A homozygous founder missense variant in arylsulfatase G abolishes its enzymatic activity causing atypical Usher syndrome in humans

Abstract

Homozygosity for ARSG-p.D45Y in humans leads to protein dysfunction, causing an atypical combination of late-onset Usher syndrome. Although there is no evidence for generalized clinical manifestations of lysosomal storage diseases in this set of patients, we cannot rule out the possibility that mild and late-onset symptoms may appear.

A nationwide genetic analysis of inherited retinal diseases in Israel as assessed by the Israeli inherited retinal disease consortium (IIRDC)

“…Since 2012, patients’ DNAs were subjected to NGS, using either T‐NGS and/or WES. Novel IRD genes identified by IIRDC members using this approach include MAK , ARL2BP , CEP250 , CEP78 , IDH3A , SCAPER , ARMC9 , and ARSG (Davidson et al, ; Khateb et al, , ; Namburi et al, ; Özgül et al, ; Pierrache et al, ; Tatour et al, ; van de Weghe et al, ; Table S1). In total, 23% of the families were solved using this approach (41% of solved families).…”

“…For some of the genes, additional associated phenotypes have been reported over the years (Table S1). In addition to novel genes, a large number of founder mutations segregating in various ethnic groups were discovered (Auslender et al, , ; Khateb et al, , ; Tatour et al, ; Zelinger et al, ). Many of these findings have already been implemented into the clinical practice in Israel enhancing our ability for molecular diagnosis and genetic counseling to IRD patients and their relatives.…”

“…Targeted next‐generation sequencing (T‐NGS) of 108 known IRD genes was performed using the molecular inversion probes technique (Weisschuh et al, ). Whole‐exome sequencing (WES) and whole‐genome sequencing (WGS) were performed as previously described (Khateb et al, ; Tatour et al, ). Variant filtering was based on both external databases (including gnomAD, https://gnomad.broadinstitute.org/), which includes data on the Ashkenazi Jewish population, and the 1000 Genomes Project (http://www.internationalgenome.org/), as well as our internal database of approximately 1,450 samples analyzed by NGS.…”

The combination of whole‐exome sequencing and clinical analysis allows better diagnosis of rare syndromic retinal dystrophies

“…; Khateb et al. ). Inherited retinal diseases (IRDs) frequently have a large spectrum of clinical phenotypes, even when caused by the same causative mutation/gene.…”

The Genetics of Usher Syndrome in the Israeli and Palestinian Populations

“…5 In addition, c.133G>T mutation in the ARSG gene was found recently to cause atypical USH in three Yemenite Jewish families. 25 The Israeli population consists of different ethnicities, including Jews, Christians, Muslims, Bedouins, and Druze; however, founder mutations causing different USH types have been reported in the Jewish population. The most common are a missense mutation (c.144T>G, p.N48K) in the CLRN1 gene and a nonsense mutation (c.733C>T, p.R245*) in the PCDH15 gene in Ashkenazi Jews, 26,27 as well as four USH2A mutations: a splicing mutation (c.12067-2A>G), a frameshift (p.T80fs*28), a nonsense mutation (c.2209C>T, p.R737*), and a missense mutation (c.1000C>T, p.R334W) in non-Ashkenazi Jews of various origins.…”