Genetic history, pedigree construction and inheritance patterns — formative SAQs

SAQ 1 (10)

A three-year-old boy is referred for global developmental delay. On taking a family history you learn that he has two unaffected older sisters, his parents are first cousins, and his mother had two first-trimester miscarriages. A maternal uncle died in infancy of an undiagnosed illness. You decide to construct a pedigree. [1] [2]

a) Outline the essential elements of a standardised three-generation pedigree, naming the minimum generations and the specific items you would document on each parental line. (3 marks) [1] [2]

b) Describe the standardised pedigree symbols for: a male, a female, an affected individual, a carrier, a deceased individual, the proband, and consanguinity. (3 marks) [1]

c) Given that the parents are first cousins, state the approximate additional risk of a serious genetic or congenital disorder in their offspring over the population baseline, and explain the genetic reason. (2 marks) [3]

d) Explain why an isolated affected child does not exclude autosomal recessive inheritance, naming two reasons. (2 marks) [4]

SAQ 2 (10)

A six-month-old infant presents with severe hypotonia, feeding difficulty, and failure to thrive. There is no consanguinity. Genetic testing reveals a deletion at chromosome 15q11-q13. The laboratory report notes that the parent of origin cannot be determined from the test performed. [5] [1]

a) Name the two syndromes that can arise from a 15q11-q13 deletion and the inheritance mechanism that determines which syndrome occurs. (3 marks) [5]

b) State the preferred first-line laboratory investigation for this region and explain why it is preferred over a standard chromosomal microarray. (2 marks) [5]

c) Contrast the pedigree shapes of autosomal dominant, autosomal recessive, and X-linked recessive inheritance, naming the single feature that most reliably distinguishes each. (3 marks) [2] [4]

d) Explain how reduced penetrance and variable expressivity can each confound the recognition of an autosomal dominant pattern on a pedigree. (2 marks) [4]