Biallelic loss-of-function variants in NEMF cause central nervous system impairment and axonal polyneuropathy

A Splice-site Variant (C.3289-1G>T) in OTOF Underlies Profound Hearing Loss in a Pakistani Kindred

“…Subjects with intellectual disability showed axonal polyneuropathy and other physical features [16]. There were seven deaf patients (four males and three females) in this ve-generation pedigree.…”

“…Variants were called by GATK (version 3.5) and annotated by ANNOVAR (version 2015-06-17). We ltered WES data variants as the strategy in Ahmed et al [16] and excluded the variants with allele frequencies > 0.01 as reported in the GnomAD, Exome Aggregation Consortium (ExAC), 1000 Genome and ESP6500 databases. Missense mutations, nonsense mutations and splicing variants were evaluated.…”

A splice-site variant (c.3289-1G>T) in OTOF underlies profound hearing loss in a Pakistani kindred

“…The consanguineous family, recruited from rural suburbs in southern Pakistan, included the two phenotypes of intellectual disability and deafness, but none of the patients showed both phenotypes. Subjects with intellectual disability showed axonal polyneuropathy and other physical features [16]. There were seven deaf patients (four males and three females) in this five-generation pedigree.…”

“…Variants were called by GATK (version 3.5) and annotated by ANNOVAR (version 2015-06-17). We filtered WES data variants as the strategy in Ahmed et al [16] and excluded the variants with allele frequencies > 0.01 as reported in the GnomAD, Exome Aggregation Consortium (ExAC), 1000 Genome and ESP6500 databases. Missense mutations, nonsense mutations and splicing variants were evaluated.…”

“…After the filtering strategy was applied to the WES data (see Methods), 209 variants were found in the affected subject V-2, 210 in the affected subject V-11, and 193 in the unaffected subject IV- 16 CAG CAG CAG CAG CAG CAG C:p.C20delinsSSSSSSSC) were present in both affected subjects but not in the unaffected individual. The candidate gene OTOF has already been reported to be associated with a hearing loss phenotype matching this family's phenotype, and the allele frequency (NM_194248: c.3289-1G>T) is 0.000004 (allele count: 1 out of 249,936) according to the GnomAD databases.…”