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      Identification of a novel homozygous mutation in transmembrane channel like 1 ( TMC1) gene, one of the second-tier hearing loss genes after GJB2 in India

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          Abstract

          Background & objectives:

          Hearing impairment is a common and heterogeneous sensory disorder in humans. Among about 90 genes, which are known to be associated with hearing impairment, mutations in the GJB2 (gap junction protein beta 2) gene are the most prevalent in individuals with hereditary hearing loss. Contribution of the other deafness-causing genes is relatively poorly understood. Here, we present our findings on two families with transmembrane channel like 1 ( TMC1) gene variants of the 47 families with nonsyndromic hearing loss (NSHL) studied.

          Methods:

          Forty seven families including 26 consanguineous families with at least two hearing impaired children and one normal hearing child and 21 non-consanguineous families having at least three hearing impaired children and one normal hearing child were enrolled for this study. Genetic linkage studies were carried out in 41 families that were GJB2 (Connexin 26) negative. Seven polymorphic short tandem repeat markers at the DFNB7/11 locus were studied employing fluorescently labelled markers.

          Results:

          A novel homozygous missense mutation c.1283C>A (p.Ala428Asp) was identified co-segregating with hearing loss. This change results in substitution of a highly conserved polar alanine to a charged aspartic acid and is predicted to be deleterious. In addition, a previously reported nonsense mutation, p.R34X in TMC1, was found.

          Interpretation & conclusions:

          While mutations in TMC1 are not as common a cause of NSHL as those in GJB2, TMC1 should be considered for diagnostic investigations in cases of NSHL in GJB2-negative families.

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          Most cited references28

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          Origins and frequencies of SLC26A4 (PDS) mutations in east and south Asians: global implications for the epidemiology of deafness.

          Recessive mutations of SLC26A4 (PDS) are a common cause of Pendred syndrome and non-syndromic deafness in western populations. Although south and east Asia contain nearly one half of the global population, the origins and frequencies of SLC26A4 mutations in these regions are unknown. We PCR amplified and sequenced seven exons of SLC26A4 to detect selected mutations in 274 deaf probands from Korea, China, and Mongolia. A total of nine different mutations of SLC26A4 were detected among 15 (5.5%) of the 274 probands. Five mutations were novel and the other four had seldom, if ever, been identified outside east Asia. To identify mutations in south Asians, 212 Pakistani and 106 Indian families with three or more affected offspring of consanguineous matings were analysed for cosegregation of recessive deafness with short tandem repeat markers linked to SLC26A4. All 21 SLC26A4 exons were PCR amplified and sequenced in families segregating SLC26A4 linked deafness. Eleven mutant alleles of SLC26A4 were identified among 17 (5.4%) of the 318 families, and all 11 alleles were novel. SLC26A4 linked haplotypes on chromosomes with recurrent mutations were consistent with founder effects. Our observation of a diverse allelic series unique to each ethnic group indicates that mutational events at SLC26A4 are common and account for approximately 5% of recessive deafness in south Asians and other populations.
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            Nonsyndromic recessive deafness DFNB18 and Usher syndrome type IC are allelic mutations of USHIC.

            Human chromosome 11 harbors two Usher type I loci, USHIB and USHIC, which encode myosin VIIA and harmonin, respectively. The USHIC locus overlaps the reported critical interval for nonsyndromic deafness locus DFNB18. We found an IVS12+5G-->C mutation in the USHIC gene, which is associated with nonsyndromic recessive deafness ( DFNB18) segregating in the original family, S-11/12. No other disease-associated mutation was found in the other 27 exons or in the intron-exon boundaries, and the IVS12+5G-->C mutation was not present in 200 representative unaffected individuals ascertained from the same area of India. An exon-trapping assay with a construct harboring IVS12+5G-->C generated wildtype spliced mRNA having exons 11 and 12 and mRNA that skipped exon 12. We conclude that mutations of USHIC can cause both Usher syndrome type IC and nonsyndromic recessive deafness DFNB18.
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              The Colorado newborn hearing screening project, 1992-1999: on the threshold of effective population-based universal newborn hearing screening.

