Syndromes

Question 1

Fragile X Syndrome

Answer 1

• FMR1 gene with -CGG- repeats in 5’ untranslated region, X-linked
  Range of severity from normal → intermediate → permutation → full mutation
  Anticipation: 55-200 CGG repeats may expand to full mutation in subsequent generations
  Expansion is with maternal transmission
  Intellectual disability, hypotonia, seizures
  Prominent forehead, large ears, long narrow face, macroorchidism
  Female carriers still at risk for Ataxia (FXTAS) and primary ovarian insufficiency (FXPOI) when in the premutation stage
  Males more severely affected than females

C gyn gyn

Repeat Expansion Disorder

Question 2

Myotonic Dystrophy

Answer 2

DMPK gene with -CTG- repeats in 3’ UTR,
Autosomal Dominant
Anticipation: < 49 repeats is premutation, > 50 is full mutation, but mutation ranges up to > 1,000 (congenital)
Expansion with maternal transmission
Mild: onset 20-70 yo, cataracts, mild myotonia
Classic: cataracts, baldness, myotonia, arrhythmia
Congenital: respiratory deficits, ID, infantile hypotonia, classic signs

Repeat Expansion Disorder

Question 3

Huntington’s Disease

Answer 3

HHT gene with -CAG- repeats in Exon 1,
Autosomal Dominant
Anticipation: Most common with paternal transmission
Normal: <26 CAG repeats
Intermediate: 27-35 CAG repeats
Pathogenic: 36+ CAG repeats
–Reduced penetrance: 36-39 CAG repeats
–Full penetrance: 40+ CAG repeats
Average age of onset ~45 yrs for normal, < 20 years for juvenile
Progressive motor ability loss, loss of voluntary movement, “clumsiness,” chorea (aneurologicaldisorder characterized byspasmodicinvoluntarymovements of thelimbsor facial muscles), inability to walk, speak or eat in late stages
High rates of depression/suicide due to symptoms and lack of treatment

Repeat Expansion Disorder

Question 4

Beckwith-Wiedemann Syndrome

Answer 4

Imprinting Disorder
Chromosome 11p15.5 (exactly the same as RS)
Overgrowth (macrosomia) and/or uneven growth (hemihyperplasia)
Macroglossia - large tongue obstructs breathing or feeding, omphalocele possible
Higher risk for certain blastomas and renal tumors until age 7
Approx. 50% of cases are from a loss of maternal methylation on KCNQ1
“Becky → no Becky” → no maternal methylation “Becky” is mom’s name
OR paternal UPD
Losing mom’s methylation OR two of dad
Dad wants baby to be big.

opposite of Russell Silver

Question 5

Russell Silver Syndrome

Answer 5

Chromosome 11p15.5 (exactly the same as BW)
Undergrowth and body asymmetry
Relative macrocephaly at birth, frontal bossing, micrognathia, speech and motor delays (35%)
Feeding difficulties and dental crowding
Hypomethylation of paternal imprinted
control region (ICR1)
Can also be caused by maternal uniparental disomy – chromosome 7
“No Russell” → dad’s name is Russell
Losing dad OR two of mom (chromosome 7)
This is the opposite of Beckwith!
Mom wants baby to be small.

opposite of Beckwith-Wiedemann

Question 6

Prader Willi Syndrome

Answer 6

Chromosome 15q11.2-q13
Obesity and consistent hunger in older patients
Infants are small w/ feeding difficulties until 2-3 yo
Majority of cases caused by 4-6 Mb deletion
Maternal UPD and imprinting can also cause
“Prader lacks father” → maternal uniparental disomy

Question 7

Angelman Syndrome

Answer 7

Chromosome 15q11.2-q13
Microcephaly, learning/language delay
90% have seizure activity
Happy/excited demeanor or ASD traits
Majority caused by maternal deletion, but some caused by paternal UPD
“Angel misses mom” → paternal uniparental disomy

Question 8

All of the repeat expansion disorders are autosomal dominant except for 2, which are those and what is their inheritance pattern?

Answer 8

Fragile X = X linked recessive
Friedreich Ataxia = autosomal recessive