Case studies: Achondroplasia, syndromic/non-syndromic deafness, Fragile-X

Question 1

Achondroplasia phenotype



Answer 1

KNOW:
Rhizomelic short stature
Spinal cord compression (3-7% die unexpectedly during the first year of life due to brainstem compression)
Bonus:
•midface hypoplasia (otitis, sleep apnea)…small cranial foramina, increased frequency of hypotonia, quadriparesis, failure to thrive, central apnea, and sudden death).

Question 2

What causes achondroplasia (at protein level)

Answer 2

Gly380Arg substitution (Caused by specific mutations in Fibroblast Growth Factor Receptor 3 (FGFR3))

Question 3

Achondroplasia: Pathogenesis

Answer 3

FGFR3 is a transmembrane tyrosine kinase receptor!binds fibroblast growth factors! ini;ates a signaling cascade!~ inhibits bone growth (over-simplified)

FGFR3 c.1138 G>A Gly380Arg = gain-of- function mutations that cause ligand- independent activation of FGFR3. FGFR3 turned on —> inappropriately inhibits bony growth

Question 4

Mutation at DNA level that causes achondroplasia?

Answer 4

Two mutations, 1138G>A (∼98%) and 1138G>C (1% to 2%), account for more than 99% of cases of achondroplasia. (most mutable nucleotide that we know of)

Question 5

What are the inheritance patterns of congenital vs. progressive deafness?

Answer 5

Congenital deafness in the recessive form

Progressive childhood deafness in the dominant form

Question 6

Non Syndromic Deafness

Answer 6

• 1:500-1000 neonates
• Diagnose with newborn screening
-genetic, not associated with other problems
-congenital is recessive, progressive is dominant

Question 7

Nerve-based hearing loss is called ____? Anatomical hearing loss is called ___?

Answer 7

• Conductive: anatomy

* Nervous: sensiorineural

Question 8

Non Syndromic Deafness

Answer 8

Genetic partition
• ~1/2congenital deafness = genetic
• Of genetic, 3/4 is nonsyndromic, 1/4 is syndromic
• of non-syndromic:
– GJB2 mutations most common–>1⁄2 of all nonsyndromic autosomal recessive deafness

Question 9

Nonsyndromic deafness can occur at any age. Hearing loss that is present before a child learns to speak is classified as______ or congenital. Hearing loss that occurs after the development of speech is classified as_____.

Answer 9

prelingual; postlingual