Clinical Genetics - General = Hearing Loss (TRANSFERRED)

Question 1

Reference: Genetics residents in-training examination – Fall 2020

A 3-month-old boy is referred to you for profound sensorineural hearing impairment (SNHL). Answer the following questions:

a) What is the most common non-genetic cause of congenital SNHL?
b) The ENT specialist who made the referral already sent genetic testing for the 2 most common genes known to cause congenital SNHL, and the testing was negative. Which gene(s) were tested?
c) While taking the family history, you learn that your patient’s parents are consanguineous. They report no hearing loss for themselves or for any of their other three children. However, the proband has a “double first cousin” who was born deaf and has recently developed vision loss at the age of 10 years. What genetic condition might be compatible with this history?
d) Give 2 reasons why SNHL in the proband is unlikely to be autosomal dominant.
e) When you examine the patient, name 4 physical features you are looking for when considering syndromes that can cause SNHL. For each feature, name the syndrome as well.

Answer 1

a) congenital CMV infection
b) GJB2 (could also answer connexion 26) and GJB6 (could also answer connexin 30)
c) Usher syndrome
d) There is no SNHL in either parent, AND most autosomal dominant forms of SNHL have a post-lingual onset.

MNEMONIC: Dominant is one allele, so the onset is post-lingual; Recessive is both alleles, so it’s pre-lingual (earlier onset).

e) 
midface hypoplasia (Stickler syndrome), 
heterochromia (Waardenburg syndrome), 
branchial cleft cyst (BOR syndrome), 
outer ear malformations (CHARGE syndrome, BOR syndrome, etc)

Question 2

Reference: Genetics residents in-training examination – Spring 2021

A pediatrician refers a family to you because the couple’s first child, now aged 3, has short stature, renal insufficiency and mild sensorineural hearing loss. Investigations have revealed a non-functioning small right kidney and bilateral grade IV vesicoureteral reflux. On taking the family history, the 28 year old mother reveals that her father died of chronic renal failure in his early forties and was visually impaired. She, herself, has been well and is normotensive, but has myopia. On examining her, you find that she has bilateral optic nerve dysgenesis and tortuous retinal vessels. The child has no obvious eye anomalies.

a) What is the most likely diagnosis in this family and the mode of inheritance? (2)
b) Which molecular investigation would you utilize to confirm the diagnosis? (1)
c) What is the underlying pathogenetic mechanism for this condition? (1)
d) What is the prognosis for this child with respect to renal function? (1)

Answer 2

a)
Papillorenal / renal coloboma syndrome (1)
Autosomal dominant (0.5) with highly variable expressivity (0.5)

b)
PAX2 sequencing with del/dup analysis (1)

c)
Abnormal angiogenesis (1)

d)
Progressive chronic renal disease eventually requiring transplantation (1)