scholarly journals Identification of Novel CDH23 Variants Causing Moderate to Profound Progressive Nonsyndromic Hearing Loss

Genes ◽  
2020 ◽  
Vol 11 (12) ◽  
pp. 1474
Author(s):  
Khushnooda Ramzan ◽  
Nouf S. Al-Numair ◽  
Sarah Al-Ageel ◽  
Lina Elbaik ◽  
Nadia Sakati ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Phenotypic Variability ◽  
Usher Syndrome ◽  
Three Dimensional ◽  
Homozygosity Mapping ◽  
Dimensional Structure ◽  
Molecular Testing ◽  
Compound Heterozygous ◽  
Nonsyndromic Hearing Loss ◽  
Missense Variants

Mutant alleles of CDH23, a gene that encodes a putative calcium-dependent cell-adhesion glycoprotein with multiple cadherin-like domains, are responsible for both recessive DFNB12 nonsyndromic hearing loss (NSHL) and Usher syndrome 1D (USH1D). The encoded protein cadherin 23 (CDH23) plays a vital role in maintaining normal cochlear and retinal function. The present study’s objective was to elucidate the role of DFNB12 allelic variants of CDH23 in Saudi Arabian patients. Four affected offspring of a consanguineous family with autosomal recessive moderate to profound NSHL without any vestibular or retinal dysfunction were investigated for molecular exploration of genes implicated in hearing impairment. Parallel to this study, we illustrate some possible pitfalls that resulted from unexpected allelic heterogeneity during homozygosity mapping due to identifying a shared homozygous region unrelated to the disease locus. Compound heterozygous missense variants (p.(Asp918Asn); p.(Val1670Asp)) in CDH23 were identified in affected patients by exome sequencing. Both the identified missense variants resulted in a substitution of the conserved residues and evaluation by multiple in silico tools predicted their pathogenicity and variable disruption of CDH23 domains. Three-dimensional structure analysis of human CDH23 confirmed that the residue Asp918 is located at a highly conserved DXD peptide motif and is directly involved in “Ca2+” ion contact. In conclusion, our study identifies pathogenic CDH23 variants responsible for isolated moderate to profound NSHL in Saudi patients and further highlights the associated phenotypic variability with a genotypic hierarchy of CDH23 mutations. The current investigation also supports the application of molecular testing in the clinical diagnosis and genetic counseling of hearing loss.

scholarly journals Association of a novel missense mutation in MYO15A with nonsyndromic hearing loss: a case report

2020 ◽  
Author(s):  
Siji Wang ◽  
Ziqi Chen ◽  
Jiaqiu Dai ◽  
Xi Ouyang ◽  
Lin Zhu ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Missense Mutation ◽  
Sanger Sequencing ◽  
Three Dimensional ◽  
Sensorineural Deafness ◽  
Chinese Family ◽  
Common Disease ◽  
Compound Heterozygous ◽  
Nonsyndromic Hearing Loss ◽  
Genetic Sequencing

Abstract Background Hearing loss is a common disease globally, and more than 50% of the cases are genetic. Autosomal recessive nonsyndromic hearing loss (ARNSHL) is one of the most common types of hereditary hearing loss. Here, a novel MYO15A missense mutation was identified in a Chinese family with ARNSHL, using targeted genetic sequencing and Sanger sequencing. Case presentation: A 6-year-old girl with congenital nonsyndromic sensorineural deafness was presented from the First Affiliated hospital of Chongqing Medical University, China. We used targeted region sequencing, Sanger sequencing, functional prediction, and three-dimensional protein structure modeling to identify and verify the genes responsible for deafness in the family. Conclusions We found pathogenic compound heterozygous mutations in MYO15A, including a novel missense mutation, c.6353T > C (p.Leu2118Pro). It could provide help not only for genetic counseling but also for further understanding of the functional role of MYO15A mutations.

scholarly journals A novel compound heterozygous mutation of SLC26A4 in two Chinese families with nonsyndromic hearing loss and enlarged vestibular aqueducts

