Asunto(s)
Secuenciación del Exoma , Pérdida Auditiva/genética , Adolescente , Adulto , Anciano , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Persona de Mediana Edad , Mutación , Fenotipo , Estudios Retrospectivos , Encuestas y Cuestionarios , Adulto JovenRESUMEN
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 (nâ=â14/15) and in 100% of patients with classic Usher syndrome type IIa (nâ=â8/8). Furthermore, when two large external cohorts of cases were combined, the allelic hierarchy model was valid across 85.7% (nâ=â78/91) of individuals with nonsyndromic USH2A-retinopathy and 95% (nâ=â123/129) of individuals with classic Usher syndrome type II (pâ=â0.012, χ 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.
Asunto(s)
Síndromes de Usher , Adulto , Proteínas de la Matriz Extracelular/genética , Estudios de Asociación Genética , Genotipo , Humanos , Mutación , Síndromes de Usher/genéticaRESUMEN
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.
Asunto(s)
Aminoacil-ARNt Sintetasas/genética , Predisposición Genética a la Enfermedad , Pérdida Auditiva Sensorineural/genética , Histidina-ARNt Ligasa/genética , Alelos , Niño , Preescolar , Exoma/genética , Femenino , Disgenesia Gonadal 46 XX/genética , Disgenesia Gonadal 46 XX/fisiopatología , Pérdida Auditiva Sensorineural/fisiopatología , Heterocigoto , Homocigoto , Humanos , Lactante , Masculino , Mitocondrias/genética , Mutación Missense/genética , Linaje , Insuficiencia Ovárica Primaria/genética , Insuficiencia Ovárica Primaria/fisiopatologíaRESUMEN
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.