Exome sequencing in infants with congenital hearing impairment: a population-based cohort study.
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ABSTRACT:
SUBMITTER: Downie L
PROVIDER: S-EPMC7171096 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The aetiology of congenital hearing loss is heterogeneous, and in many infants a genetic cause is suspected. Parents face a diagnostic odyssey when searching for a cause of their infant's hearing loss. Through the Melbourne Genomics Health Alliance, a prospective cohort of infants will be offered whole-exome sequencing (WES) with targeted analysis in conjunction with chromosome microarray to determine the genetic causes of congenital hearing loss. Parents will also be offered the opportunity to receive additional results from their infant's WES.Eligible infants will be identified through the Victorian Infant Hearing Screening Program and offered an appointment in a paediatrician-run clinic, a genetics assessment and enrolment in the Victorian Childhood Hearing Impairment Longitudinal Databank. If parents consent to WES, genes causing deafness will be analysed and they can choose to obtain additional findings. For the additional results component, a modified laboratory protocol has been designed for reporting of results in the absence of a relevant phenotype. Parents' experience of being offered WES will be evaluated using surveys.This project will provide descriptive analysis of the genetic aetiology of congenital hearing loss in this cohort and may provide data on genotype-phenotype correlations. Additionally, choices regarding additional findings will be analysed. Participants will represent a diverse cross section of the population, increasing the ability to generalise results beyond the study group. Evaluation surveys will allow analysis of preferences around counselling, usefulness of a decision aid and adequacy of information provision.
| S-EPMC5862171 | biostudies-literature
Project description:PurposeTo examine the associations of specific dietary fats with the risk of disabling hearing impairment in the UK Biobank study.MethodsThis cohort study investigated 105,592 participants (47,308 men and 58,284 women) aged ≥ 40 years. Participants completed a minimum of one valid 24-h recall (Oxford Web-Q). Dietary intake of total fatty acids, polyunsaturated fatty acids (PUFA), saturated fatty acids (SFA), and monounsaturated fatty acids (MUFA) was assessed at baseline. Functional auditory capacity was measured with a digit triplet test (DTT), and disabling hearing impairment was defined as a speech reception threshold in noise > - 3.5 dB in any physical exam performed during the follow-up.ResultsOver a median follow-up of 3.2 (SD: 2.1) years, 832 men and 872 women developed disabling hearing impairment. After adjustment for potential confounders, including lifestyles, exposure to high-intensity sounds, ototoxic medication and comorbidity, the hazard ratios (HRs), and 95% confidence interval (CI) of disabling hearing function, comparing extreme quintiles of intakes were 0.91 (0.71-1.17) for total fat, 1.09 (0.83-1.44) for PUFA, 0.85 (0.64-1.13) for SFA and 1.01 (0.74-1.36) for MUFA among men. Among women, HRs comparing extreme intakes were 0.98 (0.78-1.24) for total fat, 0.69 (0.53-0.91) for PUFA, 1.26 (0.96-1.65) for SFA, and 0.91 (0.68-1.23) for MUFA. Replacing 5% of energy intake from SFA with an equivalent energy from PUFA was associated with 25% risk reduction (HR: 0.75; 95% CI: 0.74-0.77) among women.ConclusionsPUFA intake was associated with decreased risk of disabling hearing function in women, but not in men.
| S-EPMC8783872 | biostudies-literature
Project description:We investigated hearing impairment (HI) in 51 families from Ghana with at least two affected members that were negative for GJB2 pathogenic variants. DNA samples from 184 family members underwent whole-exome sequencing (WES). Variants were found in 14 known non-syndromic HI (NSHI) genes [26/51 (51.0%) families], five genes that can underlie either syndromic HI or NSHI [13/51 (25.5%)], and one syndromic HI gene [1/51 (2.0%)]. Variants in CDH23 and MYO15A contributed the most to HI [31.4% (16/51 families)]. For DSPP, an autosomal recessive mode of inheritance was detected. Post-lingual expression was observed for a family segregating a MARVELD2 variant. To our knowledge, seven novel candidate HI genes were identified (13.7%), with six associated with NSHI (INPP4B, CCDC141, MYO19, DNAH11, POTEI, and SOX9); and one (PAX8) with Waardenburg syndrome. MYO19 and DNAH11 were replicated in unrelated Ghanaian probands. Six of the novel genes were expressed in mouse inner ear. It is known that Pax8-/- mice do not respond to sound, and depletion of Sox9 resulted in defective vestibular structures and abnormal utricle development. Most variants (48/60; 80.0%) have not previously been associated with HI. Identifying seven candidate genes in this study emphasizes the potential of novel HI genes discovery in Africa.
