clinical genetics assignment

7/31/2019 Clinical Genetics Assignment

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CLINICAL GENETICS ASSIGNMENT REFERRAL 1: KLINEFELTER SYNDROME

Amanda Tan

Reason for referral and family history

The patient is a 27-year-old male who has been referred by Dr X for genetic counseling after investigation

for infertility revealed a karyotype of 47,XXY. No other details regarding the patients family history are

known.

Disease characteristics

A karyotype of 47,XXY is consistent with Klinefelter Syndrome (KS), which is the most common sex-

chromosome abnormality, present in approximately 1 in 600 newborn males. [1] It is characterized by

abnormalities in physical, social and language development. While there are typical clinical findings (see

below), a broad phenotypic spectrum exists and the severity of symptoms are variable from individual to

individual. As a result, KS is an underdiagnosed disorder - only 25% of adult males with KS receiving a

diagnosis, with less than 10% of these being diagnosed before puberty. [2]

The clinical features of KS are as follows: small testes, infertility (azoospermia or oligospermia),

gynaecomastia, tall slim body habitus with long legs and short torso, developmental delay, speech and

language deficits, learning disabilities, psychosocial difficulties and behavioural issues. Individuals with KS

also have androgen deficiency, which if not detected and corrected by adulthood, can also lead to decreased

libido, low muscle bulk and tone, decreased bone mineral density leading to osteopenia and osteoporosis,and increased mortality from cardiovascular and diabetic complications. [3,4,5]

Genetic issues

KS is a sex-chromosome aneuploidy where there are one or more supernumerary X-chromosomes. In

classic KS (47,XXY), which accounts for 80% of individuals with KS, the main mechanism responsible

for the supernumerary X-chromosome is non-disjunction in parental gametes during meiosis. [5,6] The other

20% of KS cases have been attributed to other variant karyotypes such as higher-grade chromosome

aneuploidies (eg. 48,XXXY) and mosiacism (46,XY/47,XXY). [5] There is evidence relating the severity of

physical manifestations and the number of sex chromosomes present. [3]

Risk to family members, and risk of recurrence

There has been no increased risk found in family members of the individual with KS compared to the

general population, as there is no evidence of a higher likelihood of chromosomal non-disjunction within thesame family. [3] This may not be applicable to this patients case, though, as he is seeking for pre-

conception genetic counseling for himself and his partner.

Genetic testing

Genetic testing is diagnostic of KS, and can be performed prenatally and at any time during life. No tests on

any affected relatives are required as the chromosome aberration is well known. Diagnosis is made via

chromosome karyotyping of cells either from the individuals peripheral blood or tissue obtained via

amniocentesis or chorionic villus sampling in a neonate. [3]

Genetic counseling and clinical recommendations

It is important that this patient should be educated about what the diagnosis means, both physically and

psychosocially. Links to patient support groups should be provided, along with a referral for psychological

counseling if needed.There is no cure for KS, but measures can be taken to lessen the impact of symptoms on the individual.

Biochemical studies should be carried out to determine this patients androgen levels. Testosterone

supplementation in post-pubertal KS individuals has been shown to increase libido, energy levels,

confidence and sense of well being. [7]

The problem that led to the diagnosis in this 27 year-old male was infertility. Individuals with KS either do

not produce sperm at all, or do so at very low levels. If this patient does produce sperm, the sperm can be

extracted and used in assisted reproduction. [8] The patient and his partners options for such reproductive

techniques should be explored.


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References

[1] Wikstrom AM, Dunkel L. Klinefelter syndrome. Best Pract Res Clin Endocrinol Metab. 2011

Apr;25(2):239-50.

[2] Bojesen A, Juul S, Gravholt CH. Prenatal and postnatal prevalence of Klinefelter syndrome: a national

registry study. J Clin Endocrinol Metab. 2003 Feb;88(2):622-6.

[3] Visootsak J, Graham JM, Jr. Klinefelter syndrome and other sex chromosomal aneuploidies. Orphanet J

Rare Dis. 2006;1:42.

[4] Wattendorf DJ, Muenke M. Klinefelter syndrome. Am Fam Physician. 2005 Dec 1;72(11):2259-62.

