49853 F* 3/68; M 2/69 6/44 8/50

Three-child families806 F* 10/65; M 7/67; M 1/70 7/36 4/42813 M NK; M NK; F* 9/66 NK NK824 M 12/58; M 12/62; F* 6/67 9/34 10/40831 F 9/65; F* 8/67; M 5/69 9/42 9/45832 F 12/52; F 3/56; F* 8/67 4/25 8/25813 i F 6/54; F 9/55; F*e 12/67 12/28 7/29848 F 12/54; F 5/56; F* 1/68 6/30 10/31

Four-child families807 M 4/63; M 9/64; F* 10/65; F 4/69 3/38 2/41817 F 6/60- F 7/63; M 9/65; F* 4/67 2/34 9/33821 M 10/54; M 7/61; F*e 6/67; M 8/68 2/26 12/28825 M -/49; M -/52; F -/53; F* 7/67 -/25 NK826 M 5/55; M 3/57; M 2/59; F* 7/67 10/28 12/32

Five-child families

845 M 7/52; M 1/55; F 2/56; F 6/63; F* 12167 4/30 4/32851 M 11/57; M 4/59; F 9/61; F 4/64; F* 2/68 5/35 2/39

ANENCEPHALUS-MALESOne-child families

861 M* 2/68 12/34 9/35

Three-child families856 F 9/59; F 2/62; M* 8/65 1/31 6/38858 F -/64; M* 9/67; F 3/72 NK 11/34863I M* 12/67; M 12/69; M 1/71 3/24 5/35

Four-child families855 F 12/57; F 3/61; M* 5/65; M 3/67 2/28 6/28857 M -/63; F -/64 sb; M* 12/65, F -/68 5/43 2/44859 M(A) 3/61; F 6/64; F 9/65; M* 10/67 5/38 2/39

ANENCEPHALUS-FEMALETwo-child families

864 F(A) 10/61; F* 9/65 F 10/68 11/39 11/41869 F(S) 5/66 No. 810; F* 2/68 9/38 4/41

Three-child families852 F* 4/165; M 3/56; M 1/69 8/40 11/44863 F -/64; F* 7/65; M 4/69 NK NK865 F 6/61; F 8/64; F* 7/66 8/39 8/39867 F 8/47; M(S) 2/55; F* 12/66 9/23 9/26868 F* 2/67; F 4/68; M 5/69 NK NK

Four-child families866 F 1/63; M 11/64; F* 7/66; M 8/68 12/38 3/39

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Appendix IIIMALFORMATIONS (OTHER THAN THAT OF THE NEURAL TUBE) IN SIBS OF INDEX PATIENTS

Spina bifida index patients Anencephaly index patientsFamily 100 Cleft lip Family 490 Klippel Feil, exomphalos and atresia aorta

132 Talipes 426 Cleft palate2 Congenital heart disease and pyloric stenosis 567 Congenital dislocation hip

71 Congenital dislocation hip (both twins affected) 676 Thyroglossal cyst152 Pyloric stenosis 723 Congenital heart disease (ventricular septal defect)300 Hypospadias 724 Congenital deafness276 Down's syndrome 525 Congenital heart disease490 Radial polydactyly 535 Acephalus and holocardius387 Congenital dislocation hip 619 Congenital heart disease and pyloric stenosis345 Trigonencephaly 617 Congenital dislocation hip348 Congenital heart disease (transposition great vessels) 681 Imperforate anus in two sibs379 Down's syndrome 620 Hirschsprung's disease787 Bilateral talipes, club hand 741 Congenital heart disease (ventricular septal defect)

745 Sacroccygeal tumour704 Congenital heart disease482 Hydrocephalus-gross with platybasia857 Hydrocephalus-large internal

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spina bifida and anencephalus in greater london · journalofmedicalgenetics (1973). 10, 209. spina...

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