| S-EPMC9019055 | biostudies-literature
Project description:The purpose of this study is to evaluate the association between perinatal asphyxia, neonatal encephalopathy, and childhood hearing impairment. This is a population-based study including all Norwegian infants born ≥ 36 weeks gestation between 1999 and 2014 and alive at 2 years (n = 866,232). Data was linked from five national health registries with follow-up through 2019. Perinatal asphyxia was defined as need for neonatal intensive care unit (NICU) admission and an Apgar 5-min score of 4-6 (moderate) or 0-3 (severe). We coined infants with seizures and an Apgar 5-min score < 7 as neonatal encephalopathy with seizures. Infants who received therapeutic hypothermia were considered to have moderate-severe hypoxic-ischemic encephalopathy (HIE). The reference group for comparisons were non-admitted infants with Apgar 5-min score ≥ 7. We used logistic regression models and present data as adjusted odds ratios (aORs) with 95% confidence intervals (CI). The aOR for hearing impairment was increased in all infants admitted to NICU: moderate asphyxia aOR 2.2 (95% CI 1.7-2.9), severe asphyxia aOR 5.2 (95% CI 3.6-7.5), neonatal encephalopathy with seizures aOR 7.0 (95% CI 2.6-19.0), and moderate-severe HIE aOR 10.7 (95% CI 5.3-22.0). However, non-admitted infants with Apgar 5-min scores < 7 did not have increased OR of hearing impairment. The aOR for hearing impairment for individual Apgar 5-min scores in NICU infants increased with decreasing Apgar scores and was 13.6 (95% CI 5.9-31.3) when the score was 0. Conclusions: An Apgar 5-min score < 7 in combination with NICU admission is an independent risk factor for hearing impairment. Children with moderate-severe HIE had the highest risk for hearing impairment. What is Known: • Perinatal asphyxia and neonatal encephalopathy are associated with an increased risk of hearing impairment. • The strength of the association, and how other co-morbidities affect the risk of hearing impairment, is poorly defined. What is New: • Among neonates admitted to a neonatal intensive care unit (NICU), decreased Apgar 5-min scores, and increased severity of neonatal encephalopathy, were associated with a gradual rise in risk of hearing impairment. • Neonates with an Apgar 5-min score 7, but without NICU admission, did not have an increased risk of hearing impairment.
| S-EPMC10950958 | biostudies-literature
Project description:BackgroundHearing impairment (HI) genes are poorly studied in African populations.MethodsWe used whole exome sequencing (WES) to investigate pathogenic and likely pathogenic (PLP) variants in 10 individuals with HI, from four multiplex families from Cameroon, two of which were previously unresolved with a targeted gene enrichment (TGE) panel of 116 genes. In silico protein modelling, western blotting and live imaging of transfected HEK293 cells were performed to study protein structure and functions.ResultsAll PLP variants previously identified with TGE were replicated. In one previously unresolved family, we found a homozygous frameshift PLP variant in GRXCR2 (OMIM: 615762), NM_001080516.1(GRXCR2):c.251delC p.(Ile85SerfsTer33), in two affected siblings; and additionally, in 1/80 unrelated individuals affected with non-syndromic hearing impairment (NSHI). The GRXCR2-c.251delC variant introduced a premature stop codon, leading to truncation and loss of a zinc-finger domain. Fluorescence confocal microscopy tracked the wild-type GRXCR2 protein to the cellular membrane, unlike the mutated GRXCR2 protein.ConclusionThis study confirms GRXCR2 as a HI-associated gene. GRXCR2 should be included to the currently available TGE panels for HI diagnosis.
