Targeted next-generation sequencing identifies a homozygous nonsense mutation in ABHD12, the gene underlying PHARC, in a family clinically diagnosed with Usher syndrome type 3

Abstract

BackgroundUsher syndrome (USH) is an autosomal recessive genetically heterogeneous disorder with congenital sensorineural hearing impairment and retinitis pigmentosa (RP). We have identified a consanguineous Lebanese family with two affected members displaying progressive hearing loss, RP and cataracts, therefore clinically diagnosed as USH type 3 (USH3). Our study was aimed at the identification of the causative mutation in this USH3-like family.MethodsCandidate loci were identified using genomewide SNP-array-based homozygosity mapping followed by targeted enrichment and next-generation sequencing.ResultsUsing a capture array targeting the three identified homozygosity-by-descent regions on chromosomes 1q43-q44, 20p13-p12.2 and 20p11.23-q12, we identified a homozygous nonsense mutation, p.Arg65X, in ABHD12 segregating with the phenotype.ConclusionMutations of ABHD12, an enzyme hydrolyzing an endocannabinoid lipid transmitter, cause PHARC (polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and early-onset cataract). After the identification of the ABHD12 mutation in this family, one patient underwent neurological examination which revealed ataxia, but no polyneuropathy. ABHD12 is not known to be related to the USH protein interactome. The phenotype of our patient represents a variant of PHARC, an entity that should be taken into account as differential diagnosis for USH3. Our study demonstrates the potential of comprehensive genetic analysis for improving the clinical diagnosis.

ABHD12 controls brain lysophosphatidylserine pathways that are deregulated in a murine model of the neurodegenerative disease PHARC

“…In 2010, PHARC was reported to be caused by homozygous mutations in ABHD12, which codes for the poorly characterized serine hydrolase enzyme α/β-hydrolase domain-containing (ABHD)12 (3). To date, five distinct ABHD12 mutations have been identified in patients with PHARC, all of which are expected to lead to complete loss of ABHD12 expression (3,4). PHARC, therefore, likely represents a human ABHD12 null model.…”

Next-generation whole-exome sequencing contribution to identification of rare autosomal recessive diseases

“…Retinitis pigmentosa (RP) is a heterogeneous group of (33), and Züchner and his team's work with the Ashkenazi Jewish family, which showed that the DHDDS gene also harbors retinitis pigmentosa causing mutation (34). Hearing diseases were also studied by exome sequencing including Usher, Perrault and Brown-Vialetto-van Laere syndromes, nonsyndromic hearing loss (11,(35)(36)(37)(38)(39). Usher syndrome is a retinitis pigmentosa syndromic form when a patient not only has a condition of vision loss, but also has hearing loss.…”

“…Usher syndrome is a retinitis pigmentosa syndromic form when a patient not only has a condition of vision loss, but also has hearing loss. With the help of homozygosity mapping and next-generation targeted exons sequencing in the Lebanese family which has Usher syndrome type 3 phenotype, causative mutation was found in AB-HD12 gene (35). Perrault and Brown-Vialetto-van Laere syndromes are two more examples of hearing disorders investigated by exome sequencing.…”

Challenges confronting precision medicine in the context of inherited retinal disorders

“…By testing a large number of genes known to cause retinal disorders, there have been numerous instances in which genetic mutations have been attributable to novel disease manifestations. [21][22][23] However, all of this genetic testing for numerous genes comes at a price as we acquire more information that is complicated to interpret and that challenges our ability to provide definitive answers to our patients.…”