2017 ◽  
Vol 16 (6) ◽  
pp. 9011-9016 ◽  
Author(s):  
Guang-Jie Zhu ◽  
Lu-Sen Shi ◽  
Han Zhou ◽  
Ye Yang ◽  
Jie Chen ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Compound Heterozygous Mutation ◽  
Heterozygous Mutation ◽  
Compound Heterozygous ◽  
Nonsyndromic Hearing Loss ◽  
Chinese Families

scholarly journals Mechanisms of Congenital Myasthenia Caused by Three Mutations in the COLQ Gene

2021 ◽  
Vol 9 ◽  
Author(s):  
Xiaona Luo ◽  
Chunmei Wang ◽  
Longlong Lin ◽  
Fang Yuan ◽  
Simei Wang ◽  
...  
Keyword(s):  
Missense Mutation ◽  
Neuromuscular Junctions ◽  
Three Dimensional ◽  
Missense Variant ◽  
Homozygous Deletion ◽  
Dimensional Structure ◽  
Compound Heterozygous ◽  
Splicing Mutation ◽  
Gene Encoding ◽  
Congenital Myasthenia

The gene encoding collagen like tail subunit of asymmetric acetylcholinesterase (COLQ) is responsible for the transcription of three strands of collagen of acetylcholinesterase, which is attached to the endplate of neuromuscular junctions. Mutations in the COLQ gene are inherited in an autosomal-recessive manner and can lead to type V congenital myasthenia syndrome (CMS), which manifests as decreased muscle strength at birth or shortly after birth, respiratory failure, restricted eye movements, drooping of eyelids, and difficulty swallowing. Here we reported three variants within COLQ in two unrelated children with CMS. An intronic variant (c.393+1G>A) and a novel missense variant (p.Q381P) were identified as compound heterozygous in a 13-month-old boy, with the parents being carriers of each. An intragenic deletion including exons 14 and 15 was found in a homozygous state in a 12-year-old boy. We studied the relative expression of the COLQ and AChE gene in the probands' families, performed three-dimensional protein structural analysis, and analyzed the conservation of the missense mutation c.1142A>C (p.Q381P). The splicing mutation c.393+1G>A was found to affect the normal splicing of COLQ exon 5, resulting in a 27-bp deletion. The missense mutation c.1142A>C (p.Q381P) was located in a conserved position in different species. We found that homozygous deletion of COLQ exons 14–15 resulted in a 241-bp deletion, which decreased the number of amino acids and caused a frameshift translation. COLQ expression was significantly lower in the probands than in the probands' parents and siblings, while AChE expression was significantly higher. Moreover, the mutations were found to cause significant differences in the predicted three-dimensional structure of the protein. The splicing mutation c.393+1G>A, missense mutation c.1A>C (p.Q381P), and COLQ exon 14–15 deletion could cause CMS.

Homozygosity mapping identifies a novel GIPC3 mutation causing congenital nonsyndromic hearing loss in a Saudi family

Gene ◽  
2013 ◽  
Vol 521 (1) ◽  
pp. 195-199 ◽  
Author(s):  
Khushnooda Ramzan ◽  
Mohammed Al-Owain ◽  
Rabab Allam ◽  
Amal Berhan ◽  
Gheid Abuharb ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Homozygosity Mapping ◽  
Nonsyndromic Hearing Loss ◽  
Saudi Family

scholarly journals Spectrum and Frequency of the GJB2 Gene Mutations Among Latvian Patients with Prelingual Nonsyndromic Hearing Loss

2009 ◽  
Vol 63 (4-5) ◽  
pp. 198-203
Author(s):  
Olga Šterna ◽  
Natālija Proņina ◽  
Ieva Grīnfelde ◽  
Sandra Kušķe ◽  
Astrīda Krūmiņa ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Gene Mutations ◽  
Gjb2 Gene ◽  
Connexin 26 ◽  
Compound Heterozygous ◽  
Nonsyndromic Hearing Loss ◽  
Profound Hearing Loss ◽  
Common Cause ◽  
Gjb2 Mutation ◽  
35Delg Mutation