| S-EPMC8104159 | biostudies-literature
Project description:BackgroundHearing loss (HL) is a leading cause of disability worldwide, but its clinical consequences and population burden have been incompletely studied.MethodsWe did a retrospective population-based cohort study of 4,724,646 adults residing in Alberta between April 1, 2004 and March 31, 2019, of whom 152,766 (3.2%) had HL identified using administrative health data. We used administrative data to identify comorbidity and clinical outcomes, including death, myocardial infarction, stroke/transient ischemic attack, depression, dementia, placement in long-term care (LTC), hospitalization, emergency visits, pressure ulcers, adverse drug events and falls. We used Weibull survival models (binary outcomes) and negative binomial models (rate outcomes) to compare the likelihood of outcomes in those with vs without HL. We calculated population-attributable fractions to estimate the number of binary outcomes associated with HL.FindingsThe age-sex-standardized prevalence of all 31 comorbidities at baseline was higher among participants with HL than those without. Over median follow-up of 14.4 y and after adjustment for potential confounders at baseline, participants with HL had higher rates of days in hospital (rate ratio 1.65, 95% CI 1.39, 1.97), falls (RR 1.72, 95% CI 1.59, 1.86), adverse drug events (RR 1.40, 95% CI 1.35, 1.45), and emergency visits (RR 1.21, 95% CI 1.14, 1.28) compared to those without, and higher adjusted hazards of death, myocardial infarction, stroke/transient ischemic attack, depression, heart failure, dementia, pressure ulcers and LTC placement. The estimated number of people with HL who required new LTC placement annually in Canada was 15,631, of which 1023 were attributable to HL. Corresponding estimates for new dementia among people with HL were 14,959 and 4350, and for stroke/TIA the estimates were 11,582 and 2242.InterpretationHL is common, is often accompanied by substantial comorbidity, and is associated with significant increases in risk for a broad range of adverse clinical outcomes, some of which are potentially preventable. This high population health burden suggests that increased and coordinated investment is needed to improve the care of people with HL.FundingCanadian Institutes of Health Research; David Freeze chair in health services research.
| S-EPMC10331811 | biostudies-literature
Project description:Hearing impairment (HI) is genetically heterogeneous which hampers genetic counseling and molecular diagnosis. Testing of several single HI-related genes is laborious and expensive. In this study, we evaluate the diagnostic utility of whole-exome sequencing (WES) targeting a panel of HI-related genes. Two hundred index patients, mostly of Dutch origin, with presumed hereditary HI underwent WES followed by targeted analysis of an HI gene panel of 120 genes. We found causative variants underlying the HI in 67 of 200 patients (33.5%). Eight of these patients have a large homozygous deletion involving STRC, OTOA or USH2A, which could only be identified by copy number variation detection. Variants of uncertain significance were found in 10 patients (5.0%). In the remaining 123 cases, no potentially causative variants were detected (61.5%). In our patient cohort, causative variants in GJB2, USH2A, MYO15A and STRC, and in MYO6 were the leading causes for autosomal recessive and dominant HI, respectively. Segregation analysis and functional analyses of variants of uncertain significance will probably further increase the diagnostic yield of WES.
| S-EPMC5315517 | biostudies-literature
Project description:Autosomal recessive non-syndromic hearing loss (ARNSHL) is a public health concern in the Iranian population, with an incidence of 1 in 166 live births. In the present study, the whole exome sequencing (WES) method was applied to identify the mutation spectrum of NSHL patients negative for GJB2 gene mutations. First, using ARMS PCR followed by Sanger sequencing of the GJB2 gene, 63.15% of mutations in patients with NSHL were identified. Among the identified mutations in GJB2:p.Val43Met and p.Gly21Arg were novel. The remaining patients were subjected to WES, which identified novel mutations including MYO15A:p.Gly39LeufsTer188, ADGRV1:p.Ser5918ValfsTer23, MYO7A: c.5856+2T>c (splicing mutation), FGF3:p.Ser156Cys. The present study emphasized the application of WES as an effective method for molecular diagnosis of NSHL patients negative for GJB2 gene mutations in the Iranian population.
