Med Gen Conditions

Question 1

Which inborn error of metabolism disorder produces a distinctive odor of sweaty feet?

Answer 1

Isovaleric acidemia

Question 2

Name the gene and AA substitution responsible for 99% of Achondroplasia

Answer 2

FGFR3–> 99% caused by Gly380Arg substitution

point mutation 1138G>A for 98%, 1138G>C for 2%

Question 3

What are some genes associated with AUTOSOMAL DOMINANT Alzheimer’s versus an Alzheimer’s risk modifier gene.

Answer 3

APOE is a modifier allele (Ex: e4 homozygotes at increased risk for Alzheimers)
PSEN1, PSEN2, and APP are associated with AD Alzheimer’s with
PSEN1 (early onset) and APP (late onset) considered fully penetrant.

**Note: 10% of Alzheimer’s disease is autosomal dominant
Another 15% is multifactorial/familial (APOE may modify here)
75% is sporadic

Question 4

Name the disorder characterized by:

1) increased spontaneous sister chromatid exchange
2) AR inheritance
3) sun-sensitivity with characteristic skin lesion in “butterfly area” of face following exposure
4) growth deficiency and micrognathia
5) Ashkenazi Jewish founder mutation with 1/100 carrier frequency (c.2207_2212delinsTAGATTC)

Answer 4

Bloom syndrome (BLM gene)

Question 5

Name 3 syndromes associated with mutations of FGFR3

Answer 5

1. Achondroplasia (Gly380Arg)
2. Hypochondroplasia (less severe, Asn540Lys common, but others possible)
3. Thanatophoric dysplasia (lethal)

*all are caused by AD GOF mutations

Question 6

GOF mutations in this gene lead to Noonan syndrome; LOF mutations lead to Leopard syndrome (aka multiple lentigenes).

Answer 6

PTPN11

Question 7

Name 3 conditions associated with mutations in IRF6

Answer 7

1. Van der Woude syndrome (clefting and lip pits)
2. Popliteal pterygium syndrome (celfting and lip pits PLUS px webs of skin across the knee joint, syndactyly, triangular folds of skin over the nails of the large toes, tissue connecting upper and lower eyelids or upper and lower jaws, genital abnormalities)
3. 6% of nonsyndromic cleft lip/palate… (not sure about this?)

Question 8

-2/3 have mutation in COL2A1
-myopia (mild-severe) with retinal
detachment, flat midface, cleft palate (25%)
with Pierre Robin features, cataracts, and
sensorineural deafness, mild skeletal features
-AD

Answer 8

Stickler syndrome

COL11A1 and COL11A2 are associated with hearing loss and non-ocular forms, respectively

Question 9

GJB2 mutations

Answer 9

Most common AR cause of nonsyndromic hearing loss.
SNHL, typically present at birth, bilateral, nonprogressive, range mild-profound
Can also have 1 GJB2 and 1 GJB6 deletion or bilallelic GJB2 deletions

Question 10

Waardenburg syndrome

Answer 10

PAX3, MITF, SOX10 genes
AD; 20-50% will have HL
Some have pigmentary anomalies (white forelock, iris heterochromia)

Question 11

BOR syndrome

Answer 11

branchio-oto-renal syndrome; AD; EYA1 gene (40% of families)

hearing loss, branchial arch problems (cleft cysts and fistula), preauricular pits, renal anomalies

Question 12

Stickler syndrome

Answer 12

COL2A1, COL11A1, COL11A2; AD

progressive SNHL, cleft palate, spondyloepiphyseal dysplasia-> osteoarthritis, severe myopia, retinal detachment

Question 13

Usher syndrome

Answer 13

MYO7A, USH2A; AR syndromic HL

born with SNHL, then develop RP

Question 14

Pendred syndrome

Answer 14

SLC26A4 (50% of families); AR
congenital HL from abnormality in the bony labyrinth
enlarged vestibular aqueduct, euthyroid goiter

Question 15

Jervell and Lange-Nielsen syndrome

Answer 15

AR syndromic HL

congenital HL and long QT syndrome at risk for sudden death

Question 16

Biotinidase deficiency

Answer 16

75% may have SNHL; can treat with biotin but any HL or optic atrophy typically irreversible

Question 17

Adult Refsum disease

Answer 17

PHYH, PEX7 genes; AR

SNHL and RP, anosmia

Question 18

Alport syndrome

Answer 18

SNHL after 10 years, glomerulonephritis leading to end-stage renal disease, opthalmologic findings

Question 19

What phenotype is associated with UPD(6)pat?

