A deep intronic CLRN1 (USH3A) founder mutation generates an aberrant exon and underlies severe Usher syndrome on the Arabian Peninsula

Khan, Arif O.; Becirovic, Elvir; Betz, Christian; Neuhaus, Christine; Altmüller, Janine; Riedmayr, Lisa Maria; Motameny, Susanne; Nürnberg, Gudrun; Nürnberg, Peter; Bolz, Hanno J.

doi:10.1038/s41598-017-01577-8

Cited by 38 publications

(31 citation statements)

References 54 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In patient 15DG2196, RD was found to be caused by a mutation in OAT . The diagnosis was revised to gyrate atrophy of choroid and retina prompting appropriate referral and dietary management . Lastly, in patient 12DG2155, we discovered a homozygous mutation in RPE65 making him eligible for treatment with voretigene neparvovec …”

Section: Resultsmentioning

confidence: 98%

Mutations in known disease genes account for the majority of autosomal recessive retinal dystrophies

Patel

Alkuraya²,

Alzahrani

et al. 2018

Clinical Genetics

View full text Add to dashboard Cite

Retinal dystrophies (RDs) are hereditary blinding eye conditions that are highly variable in their clinical presentation. The remarkable genetic heterogeneity that characterizes RD was a major challenge in establishing the molecular diagnosis in these patients until the recent advent of next-generation sequencing. It remains unclear, however, what percentage of autosomal recessive RD remain undiagnosed when all established RD genes are sequenced. We enrolled 75 families in which RD segregates in an apparently autosomal recessive manner. We show that the yield of a multigene panel that contains known RD genes is 67.5%. The higher yield (82.3%) when whole exome sequencing was implemented instead was often due to hits in genes that were not included in the original design of the panel. We also show the value of homozygosity mapping even during the era of exome sequencing in uncovering cryptic mutations. In total, we describe 45 unique likely deleterious variants (of which 18 are novel including one deep intronic and one genomic deletion mutation). Our study suggests that the genetic heterogeneity of autosomal recessive RD is approaching saturation and that any new RD genes will probably account for only a minor role in the mutation burden.

show abstract

Section: Resultsmentioning

confidence: 98%

Mutations in known disease genes account for the majority of autosomal recessive retinal dystrophies

Patel

Alkuraya²,

Alzahrani

et al. 2018

Clinical Genetics

View full text Add to dashboard Cite

show abstract

“…Very recently, however, by whole‐genome sequencing, we found evidence that a deep intronic founder mutation in CLRN1 may significantly contribute to USH1 on the Arabian Peninsula (Khan et al. ). Such recurrent “hidden” splice mutations should be considered at least in patients with the respective ethnic background.…”

Section: Discussionmentioning

confidence: 99%

Next-generation sequencing reveals the mutational landscape of clinically diagnosed Usher syndrome: copy number variations, phenocopies, a predominant target for translational read-through, andPEX26mutated in Heimler syndrome

Neuhaus¹,

Eisenberger²,

Decker³

et al. 2017

Mol Genet Genomic Med

Self Cite

View full text Add to dashboard Cite

BackgroundCombined retinal degeneration and sensorineural hearing impairment is mostly due to autosomal recessive Usher syndrome (USH1: congenital deafness, early retinitis pigmentosa (RP); USH2: progressive hearing impairment, RP).MethodsSanger sequencing and NGS of 112 genes (Usher syndrome, nonsyndromic deafness, overlapping conditions), MLPA, and array‐CGH were conducted in 138 patients clinically diagnosed with Usher syndrome.ResultsA molecular diagnosis was achieved in 97% of both USH1 and USH2 patients, with biallelic mutations in 97% (USH1) and 90% (USH2), respectively. Quantitative readout reliably detected CNVs (confirmed by MLPA or array‐CGH), qualifying targeted NGS as one tool for detecting point mutations and CNVs. CNVs accounted for 10% of identified USH2A alleles, often in trans to seemingly monoallelic point mutations. We demonstrate PTC124‐induced read‐through of the common p.Trp3955* nonsense mutation (13% of detected USH2A alleles), a potential therapy target. Usher gene mutations were found in most patients with atypical Usher syndrome, but the diagnosis was adjusted in case of double homozygosity for mutations in OTOA and NR2E3, genes implicated in isolated deafness and RP. Two patients with additional enamel dysplasia had biallelic PEX26 mutations, for the first time linking this gene to Heimler syndrome.ConclusionTargeted NGS not restricted to Usher genes proved beneficial in uncovering conditions mimicking Usher syndrome.

show abstract

“…One is spinal muscular atrophy with respiratory distress type 1 (SMARD1) [OMIM 604320] an autosomal recessive condition is characterized by severe neonatal polyneuropathy diaphragmatic weakness and respiratory failure in the first few years of life (Guenther et al., ). The other is CMT2S [OMIM 616155] which has a milder presentation with distal muscle atrophy, weakness with areflexia and relatively minor sensory involvement (Khan et al., ; Lim, Bowler, Lai, & Song, ; Liu et al., ; Noensie & Dietz, ). Poor genotype‐phenotype correlation has been reported between these clinical variants (Pedurupillay et al., ).…”

Section: Introductionmentioning

confidence: 99%

Whole genome sequencing reveals novel IGHMBP2 variant leading to unique cryptic splice‐site and Charcot‐Marie‐Tooth phenotype with early onset symptoms

Cassini

Duncan

Rives

et al. 2019

Molec Gen & Gen Med

View full text Add to dashboard Cite

Background Rare variants (RV) in immunoglobulin mu‐binding protein 2 (IGHMBP2) [OMIM 600502] can cause an autosomal recessive type of Charcot‐Marie‐Tooth (CMT) disease [OMIM 616155], an inherited peripheral neuropathy. Over 40 different genes are associated with CMT, with different possible inheritance patterns. Methods and Results An 11‐year‐old female with motor delays was found to have distal atrophy, weakness, and areflexia without bulbar or sensory findings. Her clinical evaluation was unrevealing. Whole exome sequencing (WES) revealed a maternally inherited IGHMBP2 RV (c.1730T>C) predicted to be pathogenic, but no variant on the other allele was identified. Deletion and duplication analysis was negative. She was referred to the Undiagnosed Disease Network (UDN) for further evaluation. Whole genome sequencing (WGS) confirmed the previously identified IGHMBP2 RV and identified a paternally inherited non‐coding IGHMBP2 RV. This was predicted to activate a cryptic splice site perturbing IGHMBP2 splicing. Reverse transcriptase polymerase chain reaction (RT‐PCR) analysis was consistent with activation of the cryptic splice site. The abnormal transcript was shown to undergo nonsense‐mediated decay (NMD), resulting in halpoinsufficiency. Conclusion This case demonstrates the deficiencies of WES and traditional molecular analyses and highlights the advantages of utilization of WGS and functional studies.

show abstract

A deep intronic CLRN1 (USH3A) founder mutation generates an aberrant exon and underlies severe Usher syndrome on the Arabian Peninsula

Cited by 38 publications

References 54 publications

Mutations in known disease genes account for the majority of autosomal recessive retinal dystrophies

Mutations in known disease genes account for the majority of autosomal recessive retinal dystrophies

Next-generation sequencing reveals the mutational landscape of clinically diagnosed Usher syndrome: copy number variations, phenocopies, a predominant target for translational read-through, andPEX26mutated in Heimler syndrome

Whole genome sequencing reveals novel IGHMBP2 variant leading to unique cryptic splice‐site and Charcot‐Marie‐Tooth phenotype with early onset symptoms

Contact Info

Product

Resources

About