Wallach's Interpretation of Diagnostic Tests: Pathways to Arriving at a Clinical Diagnosis (454 page)

Marfan syndrome is a disorder of fibrous connective tissue having autosomal dominant inheritance. There is marked clinical variation manifestations observed in the skeletal, ocular, and cardiovascular tissues that include increased height, disproportionately long limbs and digits, anterior chest deformity, joint laxity, scoliosis and thoracic lordosis, a narrow, arched palate, ectopia lentis, and aortic root/ aneurysm pathology.

MFS results from heterozygous mutations in the fibrillin-1 gene (FBN1) located at 15q21.1.

   Relevant Tests and Diagnostic Value

Sequence analysis of the entire coding region; deletion/duplication analysis.

Suggested Readings

Attias D, et al. Comparison of clinical presentations and outcomes between patients with TGFBR2 and FBN1 mutations in Marfan syndrome and related disorders.
Circulation.
2009;120:2541–2549.

Pyeritz RE, McKusick VA. Basic defects in the Marfan syndrome. (Editorial).
New Eng J Med.
1981;305:1011–1012.

Tiecke F, et al. Classic, atypically severe and neonatal Marfan syndrome: twelve mutations and genotype-phenotype correlations in FBN1 exons 24–40.
Eur J Hum Genet.
2001;9:13–21.

   
ONCOLOGIC HEREDITARY DISORDERS

BRCA1 AND BRCA2 HEREDITARY BREAST AND OVARIAN CANCER

MIM #604370 (BRCA1) AND #612555 (BRCA2)

   Definition

Familial breast and/or ovarian cancer are autosomal dominant multifactorial disorders and are caused by mutations in the BRCA1 and BRCA2 genes. BRCA1 and BRCA2 are tumor suppressor genes. The proteins produced from these two genes are involved in repairing damaged DNA, preventing cells from growing and dividing too rapidly in an uncontrolled way. Lifetime risk of breast cancer in BRCA1 mutation carriers is 80–90% and ovarian cancer 40–50%. Lifetime risk of breast cancer in BRCA2 mutation carriers is 60–85% and ovarian cancer 10–20%. Lifetime risk of breast cancer in male with BRCA mutation is 6%. Mutations in these genes are rare in the general population and are estimated to account for no more than 5–10% of breast and ovarian cancer cases overall.

   Relevant Tests and Diagnostic Value

   Genetic testing for mutations in BRCA1 and BRCA2, two genes predisposing to breast and ovarian cancers, is available to women with a relevant family history. Testing of the family member with breast or ovarian cancer is recommended first. If a BRCA1 or BRCA2 mutation is found, other family members can be tested for the specific BRCA mutation. If no mutation is found, the cancer is probably not due to an inherited BRCA1 and BRCA2 gene mutation, and other family members should not be tested for mutations in these genes.

   No currently available technique can guarantee the identification of all cancer-predisposing mutations in BRCA1 or BRCA2.

   Mutations of uncertain clinical significance may be identified.

   Mutations in the genes p53 and PTEN/MMAC1 increase breast cancer risk.

   Clinical testing

   Targeted mutation analysis—may be used when familial mutation is known and in ethnic-specific studies, which include mutations known to be found at greater frequencies in individuals of certain ethnic backgrounds. In persons of Ashkenazi Jewish heritage, three founder germ line mutations are observed: c.68_69delAG (BRCA1), c.5266dupC (BRCA1), and c.5946delT (BRCA2). One in 40 Ashkenazi individuals have one of these three founder mutations.

   Sequence analysis—can detect both common and family-specific BRCA1 and BRCA2 mutations.