Objective: USH2A-related disorders are characterised by genetic and phenotypic heterogeneity, and are associated with a spectrum of sensory deficits, ranging from deaf blindness to blindness with normal hearing. It has been previously proposed that the presence of specific USH2A alleles can be predictive of unaffected hearing. This study reports the clinical and genetic findings in a group of patients with USH2A-related disease and evaluates the validity of the allelic hierarchy model. Patients and Intervention: USH2A variants from 27 adults with syndromic and nonsyndromic USH2A-related disease were analyzed according to a previously reported model of allelic hierarchy. The analysis was replicated on genotype–phenotype correlation information from 197 individuals previously reported in 2 external datasets. Main Outcome Measure: Genotype–phenotype correlations in USH2A-related disease. Results: A valid allelic hierarchy model was observed in 93% of individuals with nonsyndromic USH2A-retinopathy (n = 14/15) and in 100% of patients with classic Usher syndrome type IIa (n = 8/8). Furthermore, when two large external cohorts of cases were combined, the allelic hierarchy model was valid across 85.7% (n = 78/91) of individuals with nonsyndromic USH2A-retinopathy and 95% (n = 123/129) of individuals with classic Usher syndrome type II (p = 0.012, χ 2 test). Notably, analysis of all three patient datasets revealed that USH2A protein truncating variants were reported most frequently in individuals with hearing loss. Conclusion: Genetic testing results in individuals suspected to have an USH2A-related disorder have the potential to facilitate personalized audiological surveillance and rehabilitation pathways.
Over the past two decades, significant technological advances have facilitated the identification of hundreds of genes associated with hearing loss. Variants in many of these genes result in severe congenital hearing loss with profound implications for the affected individual and their family. This review collates these advances, summarizing the current state of genomic knowledge in childhood hearing loss. We consider how current and emerging genetic technologies have the potential to alter our approach to the management and diagnosis of hearing loss. We review approaches being taken to ensure that these discoveries are used in clinical practice to detect genetic hearing loss as soon as possible to reduce unnecessary investigations, provide information about reproductive risks, and facilitate regular follow-up and early treatment. We also highlight how rapid sequencing technology has the potential to identify children susceptible to antibiotic-induced hearing loss and how this adverse reaction can be avoided.
PurposeThe increased adoption of genomic strategies in the clinic makes it imperative for diagnostic laboratories to improve the efficiency of variant interpretation. Clinical exome sequencing (CES) is becoming a valuable diagnostic tool, capable of meeting the diagnostic demand imposed by the vast array of different rare monogenic disorders. We have assessed a clinician-led and phenotype-based approach for virtual gene panel generation for analysis of targeted CES in patients with rare disease in a single institution.MethodsRetrospective survey of 400 consecutive cases presumed by clinicians to have rare monogenic disorders, referred on singleton basis for targeted CES. We evaluated diagnostic yield and variant workload to characterise the usefulness of a clinician-led approach for generation of virtual gene panels that can incorporate up to three different phenotype-driven gene selection methods.ResultsAbnormalities of the nervous system (54.5%), including intellectual disability, head and neck (19%), skeletal system (16%), ear (15%) and eye (15%) were the most common clinical features reported in referrals. Combined phenotype-driven strategies for virtual gene panel generation were used in 57% of cases. On average, 7.3 variants (median=5) per case were retained for clinical interpretation. The overall diagnostic rate of proband-only CES using personalised phenotype-driven virtual gene panels was 24%.ConclusionsOur results show that personalised virtual gene panels are a cost-effective approach for variant analysis of CES, maintaining diagnostic yield and optimising the use of resources for clinical genomic sequencing in the clinic.
HARS2 encodes mitochondrial histidyl-tRNA synthetase (HARS2), which links histidine to its cognate tRNA in the mitochondrial matrix. Biallelic variants in HARS2 are associated with Perrault syndrome, a rare recessive condition characterized by sensorineural hearing loss in both sexes and primary ovarian insufficiency in 46,XX females. Some individuals with Perrault syndrome have a broader phenotypic spectrum with neurological features, including ataxia and peripheral neuropathy. Here, we report a recurrent variant in HARS2 in association with sensorineural hearing loss. In affected individuals from three unrelated families, the variant HARS2 c.1439G>A p.(Arg480His) is present as a heterozygous variant in trans to a putative pathogenic variant. The low prevalence of the allele HARS2 c.1439G>A p. (Arg480His) in the general population and its presence in three families with hearing loss, confirm the pathogenicity of this variant and illustrate the presentation of Perrault syndrome as nonsyndromic hearing loss in males and prepubertal females.
Congenital ear anomalies and hearing impairment are often present in patients with underlying genetic disorders. Germline genomic variants are responsible for at least 50% of congenital and/or childhoodonset sensorineural hearing loss (SNHL). Furthermore, 20%-60% of patients with bilateral microtia and congenital aural atresia may have an identifiable genetic syndrome. 1Standard diagnostic approaches involving single gene testing and chromosomal microarrays have limited utility in diagnosing monogenic conditions with high degrees of genetic and phenotypic heterogeneity. 2 Delay in confirming a genetic diagnosis can lead to incorrect diagnostic workup, uncertain prognosis, inadequate treatment, delayed referral to relevant medical subspecialties and lack of anticipation of potential additional comorbidities. The development of next-generation DNA sequencing (NGS) has contributed significantly to the diagnosis, study and care of Mendelian monogenic disorders. The capacity to perform simultaneous sequencing of multiple genomic regions makes NGS particularly appropriate for the investigation of genetically and clinically heterogeneous conditions, such as hereditary hearing loss. NGSbased-targeted gene panels and exome sequencing have become increasingly available for monogenic disorders. Reported diagnostic rates range between 20% and 50%, depending upon the patient cohort and the chosen testing platform. 3Next-generation sequencing approaches can lead to molecular diagnoses which can inform clinical decision-making. Clinical exome sequencing (CES) is therefore increasingly being used for testing patients with congenital ear anomalies and hearing disorders. [4][5][6] As the clinical availability of NGS increases, there is a need to evaluate its impact in routine practice. This study reports experience with CES in 60 consecutive patients with congenital ear or hearing disorders with a suspected genetic aetiology, to determine diagnostic yield and document the clinical implications.A search was conducted in the internal referral database identifying patients with phenotypes matching query terms (Table S1, supplemental material) that indicated the presence of hearing loss and/This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
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