A Large Genome-Wide Association Study of Age-Related Hearing Impairment Using Electronic Health Records.

Age-related hearing impairment (ARHI), one of the most common sensory disorders, can be mitigated, but not cured or eliminated. To identify genetic influences underlying ARHI, we conducted a genome-wide association study of ARHI in 6,527 cases and 45,882 controls among the non-Hispanic whites from the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort. We identified two novel genome-wide significant SNPs: rs4932196 (odds ratio = 1.

Harmonin (Ush1c) is required in zebrafish Müller glial cells for photoreceptor synaptic development and function.

Usher syndrome is the most prevalent cause of hereditary deaf-blindness, characterized by congenital sensorineural hearing impairment and progressive photoreceptor degeneration beginning in childhood or adolescence. Diagnosis and management of this disease are complex, and the molecular changes underlying sensory cell impairment remain poorly understood. Here we characterize two zebrafish models for a severe form of Usher syndrome, Usher syndrome type 1C (USH1C): one model is a mutant with a newly identified ush1c nonsense mutation, and the other is a morpholino knockdown of ush1c.

HPPD: A newly recognized autosomal dominant disorder involving hypertelorism, preauricular sinus, punctal pits, and deafness mapping to chromosome 14q31.

We report on a novel autosomal dominant disorder with variable phenotypic expression in a three-generation family; the major features include hypertelorism, preauricular sinus, deafness, and punctal pits with lacrimal-duct obstruction. We ruled out the involvement of EYA1, SIX1, and SIX5 as candidate genes by direct sequencing of their exons and by SNP-based linkage analysis. Subsequent SNP-based whole-genome genotyping and parametric multipoint linkage analysis gave lod scores >1 at 14q31 (LOD = 3.

Modification of depression by COMT val158met polymorphism in children exposed to early severe psychosocial deprivation.

Objective: To examine the impact of the catechol-O-methyltransferase (COMT) val(158)met allele on depressive symptoms in young children exposed to early severe social deprivation as a result of being raised in institutions.

Methods: One hundred thirty six children from the Bucharest Early Intervention Project (BEIP) were randomized before 31 months of age to either care as usual (CAU) in institutions or placement in newly created foster care (FCG). At 54 months of age, a psychiatric assessment using the Preschool Age Psychiatric Assessment (PAPA) was completed.

Deafness and retinal degeneration in a novel USH1C knock-in mouse model.

Usher syndrome is the leading cause of combined deaf-blindness, but the molecular mechanisms underlying the auditory and visual impairment are poorly understood. Usher I is characterized by profound congenital hearing loss, vestibular dysfunction, and progressive retinitis pigmentosa beginning in early adolescence. Using the c.

Multi-site diagnosis and management of 260 patients with auditory neuropathy/dys-synchrony (auditory neuropathy spectrum disorder).

Test results and management data are summarized for 260 patients with diagnoses of Auditory Neuropathy Spectrum Disorder (ANSD). Hearing aids were tried in 85 of these patients, and 49 patients tried cochlear implants. Approximately 15% reported some benefit from hearing aids for language learning, while improvement in speech comprehension and language acquisition was reported in 85% of patients who were implanted.

The role of the dopamine transporter (DAT) in the development of PTSD in preschool children.

Population-based association studies have supported the heritability of posttraumatic stress disorder (PTSD). This study explored the influence of genetic variation in the dopamine transporter (DAT) 3' untranslated region variable number tandem repeat on the development of PTSD in preschool children exposed to Hurricane Katrina, diagnosed using a developmentally appropriate semistructured interview. A diagnosis according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition , (DSM-IV; American Psychiatric Association, 1994), total symptoms, and specifically Criterion D symptoms were significantly more likely to be found in children with the 9 allele.

Ush1c216A knock-in mouse survives Katrina.

Usher syndrome is the most common cause of inherited deafness found in combination with blindness. All Usher patients suffer progressive retinitis pigmentosa, with the degree of hearing impairment and the presence or absence of vestibular function differing among subtypes. A cryptic splice site mutation (216G-->A) in exon 3 of the USH1C gene on chromosome 11p, which encodes a PDZ-domain protein, harmonin, was found in Acadian Usher type IC patients in south Louisiana.

