Confirmation of COL4A6 variants in X-linked nonsyndromic hearing loss and its clinical implications.

Hearing loss (HL) is one of the most common sensory defects, of which X-linked nonsyndromic hearing loss (NSHL) accounts for only 1-2%. While a COL4A6 variant has been reported in a single Hungarian family with NSHL associated with inner ear malformation, causative role of COL4A6 variants and their phenotypic consequences in NSHL remain elusive. Here we report two families in which we identified a male member with X-linked HL.

Analyses of del(GJB6-D13S1830) and del(GJB6-D13S1834) deletions in a large cohort with hearing loss: Caveats to interpretation of molecular test results in multiplex families.

Background: Mutations involving the closely linked GJB2 and GJB6 at the DFNB1 locus are a common genetic cause of profound congenital hearing loss in many populations. In some deaf GJB2 heterozygotes, a 309 kb deletion involving the GJB6 has been found to be the cause for hearing loss when inherited in trans to a GJB2 mutation.

Methods: We screened 2,376 probands from a National DNA Repository of deaf individuals.

Loss of LDAH associated with prostate cancer and hearing loss.

Great strides in gene discovery have been made using a multitude of methods to associate phenotypes with genetic variants, but there still remains a substantial gap between observed symptoms and identified genetic defects. Herein, we use the convergence of various genetic and genomic techniques to investigate the underpinnings of a constellation of phenotypes that include prostate cancer (PCa) and sensorineural hearing loss (SNHL) in a human subject. Through interrogation of the subject's de novo, germline, balanced chromosomal translocation, we first identify a correlation between his disorders and a poorly annotated gene known as lipid droplet associated hydrolase (LDAH).

American College of Medical Genetics and Genomics guideline for the clinical evaluation and etiologic diagnosis of hearing loss.

Hearing loss is a common and complex condition that can occur at any age, can be inherited or acquired, and is associated with a remarkably wide array of etiologies. The diverse causes of hearing loss, combined with the highly variable and often overlapping presentations of different forms of hearing loss, challenge the ability of traditional clinical evaluations to arrive at an etiologic diagnosis for many deaf and hard-of-hearing individuals. However, identifying the etiology of a hearing loss may affect clinical management, improve prognostic accuracy, and refine genetic counseling and assessment of the likelihood of recurrence for relatives of deaf and hard-of-hearing individuals.

The clinical and audiologic features of hearing loss due to mitochondrial mutations.

Objectives: To characterize mitochondrial sequence variants present in a nationwide hereditary deafness DNA repository of samples from deaf subjects and to define the clinical presentation and audiometric characteristics of individuals with a mitochondrial sequence variant.

Study Design: Retrospective review of results for select mitochondrial mutations performed on DNA samples from subjects compiled from 1997 to 2009.

Setting: National hereditary deafness DNA repository.

Etiology of unilateral hearing loss in a national hereditary deafness repository.

Purpose: The aim of this study was to characterize the genetic, audiologic, and epidemiologic characteristics of unilateral hearing loss (HL) in a national hereditary deafness repository.

Materials And Methods: This is a prospective clinical study involving 34 subjects identified in a national hereditary deafness repository. Clinical data and family history of HL were obtained on enrollment.

Identification of p.A684V missense mutation in the WFS1 gene as a frequent cause of autosomal dominant optic atrophy and hearing impairment.

Optic atrophy (OA) and sensorineural hearing loss (SNHL) are key abnormalities in several syndromes, including the recessively inherited Wolfram syndrome, caused by mutations in WFS1. In contrast, the association of autosomal dominant OA and SNHL without other phenotypic abnormalities is rare, and almost exclusively attributed to mutations in the Optic Atrophy-1 gene (OPA1), most commonly the p.R445H mutation.

Vestibular dysfunction in DFNB1 deafness.

Mutations of GJB2 and GJB6 (connexin-26 and 30) at the DFNB1 locus are the most common cause of autosomal recessive, nonsyndromic deafness. Despite their widespread expression throughout the vestibular system, vestibular dysfunction has not been widely recognized as a commonly associated clinical feature. The observations of vertigo accompanying DFNB1 deafness in several large families prompted our hypothesis that vestibular dysfunction may be an integral, but often overlooked, component of DFNB1 deafness.

Fitness among individuals with early childhood deafness: Studies in alumni families from Gallaudet University.

The genetic fitness of an individual is influenced by their phenotype, genotype and family and social structure of the population in which they live. It is likely that the fitness of deaf individuals was quite low in the Western European population during the Middle Ages. The establishment of residential schools for deaf individuals nearly 400 years ago resulted in relaxed genetic selection against deaf individuals which contributed to the improved fitness of deaf individuals in recent times.

Provision of genetic services for hearing loss: results from a national survey and comparison to insights obtained from previous focus group discussions.

