Clinical detective storiessolutions

Genealogy - problems

seminar

No 434, course: Heredity

Pregnant woman, 36 years old.

Family without any hereditary load.

Gravidities:

5x SAB (spontaneous abortion) in the 6-12th week

Cytogenetic examination: Karyotype 46,XX

Molecular genetic examination: presence of the Leiden mutation was found.

Consultation with hematologist in the second half of gravidity was recommended.

1. Question: What is the Leiden mutation and what effect could it have for the

course of gravidity? What is the possible prevention?

Gravidity VI.: Ultrasound in the12th week: fetus proportional without conspicuous

morphologic abnormalities, normal amount of amniotic fluid, NT (nuchal translucency)

2,5 (norm up to 2,5)

Biochemical screening in the 1st trimester: PAPP-A 0,654 MoM 0,42 (norm MoM 1)

Biochemical screening in the 16th week: (norm MoM 1)

AFP 21 MoM 0,753

HCG 89317 MoM 2,578

uE3 0,690 MoM 0,699

2. Question: Evaluate the results of the screening in 1st and 2nd trimester of

gravidity. What would you recommend to the woman?

Case 1.

The risk for chromosomal abnormalities was explained to the woman.

According to her previous anamnesis, she doesn´t wish to undertake amniocentesis.

Ultrasound in the 20th week: normal finding.

Birth in 38+1 week, spont. head first, Apgar score 9,10,10, 2560g, 48cm, daughter

Hypotonia, mongoloid slant of palpebral fissures, epicantus bilat., 1 palmar linea

Cardiology: defect of ventricular septum

3. Question: What would be the next course of action after the childbirth?

Which examination would you recommend?

4. Question: After evaluation of the results of examination recommend further

care for the child to the mother. Which specialists should be consulted?

Status presens at 4 years of the child:

Gracile somatotype, general hypotonia

Mikrocephaly, mongoloid slant of palpebral fissures, epicantus bilat.

Low ears, small nose, wide nasal bridge

1 palmar linea bilat., sandal linea on both feet

Anorexia, psychomotoric development matches the basic diagnosis.

Girl, 17 years old

Family history: Mother: height 165cm, healthy, father: height 180cm, healthy

Siblings: brother :height 170cm, healthy, second brother died at the age of 5 months

of severe isolated hearth defect

Personal anamnesis: from physiological gravidity, common diseases of early age,

hypothyreosis, th. Letrox since 15 years

Gynecological anamnesis: no menstruation

Student of high school with very good results

Height records:

12 years – 129cm

14 years – 135cm

15 years – 143cm

16 years – 147cm

1. Question: Create and evaluate the percentile diagram of height (graph of

dependence of height on age).

Case 2.

Dependance of height on age

Status presens:

Height 149,8cm, weight 44,7kg

Thick stiff hair, wider neck, flat chest, wide distance of mammills, a lot of pigment

naevi, all other normal

Endocrinology: FSH 75,80, progesteron 0,2, prolactin 10,35, testosteron 0,26

2. Question: Which genetic examinations would you recommend? What is a

treatment recommendation?

Cytogenetic examination: Karyotype 46,XX

Because of small height the array examination was performed to exclude

microdeletion syndromes.

Result: the X chromosome profile shows signs of gonosomal mosaicism

45,X/46,XX

The representation of the 46,XX line is higher than 80%.

There was no other chromosomal aberration found.

3. Question: Try to explain, why the correct diagnosis wasn´t found by

cytogenetic examination of karyotype.

4. Question: Could the isolated heart defect of her brother be related with the

girl´s diagnosis?

5. Question: What are the other possibilities of treatment?

Problem No.3:

George and Grace, who have normal hearing, have 8 children. Two of their 5

daughters and 2 of their 3 sons are congenitally deaf. Their deaf son Horace married

Hedy. Hedy is deaf and her parents Gilbert and Gisele, who are congenitally deaf,

have 4 children, also deaf.

Hedy and Horace in turn have 4 deaf children. Their eldest son Isaac married Ingrid,

a daughter of Harry and Helen, both with normal hearing. Harry and Helen have 7

children and two of them are deaf. Although both Isaac and Ingrid are deaf, their 6

sons all have normal hearing.

Tasks:

1) Find out the pedigree symbols and draw a pedigree with probable

genotypes.

2) Find out how deafness can be inherited and answer following questions:

3) State the probable genotypes of the children in the last generation.

4) Why are all the children of Gilbert and Gisele and of Hedy and Horace deaf?

5) State probable genotypes of all members of all families.

Basic pedigree symbols:

male, female sex unspecified

affected deceased individual

proband, propositus ( affected) prenatal death

Heterozygote for autosomal trait misscariage

Carrier of XR disorder

mating

siblings twins (DZ)

twins (MZ)

Consanguineous mating

Extramarital offspring Incest

Two marriages

= = =

No of generations (I, II), No of individuals (1, 2, 3)

I

II

1. 2. 3.

Other genetic problems:

1. Cathy is pregnant for the second time. Her first child, Donald, has

cystic fibrosis (CF – AR disorder). Cathy has two brothers, Charles

and Colin, and a sister, Cindy. Colin and Cindy are unmarried. Charles

is married to an unrelated woman, Carolyn, and has a 2-year- old

daughter Debbie. Cathy´s parents are Bob and Betty. Betty´s sister

Barbara is the mother of Cathy´s husband, Calvin. There is no

previous family history of CF.

a) Draw a pedigree.

b) What is the risk of CF for Cathy´s next child?

c) Which people in this pedigree are obligatory heterozygotes?

d) What is the probability that Charles, Colin and Cindy are

heterozygous?

e) What is the probability Cindy´s child will be affected with CF?

2. Don and his maternal grandfather Barry both have hemophilia A. Don

´s partner Diane is his maternal aunt´s daughter. Don and Diane have

one son, Edward, and two daughters, Elise and Emily, all of them have

hemophilia A. They have also an unaffected daughter, Enid.

a) Draw the pedigree.

b) Why are Elise and Emily affected?

c) What is the probability that a son of Elise would be hemophilic?

What is the probability that her daughter would be hemophilic?

What is the probability that her daughter would be carrier ?

d) What is the probability that a son of Enid would be hemophilic?

What is the probability that her daughter would be hemophilic?

What is the probability that her daughter would be carrier?

3. John has polydactyly (AD, penetrance 80% ). His sister Jane and

brother George have normal phenotype. Their mother Barbara

has polydactyly and three from her four siblings have polydactyly

too. Barbara´s father had polydactyly.

a) Draw the pedigree.

b) What is the probability that a child of John would be affected?

c) What is the probability that a child of his healthy brother George

would be affected?

4. A Finnish woman is the mother of a child with Meckel syndrome (AR

disorder occurring 1/9000 birth in her part of Finland). She is

widowed and is now going to remarry. What is the risk of the

disease in a pregnancy if her new husband is:

a) an unrelated Finnish man from her geographic area?

b) her former husband´s brother?

c) her own first cousin?

Pedigree (AD)

Pedigree (XD)

Pedigree (AR)

Pedigree (AR) - consanquinity

Pedigree XR

Holandric heredity – Y linked

Mitochondrial heredity (maternal)

Thank for your attention

Thompson and Thompson: Genetics in Medicine, 7th edition, chapter 7: Patterns of single-gene inheritance.