Hearing impairment is the most common sensory disorder, present in 1 of every 500 newborns. With 46 genes implicated in nonsyndromic hearing loss, it is also an extremely heterogeneous trait. Here, we categorize for the first time all mutations reported in nonsyndromic deafness genes, both worldwide and more specifically in Caucasians. The most frequent genes implicated in autosomal recessive nonsyndromic hearing loss are GJB2, which is responsible for more than half of cases, followed by SLC26A4, MYO15A, OTOF, CDH23 and TMC1. None of the genes associated with autosomal dominant nonsyndromic hearing loss accounts for a preponderance of cases, although mutations are somewhat more frequently reported in WFS1, KCNQ4, COCH and GJB2. Only a minority of these genes is currently included in genetic diagnostics, the selection criteria typically reflecting: (1) high frequency as a cause of deafness (i.e. GJB2); (2) association with another recognisable feature (i.e. SLC26A4 and enlarged vestibular aqueduct); or (3) a recognisable audioprofile (i.e. WFS1). New and powerful DNA sequencing technologies have been developed over the past few years, but have not yet found their way into DNA diagnostics. Implementing these technologies is likely to happen within the next 5 years, and will cause a breakthrough in terms of power and cost efficiency. It will become possible to analyze most – if not all – deafness genes, as opposed to one or a few genes currently. This ability will greatly improve DNA diagnostics, provide epidemiological data on gene-based mutation frequencies, and reveal novel genotype–phenotype correlations.

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Forty-six genes causing nonsyndromic hearing impairment: which ones should be analyzed in DNA diagnostics?

Autosomal dominant polycystic kidney disease (ADPKD) is heterogeneous with regard to genic and allelic heterogeneity, as well as phenotypic variability. The genotype-phenotype relationship in ADPKD is not completely understood. Here, we studied 741 patients with ADPKD from 519 pedigrees in the Genkyst cohort and confirmed that renal survival associated with PKD2 mutations was approximately 20 years longer than that associated with PKD1 mutations. The median age at onset of ESRD was 58 years for PKD1 carriers and 79 years for PKD2 carriers. Regarding the allelic effect on phenotype, in contrast to previous studies, we found that the type of PKD1 mutation, but not its position, correlated strongly with renal survival. The median age at onset of ESRD was 55 years for carriers of a truncating mutation and 67 years for carriers of a nontruncating mutation. This observation allows the integration of genic and allelic effects into a single scheme, which may have prognostic value.

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Type of PKD1 mutation influences renal outcome in ADPKD.

Congenital hearing loss (hearing loss that is present at birth) is one of the most prevalent chronic conditions in children. In the majority of developed countries, neonatal hearing screening programmes enable early detection; early intervention will prevent delays in speech and language development and has long-lasting beneficial effects on social and emotional development and quality of life. A diagnosis of hearing loss is usually followed by a search for an underlying aetiology. Congenital hearing loss might be attributed to environmental and prenatal factors, which prevail in low-income settings; congenital infections, particularly cytomegalovirus infection, are also a common risk factor for hearing loss. Genetic causes probably account for the majority of cases in developed countries; mutations can affect any component of the hearing pathway, in particular, inner ear homeostasis (endolymph production and maintenance) and mechano-electrical transduction (the conversion of a mechanical stimulus into electrochemical activity). Once the underlying cause of hearing loss is established, it might direct therapeutic decision making and guide prevention and (genetic) counselling. Management options include specific antimicrobial therapies, surgical treatment of craniofacial abnormalities and implantable or non-implantable hearing devices. An improved understanding of the pathophysiology and molecular mechanisms that underlie hearing loss and increased awareness of recent advances in genetic testing will promote the development of new treatment and screening strategies.

Congenital hearing loss.

