scholarly journals Delineation of Homozygous Variants Associated with Prelingual Sensorineural Hearing Loss in Pakistani Families

Genes ◽  
2019 ◽  
Vol 10 (12) ◽  
pp. 1031 ◽  
Author(s):  
Muhammad Noman ◽  
Rafaqat Ishaq ◽  
Shazia A. Bukhari ◽  
Zubair M. Ahmed ◽  
Saima Riazuddin
Keyword(s):  
Hearing Loss ◽  
Sensorineural Hearing Loss ◽  
Sensorineural Hearing ◽  
Low Frequencies ◽  
Locus Heterogeneity ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
The Family ◽  
Novel Variants ◽  
Pakistani Families

Hearing loss is a genetically heterogeneous disorder affecting approximately 360 million people worldwide and is among the most common sensorineural disorders. Here, we report a genetic analysis of seven large consanguineous families segregating prelingual sensorineural hearing loss. Whole-exome sequencing (WES) revealed seven different pathogenic variants segregating with hearing loss in these families, three novel variants (c.1204G>A, c.322G>T, and c.5587C>T) in TMPRSS3, ESRRB, and OTOF, and four previously reported variants (c.208C>T, c.6371G>A, c.226G>A, and c.494C>T) in LRTOMT, MYO15A, KCNE1, and LHFPL5, respectively. All identified variants had very low frequencies in the control databases and were predicted to have pathogenic effects on the encoded proteins. In addition to being familial, we also found intersibship locus heterogeneity in the evaluated families. The known pathogenic c.226C>T variant identified in KCNE1 only segregates with the hearing loss phenotype in a subset of affected members of the family GCNF21. This study further highlights the challenges of identifying disease-causing variants for highly heterogeneous disorders and reports the identification of three novel and four previously reported variants in seven known deafness genes.

scholarly journals Recessive LOXHD1 Variants Cause a Milder Prelingual Hearing Loss: Genotype-Phenotype Correlation and Three Additional Patients With Novel Variants

2020 ◽  
Author(s):  
Sha Yu ◽  
Wen-xia Chen ◽  
Yun-Fei Zhang ◽  
Chao Chen ◽  
Yihua Ni ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Late Onset ◽  
Protein Domain ◽  
Low Frequencies ◽  
Genotype Combination ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
Splicing Variants ◽  
Novel Variants ◽  
Children With Hearing Loss

Abstract BackgroundBiallelic mutations in LOXHD1 have been identified as the cause of DFNB77 (deafness, autosomal recessive 77). It is a novel, progressive, severe-profound, and late-onset non-syndromic hearing loss, and is genetically and phenotypically highly heterogeneous. This study aimed to provide an additional three cases of DFNB77 to analyze this complex disease.MethodsWe presented three cases of pediatric patients with prelingual milder form of the DFNB77 with residual hearing at low frequencies. Trio whole-exome sequencing (WES) was conducted to identify the pathogenic variants. Additionally, we reviewed the literature to further analyze the relationships between the genotype and audiology phenotype of LOXHD1 worldwide.ResultsSix novel possible pathogenic LOXHD1 variants in three patients were identified by WES, including three missense, one nonsense, and two splicing variants. The literature review showed that 68.5% of DFNB77 patient onset before five years old; Most variants (60%) were associated with a milder phenotype, particularly variants in the protein domain of PLAT 7 and PLAT 9. We found that compared with homozygous LOXHD1 variants, individuals with heterozygous compound variants had a significantly milder phenotype, especially individuals carrying one missense and one splicing or bi-allelic missense variants (P <0.05). Audiometric analysis at different ages showed that the hearing loss degree was aggravated at all frequencies in adulthood and more severe in elderhood.ConclusionsWe report three children with hearing loss carrying six novel LOXHD1 variants identified by WES. Furthermore, our work indicates that DFNB77 may be milder than previously reported, and recommends considering the genotype combination and mutation location of LOXHD1 and race-specificity in DFNB77 molecular diagnoses and management.

scholarly journals Identification of Hearing Loss-Associated Variants of PTPRQ, MYO15A, and SERPINB6 in Pakistani Families

2021 ◽  
Vol 2021 ◽  
pp. 1-6
Author(s):  
Umair Mahmood ◽  
Shazia A. Bukhari ◽  
Muhammad Ali ◽  
Zubair M. Ahmed ◽  
Saima Riazuddin
Keyword(s):  
Hearing Loss ◽  
Molecular Modeling ◽  
Inner Ear ◽  
Missense Variant ◽  
Clinical History ◽  
Low Frequencies ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
The Impact ◽  
Pakistani Families