Spectrum and Frequency of the GJB2 Gene Mutations Among Latvian Patients with Prelingual Nonsyndromic Hearing Loss Mutations in the GJB2 gene (connexin 26) are the most common cause of congenital nonsyndromic severe-to-profound hearing loss. Sixty-five hearing impaired probands from Latvia were tested for mutations in the GJB2 gene to determine the percentage of hearing loss attributed to connexin 26 and the types of mutations in this population. A total of 62% of patients tested had GJB2 mutations. Four different mutations in the GJB2 gene were identified in Latvian patients with nonsyndromic sensorineural hearing loss: 35delG, 311-324del14, 235delC and M34T. The most prevalent mutation is 35delG (47% of all probands were homozygous and 8% compound heterozygous). Our findings support the conclusion that the 35delG mutation is the most prevalent GJB2 mutation and that it is the common cause of hereditary nonsyndromic hearing loss in populations of European descent.

Mutation Analysis of the Common Deafness Genes in Patients with Nonsyndromic Hearing Loss in Republic of Macedonia

2017 ◽  
Vol 71 (1) ◽  
pp. 20-26
Author(s):  
Emilija Sukarova Stefanovska ◽  
Gjorgji Bozhinovski ◽  
Ana Momirovska ◽  
Marina Davceva Cakar ◽  
Elena Sukarova-Angelovska ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Modifier Gene ◽  
Compound Heterozygous ◽  
Nonsyndromic Hearing Loss ◽  
Allelic Variants ◽  
Republic Of Macedonia ◽  
Pathogenic Variants ◽  
Molecular Etiology ◽  
The Common ◽  
The Republic

Abstract Hearing impairment is the most common sensory disorder, which occurs in 1 of 1000 newborns. It is caused by heterogeneous conditions with more than a half due to genetic etiology. Although hundreds of genes are implicated in hearing process and have been found to be associated with nonsyndromic hearing loss, pathogenic variants in GJB2 gene have been considered as the main cause of deafness among nonsyndromic hearing loss (NSHL) population worldwide. Pathogenic variants in MT-RNR1 or mtDNA12SrRNA gene were also implicated predominantly in postlingual progresive deafness. The aim of this study was to analyze the implication of GJB2 and MT-RNR1 genes in the molecular etiology of deafness among 130 NSHL patients in the Republic of Macedonia. The presence of the del (GJB6-D13S1830) was also analysed. We performed SSCP and/or sequence analysis of GJB2 and identified sequence variants in 62 out of 130 patients (47.7%); (51 homozygous or compound heterozygous and 11 with only one variant allele). We found 8 different allelic variants, the most prevalent being c.35delG (65.49%), and p.W24*(23.01%), followed by other less frequent alleles (p.V27I, p.V37I, p. P175T and cd. delE120 or delGAG at 360). In addition, two polymorphic substitutions in the GJB2 gene with no clinical significance (p.V153I and p.R127H) were detected. No del(GJB6-D13S1830) was found. SNaPshot analysis was used to screen for the five most frequent allelic variants in the MT-RNR1 gene. Two MT-RNR1 mutations (A827G and T961G) were detected in three patients where only one GJB2 pathogenic variant was found. A new MT-RNR1 gene variant G1303A was also detected. In conclusion, MT-RNR1 mutations were not a significant contributor to the etiology of deafness in Macedonia, although could be considered as a modifier gene affecting the expression of deafness in patients carrying one GJB2 variant. On the other hand, the high percenttage of GJB2 pathogenic variants identified among NSHL cases indicates the necessity of molecular newborn screening for the two most common GJB2 variants (c.35delG and p.W24*) in the Republic of Macedonia.

scholarly journals Genetic Aetiology of Nonsyndromic Hearing Loss in Moravia-Silesia

Medicina ◽  
2018 ◽  
Vol 54 (2) ◽  
pp. 28
Author(s):  
Pavlina Plevova ◽  
Petra Tvrda ◽  
Martina Paprskarova ◽  
Petra Turska ◽  
Barbara Kantorova ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Sanger Sequencing ◽  
Large Deletion ◽  
The Other ◽  
Compound Heterozygous ◽  
Nonsyndromic Hearing Loss ◽  
The Czech Republic ◽  
Gjb2 Mutation ◽  
C 23 ◽  
Gjb2 Mutations