Connexin 26 variants and auditory neuropathy/dys-synchrony among children in schools for the deaf.

Genetic and auditory studies of 731 children with severe-to-profound hearing loss in US schools for the deaf and 46 additional children receiving clinical services for hearing loss ranging from moderate to profound demonstrated that mutations in the connexin 26 (GJB2) and connexin 30 (GJB6) genes explain at least 12% of those with nonsyndromic sensorineural deafness. Otoacoustic emissions (OAEs) testing to detect functional outer hair cells indicated that 76 of the children had emissions and therefore may have (as yet unconfirmed) auditory neuropathy/dys-synchrony (AN/AD). Five of these children with OAEs were GJB2 homozygotes or compound heterozygotes with the genotypes 35delG/35delG, W77X/W77X, 35delG/360delGAG, 35delG/V95M, and V84M/M34T.

A dominantly inherited progressive deafness affecting distal auditory nerve and hair cells.

We have studied 72 members belonging to a large kindred with a hearing disorder inherited in an autosomal dominant pattern. We used audiological, physiological, and psychoacoustic measures to characterize the hearing disorders. The initial phenotypic features of the hearing loss are of an auditory neuropathy (AN) with abnormal auditory nerve and brainstem responses (ABRs) and normal outer hair cell functions [otoacoustic emissions (OAEs) and cochlear microphonics (CMs)].

The USH1C 216G-->A splice-site mutation results in a 35-base-pair deletion.

Usher syndrome is characterized by profound hearing loss and retinal degeneration. A splice-site mutation, 216G-->A, in exon 3 of USH1C is associated with Acadian Usher type IC. This mutation was reported to create an in-frame deletion of 39 base pairs (bp), resulting in an unstable transcript.

Outline of a medical genetics curriculum for internal medicine residency training programs.

To keep pace with the rapid advances in medical genetics, internal medicine residency training programs need to train internists to develop new attitudes, knowledge bases, and skill sets. Currently, such programs have no medical genetics curriculum. Thus, to set a minimum standard for genetics education in the context of training in internal medicine, the Internal Medicine Residency Training Program Genetics Curriculum Committee was formed, with members representing professional organizations of medical geneticists, internists, genetic counselors, internal medicine and genetics residency program directors, and internal medicine residents.

Replication-mediated instability of the GAA triplet repeat mutation in Friedreich ataxia.

Friedreich ataxia is caused by the expansion of a polymorphic and unstable GAA triplet repeat in the FRDA gene, but the mechanisms for its instability are poorly understood. Replication of (GAA*TTC)n sequences (9-105 triplets) in plasmids propagated in Escherichia coli displayed length- and orientation-dependent instability. There were small length variations upon replication in both orientations, but large contractions were frequently observed when GAA was the lagging strand template.

Chronic and recurrent otitis media: a genome scan for susceptibility loci.

Otitis media (OM) is the most common childhood disease. Almost all children experience at least one episode, but morbidity is greatest in children who experience chronic/recurrent OM (COME/ROM). There is mounting evidence that COME/ROM clusters in families and exhibits substantial heritability.

Genetic heterogeneity in Usher syndrome.

Mutations in seven different genes have been associated with Usher syndrome, and an additional four loci have been mapped. The identified genes encode myosin VIIa, harmonin (a PDZ-domain protein), cadherin 23, protocadherin 15, sans (a scaffold-like protein), usherin and clarin. Three clinical types of Usher syndrome have been described: USH1 patients have severe to profound congenital hearing loss, vestibular dysfunction, and retinal degeneration beginning in childhood, those with USH2 have moderate to severe congenital hearing loss, normal vestibular function, and later onset of retinitis pigmentosa, and USH3 patients have progressive hearing loss, which distinguishes them from the other two types.

Association of the T allele of an intronic single nucleotide polymorphism in the colony stimulating factor 1 receptor with Crohn's disease: a case-control study.