The inner ear is an essential part of a well-developed and well-coordinated hearing system. However, hearing loss can make communication and interaction more difficult. Inherited hearing loss (HL) can occur from pathogenic genetic variants that negatively alter the intricate inner ear sensory mechanism. Recessively inherited forms of HL are highly heterogeneous and account for a majority of prelingual deafness. The current study is designed to investigate genetic causes of HL in three consanguineous Pakistani families. After IRB approval, the clinical history and pure tone audiometric data was obtained for the clinical diagnosis of HL segregating in these three Pakistani families. We performed whole exome sequencing (WES) followed by Sanger sequencing in order to identify and validate the HL-associated pathogenic variants, respectively. The 3-D molecular modeling and the Ramachandran analysis of the identified missense variants were compiled to evaluate the impact of the variants on the encoded proteins. Clinical evaluation revealed prelingual severe to profound sensorineural HL segregating among the affected individuals in all three families. Genetic analysis revealed segregation of several novel variants associated with HL, including a canonical splice-site variant (c.55-2A>G) of PTPRQ in family GCFHL-01, a missense variant [c.1079G>A; p.(Arg360Gln)] of SERPINB6 in family LUHL-01, and an insertion variant (c.10208-10211insCCACCAGGCCCGTGCCTC) within MYO15A in family LUHL-011. All the identified variants had very low frequencies in the control databases. The molecular modeling of p.Arg360Gln missense variant also predicted impaired folding of SERPINB6 protein. This study reports the identification of novel disease-causing variants in three known deafness genes and further highlights the genetic heterogeneity of HL in Pakistani population.

scholarly journals Whole exome sequencing identifies TRIOBP pathogenic variants as a cause of post-lingual bilateral moderate-to-severe sensorineural hearing loss

2017 ◽  
Vol 18 (1) ◽  
Author(s):  
Agnieszka Pollak ◽  
Urszula Lechowicz ◽  
Victor Abel Murcia Pieńkowski ◽  
Piotr Stawiński ◽  
Joanna Kosińska ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Sensorineural Hearing Loss ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Sensorineural Hearing ◽  
Pathogenic Variants ◽  
Whole Exome

Identification of two novel variants in GAA underlying infantile-onset Pompe disease in two Pakistani families

2020 ◽  
Vol 33 (4) ◽  
pp. 553-556
Author(s):  
Aman Ullah ◽  
Bibi Zubaida ◽  
Huma Arshad Cheema ◽  
Muhammad Naeem
Keyword(s):  
Pompe Disease ◽  
Age Of Onset ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
Sequence Variations ◽  
Heterozygous Variant ◽  
Novel Variants ◽  
Carrier Identification ◽  
First Time ◽  
Pakistani Families

AbstractBackgroundPompe disease (PD) is an autosomal recessive metabolic myopathy with an average incidence of one in 40,000 live births. It has a variable age of onset and can be diagnosed within the first 3 months. Heart involvement and muscle weakness are its primary manifestations.Case presentationWe describe two families affected by PD with two rare, novel variants. To date, pathogenic variants in acid α-glucosidase (GAA) alone have accounted for all cases of the disease. Both families were screened for pathogenic sequence variations. This study presents the implications of regulatory or modifier sequences in the disease pathogenesis for the first time. A homozygous missense p.Arg854Gln variant in family A and a single heterozygous variant (p.Asn925His) in family B were found to be segregating according to the disease phenotype. The variants were not detected in our in-house database comprising 50 whole-exome sequences of healthy individuals from a local unrelated Pakistani population. In silico analyses predicted that the variants would have deleterious effects on the protein structure.ConclusionsThe variants likely underlie the infantile-onset PD (IOPD) in these Pakistani families. The study expands the mutation spectrum of GAA associated with IOPD and highlights the insufficiency of screening the GAA coding sequence to determine the cause of IOPD. The work should be helpful in carrier identification, improving genetic counselling, and prenatal diagnosis.

scholarly journals Effects of Various Extents of High-Frequency Hearing Loss on Speech Recognition and Gap Detection at Low Frequencies in Patients with Sensorineural Hearing Loss

2017 ◽  
Vol 2017 ◽  
pp. 1-9
Author(s):  
Bei Li ◽  
Yang Guo ◽  
Guang Yang ◽  
Yanmei Feng ◽  
Shankai Yin
Keyword(s):  
Hearing Loss ◽  
Speech Recognition ◽  
Sensorineural Hearing Loss ◽  
High Frequency ◽  
Hearing Threshold ◽  
Sensorineural Hearing ◽  
Gap Detection ◽  
Detection Thresholds ◽  
Low Frequencies ◽  
Compressed Speech

This study explored whether the time-compressed speech perception varied with the degree of hearing loss in high-frequency sensorineural hearing loss (HF SNHL) individuals. 65 HF SNHL individuals with different cutoff frequencies were recruited and further divided into mildly, moderately, and/or severely affected subgroups in terms of the averaged thresholds of all frequencies exhibiting hearing loss. Time-compressed speech recognition scores under both quiet and noisy conditions and gap detection thresholds within low frequencies that had normal thresholds were obtained from all patients and compared with data from 11 age-matched individuals with normal hearing threshold at all frequencies. Correlations of the time-compressed speech recognition scores with the extents of HF SNHL and with the 1 kHz gap detection thresholds were studied across all participants. We found that the time-compressed speech recognition scores were significantly affected by and correlated with the extents of HF SNHL. The time-compressed speech recognition scores also correlated with the 1 kHz gap detection thresholds except when the compression ratio of speech was 0.8 under quiet condition. Above all, the extents of HF SNHL were significantly correlated with the 1 kHz gap thresholds.

