Familial Dysautonomia via the ELP1/IKBKAP Gene - Targeted Variants Analysis

Familial dysautonomia (FD), also known as Riley–Day syndrome and hereditary sensory autonomic neuropathy type III, is characterized by hypotonia, gastrointestinal dysfunction, vomiting crises, recurrent pneumonia, altered sensitivity to pain, taste and temperature perception, absence of fungiform papillae on the tongue, decreased or absent deep tendon reflexes, absence of overflow tears, and cardiovascular instability (Shohat and Halpern 2010). These congenital symptoms result from the abnormal development and survival of the sensory and autonomic systems, which leads to progressive neurological abnormalities FD almost exclusively occurs in individuals with Ashkenazi Jewish (AJ) ancestry. Penetrance is complete, although there is variable expressivity (Axelrod 2005). The incidence of FD among individuals with AJ heritage is 1:3600 births, and has an estimated carrier frequency of 1/30. Someone who is not of AJ ancestry has a carrier risk of less than 1:150 (Slaugenhaupt et al. 2001).

FD is inherited in an autosomal recessive manner. It is caused by pathogenic variants in the ELP1/IKBKAP gene, which encodes a component of the Elongator complex. The complex allows for permissive chromatin structure for efficient mRNA elongation during transcription (Shohat and Halpern 2010). Two pathogenic variants account for more than 99% of affected individuals. (1) The c.2204+6T>C variant is a founder mutation that is responsible for disease in individuals with AJ heritage. It causes skipping of exon 20 resulting in a truncated IKAP protein (Dietrich et al. 2011). The abnormal transcript is tissue specific, as the abnormal transcript is found in the brain but not in lymphoblasts and fibroblasts (Slaugenhaupt et al. 2001). (2) The c.2087G>C (p.Arg696Pro) variant has been reported in the AJ population but is not as common as the intronic variant, and has not been reported in the homozygous state. Another variant c.2741C>T (p.Pro914Leu) has been reported in an individual with FD who inherited the variant from a non-AJ parent along with the common pathogenic variant from their AJ parent (Leyne et al. 2003). The missense variants appear to disrupt phosphorylation (Gold-von Simson and Axelrod 2006).

This sequencing test will identify all previously reported pathogenic variants in the ELP1/IKBKAP gene.

The elongator complex protein 1 is encoded by 36 exons (2-37) of the ELP1/IKBKAP gene on chromosome 9q31. This test involves bidirectional Sanger sequencing using genomic DNA of selected exons /intron (exon 19, intron 20 and exon 26) for the c.2087G>C (p.Arg696Pro), c.2204+6T>C, and c.2741C>T (p.Pro914Leu) variants. We will also sequence any single exon (Test #100) in family members of patients with known mutations or to confirm research results or test only the two Ashkenazi pathogenic variants (Test #200).