Four USH2A Founder Mutations Underlie the Majority of Usher Syndrome Type 2 Cases among Non-Ashkenazi Jews

Abstract

Type 2 Usher syndrome (USH2) is a recessively inherited disorder, characterized by the combination of early onset, moderate-to-severe, sensorineural hearing loss, and vision impairment due to retinitis pigmentosa. From 74% to 90% of USH2 cases are caused by mutations of the USH2A gene. USH2A is composed of 72 exons, encoding for usherin, an extracellular matrix protein, which plays an important role in the development and maintenance of neurosensory cells in both retina and cochlea. To date, over 70 pathogenic mutations of USH2A have been reported in individuals of various ethnicities. Many of these mutations are rare private mutations segregating in single families. The aim of the current work was to investigate the genetic basis for USH2 among Jews of various origins. We found that four USH2A mutations (c.239-240insGTAC, c.1000C>T, c.2209C>T, and c.12067-2A>G) account for 64% of mutant alleles underlying USH2 in Jewish families of non-Ashkenazi descent. Considering the very large size of the USH2A gene and the high number of mutations detected in USH2 patients worldwide, our findings have significant implications for genetic counseling and carrier screening in various Jewish populations.

Identification of 11 novel mutations in USH2A among Japanese patients with Usher syndrome type 2

“…The only exception was exons 70-73, which encode a transmembrane domain or intracellular region; no mutations were identified in this sequence. This finding is consistent with those of previous reports (12, [19][20][21][25][26][27][28][29]. In five of the eight patients (C712, C116, C152, C452, and C557), two probable pathogenic alleles were identified and confirmed to be on different chromosomes by using parent or sibling samples (Table 1).…”

The USH2A c.2299delG mutation: dating its common origin in a Southern European population

“…However, c.2299delG is not a prevalent mutation in the non-Ashkenazi Jewish populations from the South and Near East regions. 11,33,34 This supports the hypothesis of the more recent migration fluxes across the Mediterranean Sea as a cause of the reduced frequency of the c.2299delG mutation within Northern Mediterranean populations. Another interesting point is the presence of c.2299delG in Asian patients.…”

Mutational screening of the USH2A gene in Spanish USH patients reveals 23 novel pathogenic mutations

“…The splice-site variant c.12062-2A > G was detected in three patients, in homozygous state in one of them. This mutation was initially described by Auslender et al (2008) [26], as one of the most USH2A prevalent mutations in non-Ashkenazi Jews. Later, it was also detected in the American population [30].…”