Hearing loss is a common sensory deficit and more than 50% of affected individuals have a genetic etiology. The discovery of 40 genes and more than 100 loci involved in hearing loss has made genetic testing for some of these genes widely available. Genetic services for deafness are also being sought more often due to the early identification of hearing loss through newborn screening services.

Impact of genetic advances and testing for hearing loss: results from a national consumer survey.

Hearing loss is a common neuro-sensory deficit; nearly 50% of children with hearing loss have a genetic etiology. With the discovery of 40 genes and more than 100 loci involved in hearing loss, genetic testing is becoming more widely available. The information obtained through genetic testing can be perceived and used in different ways by parents of deaf children and deaf adults, based on their prior knowledge and understanding of these advances.

Hypo-functional SLC26A4 variants associated with nonsyndromic hearing loss and enlargement of the vestibular aqueduct: genotype-phenotype correlation or coincidental polymorphisms?

Hearing loss with enlargement of the vestibular aqueduct (EVA) can be associated with mutations of the SLC26A4 gene encoding pendrin, a transmembrane Cl(-)/I(-)/HCO(3)(-) exchanger. Pendrin's critical transport substrates are thought to be I(-) in the thyroid gland and HCO(3)(-) in the inner ear. We previously reported that bi-allelic SLC26A4 mutations are associated with Pendred syndromic EVA whereas one or zero mutant alleles are associated with nonsyndromic EVA.

Phenotypic variability of patients homozygous for the GJB2 mutation 35delG cannot be explained by the influence of one major modifier gene.

Hereditary hearing loss (HL) is a very heterogeneous trait, with 46 gene identifications for non-syndromic HL. Mutations in GJB2 cause up to half of all cases of severe-to-profound congenital autosomal recessive non-syndromic HL, with 35delG being the most frequent mutation in Caucasians. Although a genotype-phenotype correlation has been established for most GJB2 genotypes, the HL of 35delG homozygous patients is mild to profound.

A comparative analysis of the genetic epidemiology of deafness in the United States in two sets of pedigrees collected more than a century apart.

In 1898, E.A. Fay published an analysis of nearly 5000 marriages among deaf individuals in America collected during the 19(th) century.

Ethical and social implications of genetic testing for communication disorders.

Unlabelled: Advances in genetics and genomics have quickly led to clinical applications to human health which have far-reaching consequences at the individual and societal levels. These new technologies have allowed a better understanding of the genetic factors involved in a wide range of disorders. During the past decade, incredible progress has been made in the identification of genes involved in the normal process of hearing.

Consumer motivations for pursuing genetic testing and their preferences for the provision of genetic services for hearing loss.

Genetic services for deafness are being increasingly sought due to the introduction of early hearing detection and intervention programs, as well as the rapid progress in the identification of deafness genes. This study aimed to assess the motivations of consumers for pursuing genetic testing as well as their preferences for provision of these services. We conducted 5 focus groups consisting of hearing parents of deaf children, deaf parents, and unmarried deaf adults.

Compound heterozygosity for dominant and recessive GJB2 mutations: effect on phenotype and review of the literature.

Mutations in GJB2 (which encodes the gap-junction protein connexin 26) are the most common cause of genetic deafness in many populations. To date, more than 100 deafness-causing mutations have been described in this gene. The majority of these mutations are inherited in an autosomal recessive manner, but approximately 19 GJB2 mutations have been associated with dominantly inherited hearing loss.

A focus group study of consumer attitudes toward genetic testing and newborn screening for deafness.

Purpose: Progress in identifying genes for deafness together with implementation of universal audiologic screening of newborns has provided the opportunity for more widespread use of molecular tests to detect genetic forms of hearing loss. Efforts to assess consumer attitudes toward these advances have lagged behind.

Methods: Consumer focus groups were held to explore attitudes toward genetic advances and technologies for hearing loss, views about newborn hearing screening, and reactions to the idea of adding molecular screening for hearing loss at birth.

Does universal newborn hearing screening identify all children with GJB2 (Connexin 26) deafness? Penetrance of GJB2 deafness.

Objective: Deafness is the most common neurosensory defect at birth, and GJB2 (connexin 26) mutations are the most frequent genetic cause of hearing loss in many populations. The hearing loss caused by GJB2 mutations is usually congenital in onset and moderate to profound in degree. Considerable phenotypic variation has been noted however, including two anecdotal cases of apparent non penetrance at birth.

Genetics content in the graduate audiology curriculum: a survey of academic programs.

Astounding progress has been made in the identification and characterization of genes for hearing loss, which has led to an increasing role of genetics evaluation and testing in the diagnostic process for children with hearing loss. The importance of health professionals such as audiologists gaining core competencies in genetics has been recognized. The current report describes a survey of academic programs in audiology designed to determine the extent to which genetics content is included in the curriculum.