| S-EPMC10414579 | biostudies-literature
Project description:BackgroundCongenital cytomegalovirus (CMV) infection is the leading cause of sensorineural hearing loss (SNHL), and SNHL is the most frequent sequela of congenital CMV infection. But the pathogenic mechanism remains unknown, and there is no ideal CMV intrauterine infection animal model to study the mechanisms by which SNHL develops.MethodsWe established the congenital murine cytomegalovirus (MCMV) infection model by directly injecting the virus into the placenta on day 12.5 of gestation. Then, we observed the development and the MCMV congenital infection rate of the fetuses on the day they were born. Furthermore, we detected the auditory functions, the conditions of the MCMV infection, and the histological change of the inner ears of 28-day-old and 70-day-old offspring.ResultsBoth the fetal loss rate and the teratism rate of offspring whose placentas were inoculated with MCMV increased, and their body length, head circumference, and weight decreased. The hearing level of offspring both decreased at both 28- and 70-days post birth; the 70-day-old mice developed lower hearing levels than did the 28-day old mice. No significant inflammatory changes in the cochleae of the mice were observed. MCMV DNA signals were mainly detected in the spiral ganglion neurons and the endolymph area, but not in the perilymph area. The number of neurons decreased, and their ultrastructures changed. Moreover, with age, the number of neurons dramatically decreased, and the ultrastructural lesions of neurons became much more severe.ConclusionsThe results suggest that the direct injection of MCMV into the placenta may efficiently cause fetal infection and disturb the intrauterine development of the fetus, and placental inoculation itself has no obvious adverse effects on offspring. The reduction in the number of spiral ganglion neurons and the ultrastructural lesions of the neurons may be the major cause of congenital CMV infection-induced progressive SNHL.
| S-EPMC3045346 | biostudies-literature
Project description:BackgroundAn association between hearing impairment (HI) and congenital hypothyroidism (CH) has been reported previously. However, in general, studies were retrospective and had small sample sizes, and the results were variable and inconclusive. The aim of our study was to assess the prevalence of HI among patients with CH and to examine factors potentially predictive of HI including severity of CH, etiology of CH, and timing of treatment initiation.MethodsAudiometry was undertaken prospectively in 66 patients aged 3-21 years diagnosed with primary CH and 49 healthy matched controls. All patients with HI underwent examination by an otolaryngologist, and in patients with sensorineural loss, brainstem evoked response audiometry was performed. A next-generation sequencing (NGS) panel for genes involved in deafness was performed in patients with sensorineural HI to exclude additional genetic etiologies.ResultsHI was found in 19 patients (28.7%). Among them, 5 (7.6%) had moderate to severe bilateral sensorineural impairment and 14 (21.2%) had mild conductive HI. Conductive HI was bilateral in 5 of these patients (36%). None of the controls had HI. No specific etiology was found in patients with HI, and no differences were identified in age at diagnosis, age at initiation of levothyroxine (LT4) therapy, gender, or ethnicity between patients with and without HI. A nonsignificant trend toward lower mean screening TT4 levels was found in patients with HI (compared to those without HI) (3.42 vs. 5.34 μg/dL, p = 0.095). No pathogenic variants in genes attributed to HI were identified by NGS in the 5 patients with sensorineural deafness, indicating that HI in these patients was likely attributable to CH rather than other genetic etiologies.ConclusionsOur findings indicate a high prevalence of HI among patients with CH, predominantly of the conductive type. HI was not associated with the etiology of CH or with delayed initiation of LT4 therapy. Audiometry is recommended for children diagnosed with CH and repeat monitoring may be warranted to identify acquired HI and to prevent long-term sequelae of undiagnosed deafness.
| S-EPMC8216036 | biostudies-literature