[5] Lanfranco F, Kamischke A, Zitzmann M, Nieschlag E. Klinefelter's syndrome. Lancet. 2004 Jul 17-

23;364(9430):273-83.

[6] Simpson JL, de la Cruz F, Swerdloff RS, Samango-Sprouse C, Skakkebaek NE, Graham JM, Jr., et al.

Klinefelter syndrome: expanding the phenotype and identifying new research directions. Genet Med. 2003

Nov-Dec;5(6):460-8.

[7] DeLisi LE, Maurizio AM, Svetina C, Ardekani B, Szulc K, Nierenberg J, et al. Klinefelter's syndrome

(XXY) as a genetic model for psychotic disorders. Am J Med Genet B Neuropsychiatr Genet. 2005 May

5;135B(1):15-23.

[8] Denschlag D, Tempfer C, Kunze M, Wolff G, Keck C. Assisted reproductive techniques in patients with

Klinefelter syndrome: a critical review. Fertil Steril. 2004 Oct;82(4):775-9.


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CLINICAL GENETICS ASSIGNMENT REFERRAL 2: HEREDITARY BREAST CANCER

Amanda Tan

Reason for referral

The patient is a 29-year-old female who has been referred to the Department of Clinical Genetics for genetic

counselling as she wishes to be genetically tested for hereditary breast cancer.

Family history (see next page for pedigree)

The patient has several relative affected by breast cancerher mother affected at age 78, and a paternal aunt

affected at age 68.


There were 7380 new cases of breast cancer diagnosed in Sweden in 2009, making up 28.7% of all cancer

diagnoses in females. The majority (70-75%) of breast cancer cases are sporadic; 15-20% have shown

familial clustering with an unclear inheritance pattern, while hereditary cancer accounts for 5-10%.

Hereditary breast cancer tends to have an early onset of disease, a family history of the same or associated

tumours (eg. ovarian cancer). [1] Within hereditary breast cancer, two genes that have been widely studied

at the BRCA1 and BRCA2 genes. The BRCA-related breast cancers tend to be early-onset ductal

carcinomas.

Genetic issues

Mutations in BRCA 1 and 2 are estimated to be responsible for approximately 45% of cases of hereditarybreast cancer [2] and are inherited as an autosomal dominant trait. [3,4] Cancers associated with mutations

in BRCA1 tend to be estrogen-receptor negative and HER2-receptor negative, while BRCA2-related cancers

are usually estrogen-receptor postive and HER2-receptor negative. BRCA1/2 mutations are also associated

with other cancers, namely of the ovaries, pancreas, prostate and skin (melanoma). [5] Both BRCA 1 and 2

play a role in the repair of DNA damage. There have been many genetic alterations identified in both these

genes, 85% of which are frameshift or nonsense mutations that lead to a truncated protein product. [6] This

causes a decreased ability to repair damaged DNA the resultant DNA instability is vulnerable to the

accumulation of oncogenic mutations. Mutations in other genes, such as CHK2, ATM and p53, have also

been found in some cases of familial breast cancer; however, the incidence of these mutations is rare. There

still remains a significant proportion of familial breast cancer cases where genetic mutations have yet to be

identified. [7]Risk to family members to develop the disease or have an affected child

There have been many studies attempting to quantify the risk of breast cancer associated with mutations in

BRCA1 or BRCA2, with results indicating quite a wide range of risk. A meta-analysis of 22 studies on the

topic has estimated the breast cancer risk of BRCA1 mutation carriers is 65% by age 70, and 45% for

BRCA2 mutation carriers. [8] However, it is important to note that non-genetic factors, such as pregnancy

and breastfeeding, may modify a carriers risk of developing breast cancer. [9]

Managementgenetic counselling

From the information provided in the referral it seems unlikely that the breast cancer cases within the

patients family are due to a hereditary genetic cause, as the two cases in the family do not have the

characteristics of a hereditary cancer (see above). However, further information is required about any other

cases of cancerbreast or otherwisein any other relatives, including age of diagnosis, management andoutcome.

