ACMG Guidelines

Question 1

What type and how often should children with isolated hemihyperplasia have tumor surveillance based on ACMG recommendations?

Answer 1

Increased risk for tumors (mostly embryonal, mostly in the abdomen)

1. Abdominal ultrasound every 3 months until age 7 years
2. Serum AFP (to evaluate for hepatoblastoma) every 3 months until age 4 years

Question 2

How do you make the diagnosis of Pompe disease?

Answer 2

1. Demonstrate absent (<1% of control activity) or reduced (2-40%) acid alpha glucosidase activity
   - dried blood spots or on cultured fibroblasts or muscle bx
2. Molecular genetic testing

Question 3

Name 8 disorders recommended by ACMG for Ashkenazi Jewish carrier screening?

Answer 3

1. Tay Sachs
2. Niemann Pick type A
3. Fanconi anemia (type C)
4. Bloom syndrome
5. Gaucher disease type 1
6. Familial dysautonomia
7. Cannavan
8. Mucolipidosis type IV

Question 4

Individuals with a least ____ Jewish ________ should be offered Ashkenazi Jewish carrier screening?

Answer 4

1. At least 1 Jewish grandparent is enough to recommend screening

Question 5

In a couple one partner is Jewish and the other is not. Should they both have Jewish carrier screening?

Answer 5

1. Test the Jewish person first, if screen positive for any of the disorders, then screen the other partner for carrier status for that disorder.

Question 6

What measurement of an NT is considered elevated?

Answer 6

3.5 mm (measured between 11-14 weeks)

Question 7

Name some conditions other than aneuploidy associated with an increased NT.

Answer 7

1. Congenital heart defects
2. Other genetic syndromes (ex Noonan)
3. skeletal dysplasias
4. congenital diaphragmatic hernias

Question 8

True or false: serum first and second trimester screening cannot be done in multi-fetal pregnancies.

Answer 8

False; it can be performed (best when combined with U/S) but expectant family should be counseled about reduced sensitivity for the detection of fetal aneuploidy

Question 9

Name 2 limitations to keep in mind with SMA (spinal muscular atrophy) carrier screening.

Answer 9

1. High de novo mutation rate for an autosomal recessive disease
   - 2% of SMA cases are the result of having a least 1 de novo mutation
   - the high de novo mutation rate likely accounts for the high carrier frequency in the general population (1/ 40-1/60)
2. The copy number of the SMN1 gene can vary for each chromosome
   - therefore, possible to have 2 copies of SMN1 on 1 chromosome and 0 copies of SMN1 on the other chromosome

Question 10

True or false, the copy number of SMN2 influences the severity of disease for SMA

Answer 10

True

• high copy number of SMN2 usually associated with more mild phenotype
• SMN2 differs from SMN1 because its transcript lacks exon 8 (which is produced in SMN1), therefore not able to fully compensate for loss of SMN1 and results in disease phenotype