              Although previous studies have documented the feasibility and benefits of universal newborn hearing screening in selected hospitals, none have reviewed the effectiveness of regionally mandated participation of large numbers of hospitals with variable levels of motivation to succeed. The purpose of this study was to measure hospital participation and overall screening success in a statewide program for universal newborn hearing screening and to track improvements in program establishment and outpatient follow-up over time. Four Colorado hospitals began voluntarily performing hearing screening before hospital discharge on all newborns in 1992. By 1996, 26 Colorado hospitals were participating in universal newborn hearing screening. The publication of screening results from these early years served as a catalyst for legislation requiring increased hospital participation in establishing universal screening programs. Data systems were subsequently developed to improve statistical tracking and follow-up. Eight years' worth of cumulative study data as well as the results from calendar year 1999 (the year of greatest hospital participation) were reviewed for collective measures of successful screening and follow-up. Three hospitals did not initiate newborn hearing screening programs until after the study period ended in 1999. Of the 57 hospitals that were screening newborns in 1999, the chosen method of screening at 52 hospitals was automated auditory brainstem response testing; 3 hospitals used otoacoustic emission testing, and the remaining 2 hospitals used 2-stage screening. Hearing loss was defined as a threshold of 35 decibels or greater in 1 or both ears at the time of confirmatory testing. During the full 8-year study period, 1992 to 1999, 148 240 newborns were screened. A total of 291 infants who were born during the study period received a diagnosis of congenital hearing loss. In this cohort of 291 children, the cumulative frequency of bilateral hearing loss was 71% (range: 48%-94% by calendar year), the frequency of sensorineural hearing loss was 82% (range: 67%-88%), and the frequency of 1 or more risk factors was 47% (range: 37%-61%). During calendar year 1999, a total of 63 590 births were recorded at 60 birthing hospitals in Colorado. The families of 263 (0.4%) of these newborns refused newborn hearing screening. Of the remaining 63 327 newborns, 87% (55 324 infants) were screened for hearing acuity before hospital discharge, a far greater percentage than the 19% of all newborns screened during the first 5 years of voluntary hospital participation, and approaching the American Academy of Pediatrics's recommendation of 95% of newborns completing hospital-based testing in a successful screening program. As a result of this statewide hearing screening program, congenital hearing loss was diagnosed in 86 Colorado newborns during 1999, representing an occurrence rate of approximately 1 affected child in every 650 newborns. In this group of 86 infants, 59 had bilateral sensorineural hearing loss, 17 had unilateral sensorineural hearing loss, 4 had bilateral conductive hearing loss, and 6 had unilateral conductive hearing loss. Mild hearing loss was present in 6 infants, moderate hearing loss was present in 42 infants, severe hearing loss was present in 33 infants, and profound hearing loss was present in the remaining 5 infants. Only 32 of the 86 affected newborns in 1999 had 1 or more risk factors for hearing loss subsequently identified. After failing an initial hospital-based screening at 1 of the 57 participating hospitals in 1999, 2.3% of infants screened (1283 newborns) were referred for follow-up testing, easily exceeding the standard of <4% recommended by the American Academy of Pediatrics. Similarly, the false-positive rate of 2.2% during 1999 exceeded the recommended standard of <3%. Of the infants who failed their initial screening, 76% (978 infants) had documented follow-up testing to confirm or exclude congenital hearing loss, a percentage significantly improved from a follow-up rate of 48% during the first 5 years of screening, although not yet achieving the standard of 95% recommended by the American Academy of Pediatrics. Nine participating hospitals, however, were able to document appropriate follow-up for 95% or more of the infants who failed their initial screening tests. The median age of diagnosis of congenital hearing loss during 1999 was 2.1 months; 71% of affected infants were identified by 3 months of age (the recommended standard for age of diagnosis), and 92% of affected newborns were identified by 5 months of age. Measures of screening success were compared for large, mid-sized, and small hospitals. Increasing hospital size, as measured by the number of births per year, was associated with an increasing percentage of newborns who were successfully screened. It was notable that smaller hospital size was associated with increased referral rates for follow-up testing, whereas larger hospital size was associated with the highest recapture rate for follow-up testing. Universal screening for congenital hearing loss is demonstrated to be feasible in a large regional effort of legislatively mandated participation. The success of such an endeavor is dependent on educational efforts for community professionals, commitment on the part of program planners, and data systems that more accurately track and recall infants who fail initial hospital-based screening.
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                Author and article information

                Journal
                Indian J Med Res
                Indian J. Med. Res
                IJMR
                The Indian Journal of Medical Research
                Medknow Publications & Media Pvt Ltd (India )
                0971-5916
                April 2017
                : 145
                : 4
                : 492-497
                Affiliations
                [1 ] Division of Genetics, Department of Pediatrics, All Institute of Medical Sciences, New Delhi, India
                [2 ] Molecular Biology & Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bengaluru, India
                Author notes
                Reprint requests: Dr. Madhulika Kabra, Department of Pediatrics, Division of Genetics, All India Institute of Medical Sciences, New Delhi 110 029, India e-mail: madhulikakabra@ 123456hotmail.com
                Article
                IJMR-145-492
                10.4103/ijmr.IJMR_397_15
                5663163
                28862181
                83c5ea96-9122-4e7f-8b08-301d3e694567
                Copyright: © 2017 Indian Journal of Medical Research

                This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.

                History
                : 13 March 2015
                Categories
                Original Article

                Medicine
                dfnb7/11 locus,dna sequencing,hearing impairment,india,linkage study,short tandem repeat markers,transmembrane channel like 1 gene

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