Familial dysautonomia: Detection of the IKBKAP IVS20+6T → C and R696P mutations and frequencies among Ashkenazi Jews

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Abstract
Familial dysautonomia (FD) is an autosomal recessive congenital neuropathy that occurs almost exclusively in the Ashkenazi Jewish (AJ) population. Mutations in the IκB kinase complex-associated protein (IKBKAP) gene cause FD. Two IKBKAP mutations, IVS20+6T → C and R696P, have been identified in FD patients of AJ descent. The splice site mutation IVS20+6T → C is responsible for > 99.5% of known AJ patients with FD, and haplotype analyses were consistent with a common founder. In contrast, the R696P mutation has been identified in only a few AJ patients. To facilitate carrier detection, a single PCR and allele-specific oligonucleotide (ASO) hybridization assay was developed to facilitate the detection of both the IVS20+6T → C and R696P mutations. Screening of 2,518 anonymous AJ individuals from the New York metropolitan area revealed a carrier frequency for IVS20+6T → C of 1 in 32 (3.2%; 95% CI, 2.5–3.9%), similar to the previously estimated carrier frequency (3.3%) based on disease incidence. No carrier was identified for the R696P lesion, indicating that the mutation was rare in this population (< 1 in 2,500). This sensitive and specific assay should facilitate carrier screening for FD mutations in the AJ community, as well as postnatal diagnostic testing.