A case of Usher syndrome type IIA caused by a rare USH2A homozygous frameshift variant with maternal uniparental disomy (UPD) in a Chinese family

Jiewen Fu,Hongbin Lv,Junjiang Fu,Shiyi Shen,Jingliang Cheng

doi:10.1111/jcmm.15405

Abstract

Usher syndrome encompasses a group of genetically and clinically heterogeneous autosomal recessive disorders with hearing deficiencies and retinitis pigmentosa. The mechanisms underlying the Usher syndrome are highly variable. In the present study, a Chinese family with Usher syndrome was recruited. Whole exome sequencing (WES), Sanger sequencing, homozygosity mapping, short tandem repeat (STR) analysis and segregation analysis were performed. Functional domains of the pathogenic variant for USH2A were analysed. We identified a homozygous frameshift variant c.99_100insT (p.Arg34Serfs*41) in the USH2A gene in the proband that showed discordant segregation in the father. Further homozygosity mapping and STR analysis identified an unusual homozygous variant of proband that originated from maternal uniparental disomy (UPD). The p.Arg34Serfs*41 variant produced a predicted truncated protein that removes all functional domains of USH2A. The variant was not included in the 1000 Human Genomes Project database, ExAC database, HGMD or gnomAD database, but was included in the ClinVar databases as pathogenic. Although USH2A is an autosomal recessive disease, the effects of UPD should be informed in genetic counselling since the recurrence risk of an affected child is greatly reduced when the disease is due to the UPD mechanism. To test potential patients, WES, combined with STR analysis and homozygosity mapping, provides an accurate and useful strategy for genetic diagnosis. In summary, our discoveries can help further the understanding of the molecular pathogenesis of Usher syndrome type IIA to advance the prevention, diagnosis and therapy for this disorder.

Highlights

Usher syndrome consists of a group of genetically and clinically heterogeneous autosomal recessive disorders with sensorineural hearing deficiencies and progressive retinitis pigmentosa (RP)
We identified a rare homozygous frameshift mutation in the gene USH2A that originated from maternal uniparental disomy (UPD) by whole exome sequencing (WES) and homozygosity mapping in a Chinese pedigree with Usher syndrome
The variant was not included in the 1000 Human Genome Project, ExAC, HGMD and gnomAD databases, but it was included in the database of ClinVar along with its pathogenicity[27] (Table. 2)

Summary

| INTRODUCTION

Usher syndrome consists of a group of genetically and clinically heterogeneous autosomal recessive disorders with sensorineural hearing deficiencies and progressive retinitis pigmentosa (RP). Diseases under the umbrella term Usher syndrome include Usher syndrome type I, II and III.[1,2]. Usher syndrome type IIA (USH2A locus, OMIM 276901) is caused by mutations of the USH2A gene (OMIM 608400).[3]. This gene maps to the chromosome 1q41 and encodes a protein containing 5202 amino acids that contain a pentaxin motif, laminin EGF motifs and numerous fibronectin type III domains.[4]. Detecting UPD is a practical diagnostic approach for rare Mendelian disorders and imprinting disorders caused by homozygosity.[7-9]. We identified a rare homozygous frameshift mutation in the gene USH2A that originated from maternal UPD by whole exome sequencing (WES) and homozygosity mapping in a Chinese pedigree with Usher syndrome

| MATERIALS AND METHODS

| DISCUSSION