Genetic testing, with prior genetic counselling, is available for this patient if she wishes to proceed. It is

most practical to first perform genetic testing on the patients mother and paternal aunt to identify an

oncogenic mutation which can then be searched for in the patients DNA. A blood sample will be required

from all the test subjects. The methods currently in use to screen for mutations include direct sequencing

using polymerase chain reaction, electrophoresis, and techniques analysing changes in the protein products

of the BRCA1/2 genes. Laboratories frequently use a combination of the methods. [7] Prenatal testing is not

indicated for this scenario, as it is not relevant to the patients referral.

If this patient does test positive to a known cancer-causing mutation in BRCA1 or 2, there are two potential

approaches to prevention of breast cancer. Primary cancer prevention involves prophylactic surgery

(mastectomy, and possibly oophorectomy) or drug therapy (tamoxifen). Increased surveillance for changeswithin the breast (monthly self-examination, biannual clinical examination, and annual mammography) is a

secondary prevention approach that aims to detect the cancer at an early, and thus potentially curable, stage.

[7]


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Pedigree

References

[1] Lindbom A. Familial cancer. In: Clinical genetics compendium T10. Stockholm: Karolinska Institutet;

2012.

[2] Wooster R, Weber BL. Breast and ovarian cancer. N Engl J Med. 2003 Jun 5;348(23):2339-47.

[3] Ford D, Easton DF, Stratton M, Narod S, Goldgar D, Devilee P, et al. Genetic heterogeneity and

penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. The Breast Cancer Linkage

Consortium. Am J Hum Genet. 1998 Mar;62(3):676-89.

[4] Serova OM, Mazoyer S, Puget N, Dubois V, Tonin P, Shugart YY, et al. Mutations in BRCA1 and

BRCA2 in breast cancer families: are there more breast cancer-susceptibility genes? Am J Hum Genet. 1997

Mar;60(3):486-95.

[5] Conner JM, Ferguson-Smith MA. Essential medical genetics. 5 ed. Oxford: Blackwell Science Ltd;

1997.

[6] Struewing JP, Tarone RE, Brody LC, Li FP, Boice JD, Jr. BRCA1 mutations in young women with

breast cancer. Lancet. 1996 May 25;347(9013):1493.

[7] Palma M, Ristori E, Ricevuto E, Giannini G, Gulino A. BRCA1 and BRCA2: the genetic testing and thecurrent management options for mutation carriers. Crit Rev Oncol Hematol. 2006 Jan;57(1):1-23.

[8] Antoniou A, Pharoah PD, Narod S, Risch HA, Eyfjord JE, Hopper JL, et al. Average risks of breast and

ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case Series unselected for family

history: a combined analysis of 22 studies. Am J Hum Genet. 2003 May;72(5):1117-30.

[9] Narod SA. Modifiers of risk of hereditary breast and ovarian cancer. Nat Rev Cancer. 2002

Feb;2(2):113-23.


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CLINICAL GENETICS ASSIGNMENT REFERRAL 3: POLYCYSTIC KIDNEY DISEASE

Amanda Tan

Reason for referral

This adult patient has been referred for genetic counselling after receiving the diagnosis of polycystic kidney

disease (PKD).

Family historyFrom the information provided in the referral, there seem to be no known cases of PKD within the family.

However, the patients mother is noted to have died at the age of47 from cardiac infarction. PKD is known

to be associated with cardiovascular complications as such, the patients mother might have been an

undiagnosed case of PKD. The pedigree (on the next page) has been constructed according to these

assumptions.


There are two forms of PKD autosomal recessive (ARPKD), and autosomal dominant (ADPKD).