BACKGROUND: Polymorphisms in several genes (NOD2, MDR1, SLC22A4) have been associated with susceptibility to Crohn's disease. Identification of the remaining Crohn's susceptibility genes is essential for the development of disease-specific targets for immunotherapy. Using gene expression analysis, we identified a differentially expressed gene on 5q33, the colony stimulating factor 1 receptor (CSF1R) gene, and hypothesized that it is a Crohn's susceptibility gene.

Structure, diversity, and evolution of the 45-bp VNTR in intron 5 of the USH1C gene.

Usher syndrome type IC is a rare, autosomal recessive sensorineural disorder caused by mutations in the USH1C gene, which encodes a PDZ-domain protein named harmonin. The Acadian-specific 216G-->A mutation in exon 3 and a variant 9-repeat VNTR allele (designated VNTR(t,t)) in intron 5 are in complete linkage disequilibrium. (The usual form of the allele is referred to as VNTR(t).

Mouse tales from Kresge: the deafness mouse.

Mouse models for human deafness have not only proven instrumental in the identification of genes for hereditary hearing loss, but are excellent model systems in which to examine gene function as well as the resulting pathophysiology. One mouse model for human nonsyndromic deafness is the deafness (dn) mouse, a spontaneous mutation in the curly-tail (ct) stock. The dn gene is on mouse Chromosome 19 and it was recently shown to be a novel gene called Tmc1.

A novel mitochondrial tRNA(Leu(UUR)) mutation in a patient with features of MERRF and Kearns-Sayre syndrome.

In a patient with clinical features of both myoclonus epilepsy ragged-red fibers (MERRF) and Kearns-Sayre syndrome (KSS), we identified a novel guanine-to-adenine mitochondrial DNA (mtDNA) mutation at nucleotide 3255 (G3255A) of the tRNA(Leu(UUR)) gene. Approximately 5% of the skeletal muscle fibers had excessive mitochondria by succinate dehydrogenase histochemistry while a smaller proportion showed cytochrome c oxidase (COX) deficiency. In skeletal muscle, activities of mitochondrial respiratory chain complexes I, I + III, II + III, and IV were reduced.

Early childhood hearing loss: clinical and molecular genetics. An educational slide set of the American College of Medical Genetics.

An educational slide set entitled "Early Childhood Hearing Loss: Clinical and Molecular Genetics" is offered by the American College of Medical Genetics (ACMG). The slide set is produced in Microsoft PowerPoint 2002. It is extensively illustrated and supported with teaching tools, explanations of each slide and figure, links to Internet resources, and a bibliography.

Pathology and physiology of auditory neuropathy with a novel mutation in the MPZ gene (Tyr145->Ser).

We studied a family with hereditary sensory motor neuropathy and deafness accompanying a missense mutation in the MPZ gene. Pathological examination of the cochlea in one of the family members revealed marked loss of auditory ganglion cells and central and peripheral auditory nerve fibres within the cochlea. The inner hair cells were of normal number with preserved morphology.

Genes and syndromic hearing loss.

Unlabelled: Syndromes that are associated with hearing loss include Waardenburg, Stickler (STL), Jervell and Lange-Nielsen, Usher (USH), Alport, mitochondrial encephalomyopathy, lactic acidosis, stroke-like episodes, and sensorineural hearing loss (MELAS) and mitochondrial encephalomyopathy, myoclonus epilepsy, ragged-red fibers, and sensorineural hearing loss (MERRF). Waardenburg and STL show an autosomal dominant pattern of inheritance, while Jervell and Lange-Nielsen and USH are autosomal recessive, and Alport is usually X-linked. Mutations in specific genes that are associated with each of these syndromes have been identified, and genetic diagnostic tests are becoming available.

Dominant and recessive deafness caused by mutations of a novel gene, TMC1, required for cochlear hair-cell function.

Positional cloning of hereditary deafness genes is a direct approach to identify molecules and mechanisms underlying auditory function. Here we report a locus for dominant deafness, DFNA36, which maps to human chromosome 9q13-21 in a region overlapping the DFNB7/B11 locus for recessive deafness. We identified eight mutations in a new gene, transmembrane cochlear-expressed gene 1 (TMC1), in a DFNA36 family and eleven DFNB7/B11 families.