Powerful use of automated prioritization of candidate variants in genetic hearing loss with extreme etiologic heterogeneity

Variant prioritization of exome sequencing (ES) data for molecular diagnosis of sensorineural hearing loss (SNHL) with extreme etiologic heterogeneity poses a significant challenge. This study used an automated variant prioritization system (“EVIDENCE”) to analyze SNHL patient data and assess its diagnostic accuracy. We performed ES of 263 probands manifesting mild to moderate or higher degrees of SNHL. Candidate variants were classified according to the 2015 American College of Medical Genetics guidelines, and we compared the accuracy, call rates, and efficiency of variant prioritizations performed manually by humans or using EVIDENCE. In our in silico panel, 21 synthetic cases were successfully analyzed by EVIDENCE. In our cohort, the ES diagnostic yield for SNHL by manual analysis was 50.19% (132/263) and 50.95% (134/263) by EVIDENCE. EVIDENCE processed ES data 24-fold faster than humans, and the concordant call rate between humans and EVIDENCE was 97.72% (257/263). Additionally, EVIDENCE outperformed human accuracy, especially at discovering causative variants of rare syndromic deafness, whereas flexible interpretations that required predefined specific genotype–phenotype correlations were possible only by manual prioritization. The automated variant prioritization system remarkably facilitated the molecular diagnosis of hearing loss with high accuracy and efficiency, fostering the popularization of molecular genetic diagnosis of SNHL.

Genetic and Non Genetic Hearing Loss and Associated Disabilities: An Epidemiological Survey in Emilia-Romagna Region

Hearing loss is one of the most common congenital sensory disorders. It can be associated with several comorbidities, in particular developmental disabilities (DD). In Emilia-Romagna (ER), a region in Northern Italy, Child and Adolescent Mental Health Services (CAMHS) provide the diagnostic framework and treatment for these conditions. The aim of the present study is to evaluate the prevalence of hearing loss, both isolated or in association with comorbidities, in the juvenile population. The study draws its data from the ER Childhood and Adolescent Neuropsychiatry Information System (SINPIAER), an Administrative Healthcare Database collecting the clinical data of all those who have attended CAMHS since 2010. The most frequent type of hearing loss was bilateral sensorineural hearing loss, which was present in 69–72% of the cases, while bilateral conductive hearing loss was the second most common type, ranging from 8 to 10%. Among DD, congenital malformations, mental retardation, visual impairment, and cerebral palsy were the most common. In particular, autism spectrum disorders show increasing incidence and prevalence among CAMHS users in ER region. In-depth knowledge of hearing loss epidemiology and related conditions, such as developmental disabilities, in the juvenile population is crucial for disease prevention, health planning, and resource allocation.

A Novel Missense Variant in the ESRRB Gene Causing Nonsyndromic Hearing Loss: In Silico Analyses of a Case

Background: Genetic hearing loss (GHL) is a common heterogeneous disorder that can affect all ages, ethnicities, and genders. The most common form of hearing loss (HL) is autosomal recessive non-syndromic hearing loss (ARNSHL) and in most cases specific genotype-phenotype correlation is indistinguishable. This study aimed to identify the genetic cause of hearing loss in an Iranian Azeri Turkish ethnicity family with consanguine marriage which is negative for GJB2, GJB6 and mitochondrially encoded 12S RRNA (MT-RNR1) deleterious mutations.Methods: Targeted genome sequencing was applied for the detection of possible genetic causes of HL in this family. Co-segregation and in silico analysis of variant was performed by standard procedure.Results: A missense variant, c.499G>A, was identified in the ESRRB gene. Healthy and affected members of the family confirmed co-segregation of the variant with ARNSHL in the pedigree and then the pathogenicity of the variant was confirmed by in silico analysis and ACMG Guidelines. Conclusion: We report a novel missense variant in the ESRRB gene which seems to be a pathogenic variant. The result of this study suggests that the genetic background of hearing loss patients plays important role in the pathogenicity; moreover, targeted genomic capture is a powerful method that can discover pathogenic variants in heterogeneous disorders.

How Does the “Cookie-Bite” Audiogram Shape Perform in Discriminating Genetic Hearing Loss in Adults?

“Cookie-bite” or U-shaped audiograms—specifically, those showing midfrequency sensorineural hearing loss (HL)—are traditionally taught to be associated with genetic HL; however, their utility as a screening tool has not been reported. We aim to determine the performance of a cookie-bite audiogram shape in stratifying patients carrying putative loss-of-function variants in known HL genes from wild-type controls. We merged audiometric and exome sequencing data from adults enrolled in a large biobank at a tertiary care center. Of 321 patients, 50 carried a putative loss-of-function variant in an HL gene. The cookie-bite shape was present in 9 of those patients, resulting in low sensitivity (18%) and positive predictive value (15%) in stratifying genetic carrier status; 84% of patients with a cookie-bite audiogram did not carry a genetic variant. A cookie-bite audiogram should not be used to screen adults for possible genetic testing.

Inner Ear Gene Therapy in Mouse Models of Genetic Hearing Loss

Hearing loss is the most frequent sensory disorder affecting newborns and children. About 1 newborn in every 500 suffer from congenital hearing loss, with approximately half of these having a genetic cause. In the last few decades, the study of genetic hearing loss and related mouse models has unveiled molecular, cellular, and physiological mechanisms of the disease. In addition, effective and safe viral vectors for gene delivery to the inner ear have been generated. A growing number of approaches, including gene replacement, gene silencing, and gene editing, have proved effective in mouse models. This article briefly introduces basic strategies of gene therapy, viral vectors used and surgical methods for gene delivery, and reviews the current works on mouse modes of genetic hearing loss.