ELP1 Gene Variants in Familial Dysautonomia

Background and Objectives Familial dysautonomia (FD), also known as hereditary sensory and autonomic neuropathy type III, is an autosomal recessive disease caused by variants in the elongator acetyltransferase complex subunit 1 ( ELP1 ) gene. The most common pathogenic variant, ELP1 c.2204 + 6T > C (formerly reported as IVS20 + 6T > C), is a founder variant prevalent in the Eastern European Ashkenazi Jewish (AJ) population, and more than 99.5% of patients are homozygous. This pathogenic variant impairs ELP1 pre-mRNA splicing, leading to reduced levels of full-length transcript and resulting in tissue-specific reductions in ELP1 protein. In addition to this founder variant, 2 other variants have been previously reported: the ELP1 c.2087G > C variant identified in 4 unrelated AJ-FD patients, as well as the ELP1 c.2741C > T variant described in a single non-AJ patient. All reported patients with these missense variants were compound heterozygotes carrying the ELP1 c.2204 + 6C > T founder variant. The aim of this study was to report 4 pathogenic variants in ELP1 that were identified in patients with FD who also carry the founder pathogenic variant ELP1 c.2204 + 6C > T. Methods Patients referred to the NYU Dysautonomia Center with suspected FD underwent comprehensive evaluations, including clinical assessments, neurologic examinations, and genetic testing. Results Four patients were identified as compound heterozygotes for the ELP1 c.2204 + 6T > C founder pathogenic variant and one of 4 novel ELP1 variants: ELP1 c.1361-1G > T, ELP 1 c.1229C > T, ELP1 c.2443A > G, and ELP1 c.725C > T. All patients exhibited the full spectrum of FD manifestations. Their self-reported ancestry was diverse: 1 patient was born in Canada to AJ parents, 1 was born in Poland, and 2 were born in the United States, including 1 with African American ancestry; 3 were unaware of any AJ heritage despite carrying the major AJ allele. Discussion We report 4 patients who meet clinical criteria for FD and carry the founder pathogenic ELP1 splicing variant in trans with 4 variants previously not associated with the disease. These findings expand the genetic and ancestral spectrum of FD; underscore the importance of considering the diagnosis in patients from diverse backgrounds, including African American patients; and support careful evaluation of rare ELP1 variants during genetic testing when FD is clinically suspected.