Answer 19

transient neonatal diabetes mellitus

Question 20

What phenotype is associated with UPD(7)mat?

Answer 20

Russel-Silver syndrome (IUGR, postnatal growth deficiency, proportionately short stature, normal head circumference, fifth-finger clinodactyly, typical facial features with triangular facies characterized by broad forehead and narrow chin, and limb-length asymmetry that may result from hemihypotrophy with diminished growth of the affected side)

Question 21

What phenotype is associated with UPD(11)pat?

Answer 21

Beckwith-Weidemann syndrome (also caused by paternal 11p15.5 duplication and other imprinting errors in that region)

Question 22

What phenotype is associated with UPD(14)mat?

Answer 22

short stature, hypotonia, hyperflexible, dysmorphic features, developmental delay, precocious puberty

Question 23

What phenotype is associated with UPD(14)pat?

Answer 23

(more severe than UPD(14)mat) MR, skeletal abnormalities (short-limbed dwarfism, narrow thorax leading to lung hypoplasia/decreased survival), dysmorphic features, scoliosis

Question 24

What phenotype is associated with UPD(15)mat?

Answer 24

Prader-Willi syndrome (28% maternal UPD, ~70% pat 15q12deletion, ~2% imprinting defect)

Question 25

What phenotype is associated with UPD(15)pat?

Answer 25

Angelman syndrome (~70% mat 15q12 deletion, 3-5% UPP(15)pat, ~5% has UBE3A mutations, ~3% abnormal imprinting

Question 26

What is the recommended screening for a child with BWS or isolated hemihyperplasia?

Answer 26

Serum AFP levels every 3 months until age 4 for hepatoblastoma screening
Abdominal ultrasound every 3 months until age 8, mainly for Wilm’s tumor screening but also other abdominal tumors
Consider implementing “daily caretaker abdominal exam”

Question 27

According to ACMG guidelines, what is the recurrence risk for full sibs of a child with ASD?

Answer 27

~3-10%
If the affected sib is a female, RR is 7%
If the affected sib is male, RR is 4%

Question 28

What is the approximate rate of success to find an etiology for a child with autism?

Answer 28

~6-15%
CMA has highest yield (~10% for ASD, ~30% for “complex ASDs including microcephaly, seizures, dysmorphic features, multiple congenital anomalies)
Fragile X yield about 1-5%
MECP2 yield in females about 4%
PTEN yield about 5% in those with FOC>2.5 SDs

Question 29

What are the different combination of genotypes for individuals with non-syndromic hearing loss at the DFNB1 locus?

Answer 29

GJB2 mutations (homozygous or compound het)
GJB2 mutation + GJB6 deletion
Biallelic GJB6 deletions
*Note: dominant GJB2 mutations are possible (syndromic hearing loss with skin findings)

Question 30

What testing should be sent for suspected acquired hearing loss?

Answer 30

CMV (less likely to be + when child gets older, so best yield when tested soon after birth), also consider rubella, meningitis, syphilis

Question 31

CMA is a considered a first-tier test by the ACMG for what conditions?

Answer 31

Developmental delay/Intellectual disability, multiple congenital anomalies, and autism-spectrum disorders

Question 32

What is the recommendation for individuals homozygous for the thermolabile MTHFR variant?

Answer 32

fasting total plasma homocysteine levels
If nl: reassure that there is no evidence for increased risk of VTE or recurrent pregnancy loss
If abnl: mild increased risk for VTE (OR 1.27) and RPL (OR 2.7)
Homozygous individuals also have mod increased risk (OR 1.6) to have child with NTD, especially if that child is also homozygous

Question 33

What type of prenatal diagnostic technique must be used to diagnose osteogenesis imperfecta with biochemical analysis?

Answer 33

biochemical analysis on CVS sample only BUT OI type I does not synthesize enough collagen for this testing