ARPKD is usually diagnosed soon after birth, while the mean age of diagnosis of ADPKD is in adulthood

due to the later onset of symptoms. [1] Considering the age of this patient, he has most likely been

diagnosed with ADPKD. There is both inter- and intra-familial variability in the progression and

manifestation of the disease. The renal features of PKD are: hypertension, abdominal or flank pain, and

renal failure with multiple cysts found in the kidneys on imaging. Other manifestations of PKD includecysts within other organs (liver, pancreas, seminal vesicles), vascular abnormalities (intracranial and

coronary artery aneurysms, aortic dissection), cardiac valve defects and diverticular disease. [2]

Genetic issues

As the name states, ADPKD is inherited in an autosomal dominant fashion. Mutations in two genes have

been implicated in the pathogenesis of ADPKDPKD 1 (85% of cases), which encodes polycystin 1, and

PKD 2 (15%), which encodes polycystin 2. [3] There is heterogeneity in the mutations. Homozygous or

compound heterozygous genotypes are thought to be incompatible with life. [4]

Genetic counseling

Risk to family members

As being homozygous for the ADPKD gene is incompatible with life, the patient is most likely heterozygous

for the mutation. If the patients partner is not affected, the risk of his offspring inheriting the autosomaldominant gene, and thus having ADPKD, is 50%. If the patients partner is also a heterozygous gene

carrier, the risk of his sons having inherited the gene is 66.6%. However, this is no indication of the

symptom manifestation or severity of the disease in the patients sons.

Genetic testing

Genetic testing, via linkage or sequence analysis, is available for this disease. Testing affected relatives,

such as the patient, to detect the pathogenic mutation is required. [2] The benefit to the patients sons is that

it would provide a definite diagnosis, and also influence family planning in the future. However, as the

disease is asymptomatic in 50% of those with the mutated gene [5], a positive genetic test gives no

indication for the likelihood nor progression or prognosis of future disease. Genetic testing also may not be

a useful tool in ruling out ADPKD as it can be caused by many different mutations in PKD1 and PKD2, and

current techniques can only identify approximately 70% of the known pathogenic mutations. [6]Prenatal testing

Prenatal testing and pre-implantation genetic testing is possible if the family-specific mutation is known or if

linkage has been established in the family. [7] Testing can be done on tissue obtained by chorionic villous

sampling (10-12 weeks) or amniocentesis (15-18 weeks). [8,9]

Prevention or surveillance

Screening in adults (18 years and older) with a positive family history is via ultrasound imaging of the

kidneys to identify cysts and the size of the kidneys. [3] Almost 100% of gene carriers will have ultrasound

findings consistent with ADPKD by the age of 30. [10] Thus a recommendation to the patients sons would

be to undergo regular ultrasound imaging.


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Pedigree

References

[1] Gillenwater JY. Adult and paediatric urology, volume 1. 4 ed. Philadelphia: Lippincott Williams &

Wilkins; 2002.

[2] Torres VE, Harris PC, Pirson Y. Autosomal dominant polycystic kidney disease. Lancet. 2007 Apr14;369(9569):1287-301.

[3] Vijay A, Vijay A, Pankaj P. Autosomal dominant polycystic kidney disease: a comprehensive review.

International Journal of Nephrology & Urology. 2010;2(1):172-92.

[4] Paterson AD, Wang KR, Lupea D, St George-Hyslop P, Pei Y. Recurrent fetal loss associated with

bilineal inheritance of type 1 autosomal dominant polycystic kidney disease. Am J Kidney Dis. 2002

Jul;40(1):16-20.

[5] Davies F, Coles GA, Harper PS, Williams AJ, Evans C, Cochlin D. Polycystic kidney disease re-

evaluated: a population-based study. Q J Med. 1991 Jun;79(290):477-85.

[6] Grantham JJ. Autosomal Dominant Polycystic Kidney Disease. New England Journal of Medicine.

2008;359(14):1477-85.

[7] Harris PC, Torres VE. Polycystic Kidney Disease, Autosomal Dominant. 1993.

[8] De Rycke M, Georgiou I, Sermon K, Lissens W, Henderix P, Joris H, et al. PGD for autosomal dominant

polycystic kidney disease type 1. Mol Hum Reprod. 2005 Jan;11(1):65-71.

[9] Verp MS. Prenatal diagnosis of genetic disorders. In: Gleicher N., ed. Principles and practice of medical

therapy in pregnancy. 2nd ed. Norwalk, CT: Appleton and Lange, 1992:159-70.

[10] Conner JM, Ferguson-Smith MA. Essential medical genetics. 5 ed. Oxford: Blackwell Science Ltd;

1997.

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