BackgroundWhole-exome sequencing has transformed gene discovery and diagnosis in rare diseases. Translation into disease-modifying treatments is challenging, particularly for intellectual developmental disorder. However, the exception is inborn errors of metabolism, since many of these disorders are responsive to therapy that targets pathophysiological features at the molecular or cellular level. MethodsTo uncover the genetic basis of potentially treatable inborn errors of metabolism, we combined deep clinical phenotyping (the comprehensive characterization of the discrete components of a patient’s clinical and biochemical phenotype) with whole-exome sequencing analysis through a semiautomated bioinformatics pipeline in consecutively enrolled patients with intellectual developmental disorder and unexplained metabolic phenotypes. ResultsWe performed whole-exome sequencing on samples obtained from 47 probands. Of these patients, 6 were excluded, including 1 who withdrew from the study. The remaining 41 prob...

/pdf/exome-sequencing-and-the-management-of-neurometabolic-pej67u5e8u.pdf

Exome Sequencing and the Management of Neurometabolic Disorders

Objectives/Hypothesis

To perform a systematic review of GJB2-associated hearing loss to describe genotype distributions and auditory phenotype.



Data Sources

230 primary studies identified from Pubmed.



Review Methods

Pubmed was searched systematically to screen broadly for any study reporting on genotype and carrier frequencies for biallelic GJB2-associated hearing loss in defined populations around the world. Genotype and audiometric data were extracted and subjected to meta-analysis to determine genotype distributions, carrier frequencies, rates of asymmetric or progressive hearing loss, and imaging abnormalities.



Results

A total of 216 articles comprising over 43,000 hearing-loss probands were included. The prevalence of biallelic GJB2-associated hearing loss was consistent across most of the 63 countries examined, with different mutations being predominant in different countries. Common mutations were found in greater than 3% of the general population worldwide. Meta-analysis of 48 case-control studies demonstrated a two-fold higher carrier frequency among hearing-impaired individuals compared to normal-hearing controls for truncating alleles, but not V37I. Progression, asymmetry, and imaging abnormalities were present in 14% to 19% of individuals with GJB2-associated hearing loss.



Conclusion

GJB2 mutations are highly prevalent around the world. The multiple predominant mutations present in different populations attest to the importance of this gene for normal cochlear function and suggests an evolutionary heterozygote advantage. The unusually high carrier rate for truncating mutations among hearing-impaired individuals is consistent with either the presence of complementary mutations or a carrier phenotype. The significant rate of asymmetry and progression highlights the importance of diagnostic workup and close follow-up for this highly variable condition. Laryngoscope, 124:E34–E53, 2014

GJB2-associated hearing loss: systematic review of worldwide prevalence, genotype, and auditory phenotype

Hearing impairment (HI) affects 1 in 650 newborns, which makes it the most common congenital sensory impairment. Despite extraordinary genetic heterogeneity, mutations in one gene, GJB2, which encodes the connexin 26 protein and is involved in inner ear homeostasis, are found in up to 50% of patients with autosomal recessive nonsyndromic hearing loss. Because of the high frequency of GJB2 mutations, mutation analysis of this gene is widely available as a diagnostic test. In this study, we assessed the association between genotype and degree of hearing loss in persons with HI and biallelic GJB2 mutations. We performed cross-sectional analyses of GJB2 genotype and audiometric data from 1,531 persons, from 16 different countries, with autosomal recessive, mild-to-profound nonsyndromic HI. The median age of all participants was 8 years; 90% of persons were within the age range of 0-26 years. Of the 83 different mutations identified, 47 were classified as nontruncating, and 36 as truncating. A total of 153 different genotypes were found, of which 56 were homozygous truncating (T/T), 30 were homozygous nontruncating (NT/NT), and 67 were compound heterozygous truncating/nontruncating (T/NT). The degree of HI associated with biallelic truncating mutations was significantly more severe than the HI associated with biallelic nontruncating mutations (P<.0001). The HI of 48 different genotypes was less severe than that of 35delG homozygotes. Several common mutations (M34T, V37I, and L90P) were associated with mild-to-moderate HI (median 25-40 dB). Two genotypes--35delG/R143W (median 105 dB) and 35delG/dela(GJB6-D13S1830) (median 108 dB)--had significantly more-severe HI than that of 35delG homozygotes.

/pdf/gjb2-mutations-and-degree-of-hearing-loss-a-multicenter-5fetcfi198.pdf

Pascale Hilbert

Papers

GJB2 mutations and degree of hearing loss: a multicenter study.