Wallach's Interpretation of Diagnostic Tests: Pathways to Arriving at a Clinical Diagnosis (440 page)

   Uniparental disomy—additional molecular testing involving parental bloods.

   Defects in the imprinting center (IC).

If the methylation test is negative, mutation analysis of the UBE3A gene may detect an abnormality.

Suggested Reading

Williams CA, Peters SU, Calculator SN.
Facts About Angelman Syndrome
. 7th ed. Aurora, IL: Angelman Syndrome Foundation Inc., 2009. Available from:
http://www.angelman.org/
understanding-as/facts-about-angelman-syndrome

FAMILIAL DYSAUTONOMIA

MIM #223900

   Definition

Familial dysautonomia (hereditary sensory and autonomic neuropathy type III, sometimes called Riley-Day syndrome) is an autosomal recessive disorder almost completely limited to persons of Ashkenazi Jewish heritage. It affects the development and survival of sensory, sympathetic, and parasympathetic neurons, resulting in variable symptoms including insensitivity to pain, inability to produce tears, poor growth, and labile blood pressure and leads to decreased life expectancy in affected individuals.

   Relevant Tests and Diagnostic Value

   Currently, the diagnosis of familial dysautonomia is established by molecular genetic testing of the
IKBKAP
(inhibitor of kappa light polypeptide gene enhancer in B cells, kinase complex–associated protein) gene.

   Targeted mutation analysis—available for two mutations, c.2204 + 6T>C (VS20 + 6T>C) and pR696P (Arg696Pro), which account for >99% of mutant alleles in individuals of Ashkenazi Jewish descent affected with familial dysautonomia.

   Sequence analysis: Analysis of the entire coding region of the
IKBKAP
gene.

Suggested Reading

Blumenfeld A, Slaugenhaupt SA, Liebert CB, et al. Precise genetic mapping and haplotype analysis of the familial dysautonomia gene on human chromosome 9q31.
Am J Hum Genet.
1999;64:1110–1118.

FRAGILE X SYNDROME OF MENTAL RETARDATION/FMR1-RELATED DISORDERS

(MIM #300624)

   Definition

Fragile X syndrome is the most common form of inherited mental retardation. It is caused by loss of function of the
FMR1
gene on the X chromosome (Xq27.3). Most affected individuals carry an expansion of a triplet CGG repeat in the
FMR1
gene; rarely, other causes of loss-of-function gene mutations (point mutations, deletions, abnormal gene methylation) are causal.

   Who Should Be Suspected?

Typically, male full-expansion carriers are affected with mental retardation in the moderate range; there is some variation in the extent of methylation on the expanded allele leading to some variation in phenotype. Female full-expansion carriers frequently manifest disease symptoms but typically in a milder form. Premutation (allele expansion is greater than normal but less than the full expansion associated with fragile X syndrome) is associated with increased risk of premature ovarian failure and may cause fragile X–associated tremor/ataxia syndrome (FXTAS), a late-onset neurodegenerative disorder, mostly affecting male carriers.

   Relevant Tests and Diagnostic Value

Molecular Testing: Direct diagnosis by DNA analysis using Southern blotting, PCR, and methylation analysis. This can be performed for pre- and postnatal diagnosis and to detect asymptomatic carriers. Diagnostic value: identifies affected males and heterozygous/affected females.

Stretches of CGG repeats without an AGG “anchor” are more likely to expand than those with interspersed AGG interruptions. Normal size of the CGG sequence is between 5 and 44 repeats. Between 45 and 54 CGG repeats is considered a grey or intermediate zone. Individuals with 55 to 200 CGG repeats are considered premutation carriers. Most individuals with Frag X syndrome have an expansion of more than 200 CGG repeats that causes loss of function of
FMR1
.