Localization and Spatial Discrimination in Children and Adolescents with Moderate Sensorineural Hearing Loss Tested without Their Hearing Aids

2017 ◽  
Vol 22 (6) ◽  
pp. 326-342 ◽  
Author(s):  
Sylvia Meuret ◽  
Alexandra Annemarie Ludwig ◽  
Dorothee Predel ◽  
Burkhard Staske ◽  
Michael Fuchs
Keyword(s):  
Hearing Loss ◽  
Sensorineural Hearing Loss ◽  
Children And Adolescents ◽  
Hearing Aids ◽  
Normal Hearing ◽  
Sensorineural Hearing ◽  
Spatial Discrimination ◽  
Frequency Noise ◽  
Low Frequencies ◽  
Hearing Children

The present study investigated two measures of spatial acoustic perception in children and adolescents with sensorineural hearing loss (SNHL) tested without their hearing aids and compared it to age-matched controls. Auditory localization was quantified by means of a sound source identification task and auditory spatial discrimination acuity by measuring minimum audible angles (MAA). Both low- and high-frequency noise bursts were employed in the tests to separately address spatial auditory processing based on interaural time and intensity differences. In SNHL children, localization (hit accuracy) was significantly reduced compared to normal-hearing children and intraindividual variability (dispersion) considerably increased. Given the respective impairments, the performance based on interaural time differences (low frequencies) was still better than that based on intensity differences (high frequencies). For MAA, age-matched comparisons yielded not only increased MAA values in SNHL children, but also no decrease with increasing age compared to normal-hearing children. Deficits in MAA were most apparent in the frontal azimuth. Thus, children with SNHL do not seem to benefit from frontal positions of the sound sources as do normal-hearing children. The results give an indication that the processing of spatial cues in SNHL children is restricted, which could also imply problems regarding speech understanding in challenging hearing situations.

scholarly journals Two novel likely pathogenic variants of HARS2 identified in a Chinese family with sensorineural hearing loss

Hereditas ◽  
2020 ◽  
Vol 157 (1) ◽  
Author(s):  
Jing Yu ◽  
Wei Jiang ◽  
Li Cao ◽  
Xiaoxue Na ◽  
Jiyun Yang
Keyword(s):  
Hearing Loss ◽  
Sensorineural Hearing Loss ◽  
Motor Development ◽  
Sensorineural Hearing ◽  
Chinese Family ◽  
Targeted Next Generation Sequencing ◽  
Gross Motor Development ◽  
Pathogenic Variants ◽  
Perrault Syndrome ◽  
Ear Malformations

AbstractMutations in HARS2 are one of the genetic causes of Perrault syndrome, characterized by sensorineural hearing loss (SNHL) and ovarian dysfunction. Here, we identified two novel putative pathogenic variants of HARS2 in a Chinese family with sensorineural hearing loss including two affected male siblings, c.349G > A (p.Asp117Asn) and c.908 T > C (p.Leu303Pro), through targeted next-generation sequencing methods. The two affected siblings (13 and 11 years old) presented with early-onset, rapidly progressive SNHL. The affected siblings did not have any inner ear malformations or delays in gross motor development. Combined with preexisting clinical reports, Perrault syndrome may be latent in some families with non-syndromic deafness associated with HARS2 mutations. The definitive diagnosis of Perrault syndrome based on clinical features alone is a challenge in sporadic males, and preadolescent females with no signs of POI. Our findings further expanded the existing spectrum of HARS2 variants and Perrault syndrome phenotypes, which will assist in molecular diagnosis and genetic counselling of patients with HARS2 mutations.

Autosomal-Dominant Progressive Sensorineural Hearing Loss in a Large North American Family

1996 ◽  
Vol 5 (1) ◽  
pp. 105-111 ◽  
Author(s):  
Chris Halpin ◽  
Umang Khetarpal ◽  
Michael McKenna
Keyword(s):  
Hearing Loss ◽  
Sensorineural Hearing Loss ◽  
North American ◽  
Autosomal Dominant ◽  
Family Members ◽  
Sensorineural Hearing ◽  
American Family ◽  
Dominant Mutation ◽  
The Family ◽  
Temporal Bones

Forty-nine members of a family with autosomal-dominant progressive sensorineural hearing loss were evaluated by audiologists, otologists, and geneticists. The results presented here show a nonsyndromic, autosomal-dominant mutation causing progressive sensorineural hearing loss beginning at about age 20 and becoming profound by approximately age 45. Because of the unambiguous nature of the hearing loss, the size of the family, and the availability of two previously described temporal bones from family members, a fairly complete description of the nature and impact of this mutation will be presented.

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