Background and Objective: Hearing loss is the most common sensory deficit in humans. The aim of this study was to clarify the genetic aetiology of nonsyndromic hearing loss in the Moravian-Silesian population of the Czech Republic. Patients and Methods: This study included 200 patients (93 males, 107 females, mean age 16.9 years, ranging from 4 months to 62 years) with nonsyndromic sensorineural hearing loss. We screened all patients for mutations in GJB2 and the large deletion del(GJB6-D13S1830). We performed further screening for additional genes (SERPINB6, TMIE, COCH, ESPN, ACTG1, KCNQ4, and GJB3) with Sanger sequencing on a subset of patients that were negative for GJB2 mutations. Results: We detected biallelic GJB2 mutations in 44 patients (22%). Among these patients, 63.6%, 9.1% and 2.3% exhibited homozygous c.35delG, p.Trp24*, and p.Met34Thr mutations, respectively. The remaining 25% of these patients exhibited compound heterozygous c.35delG, c.-23+1G>A, p.Trp24*, p.Val37Ile, p.Met34Thr, p.Leu90Pro, c.235delC, c.313_326del14, p.Ser139Asn, and p.Gly147Leu mutations. We found a monoallelic GJB2 mutation in 12 patients (6.6%). We found no pathogenic mutations in the other tested genes. Conclusions: One fifth of our cohort had deafness related to GJB2 mutations. The del(GJB6-D13S1830), SERPINB6, TMIE, COCH, ESPN, ACTG1, GJB3, and KCNQ4 mutations were infrequently associated with deafness in the Moravian-Silesian population. Therefore, we suggest that del(GJB6-D13S1830) testing should be performed only when patients with deafness carry the monoallelic GJB2 mutation.

scholarly journals Missense variant in LOXHD1 is associated with canine nonsyndromic hearing loss

2021 ◽  
Author(s):  
Marjo K. Hytönen ◽  
Julia E. Niskanen ◽  
Meharji Arumilli ◽  
Casey A. Brookhart-Knox ◽  
Jonas Donner ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Cell Function ◽  
Autosomal Recessive Inheritance ◽  
Missense Variant ◽  
Homozygosity Mapping ◽  
Large Animal Model ◽  
Large Animal ◽  
Hearing Disorder ◽  
Nonsyndromic Hearing Loss ◽  
Cochlear Hair Cell

AbstractHearing loss is a common sensory deficit in both humans and dogs. In canines, the genetic basis is largely unknown, as genetic variants have only been identified for a syndromic form of hearing impairment. We observed a congenital or early-onset sensorineural hearing loss in a Rottweiler litter. Assuming an autosomal recessive inheritance, we used a combined approach of homozygosity mapping and genome sequencing to dissect the genetic background of the disorder. We identified a fully segregating missense variant in LOXHD1, a gene that is known to be essential for cochlear hair cell function and associated with nonsyndromic hearing loss in humans and mice. The canine LOXHD1 variant was specific to the Rottweiler breed in our study cohorts of pure-bred dogs. However, it also was present in some mixed-breed dogs, of which the majority showed Rottweiler ancestry. Low allele frequencies in these populations, 2.6% and 0.04%, indicate a rare variant. To summarize, our study describes the first genetic variant for canine nonsyndromic hearing loss, which is clinically and genetically similar to human LOXHD1-related hearing disorder, and therefore, provides a new large animal model for hearing loss. Equally important, the affected breed will benefit from a genetic test to eradicate this LOXHD1-related hearing disorder from the population.

scholarly journals Genomic analysis of childhood hearing loss in the Yoruba population of Nigeria

2021 ◽  
Author(s):  
Adebolajo Adeyemo ◽  
Rabia Faridi ◽  
Parna Chattaraj ◽  
Rizwan Yousaf ◽  
Risa Tona ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Molecular Genetic ◽  
Usher Syndrome ◽  
Sensorineural Deafness ◽  
Genomic Analysis ◽  
Nonsyndromic Hearing Loss ◽  
Pathogenic Variants ◽  
Causal Variants ◽  
High Level ◽  
Ibadan Nigeria

AbstractAlthough variant alleles of hundreds of genes are associated with sensorineural deafness in children, the genes and alleles involved remain largely unknown in the Sub-Saharan regions of Africa. We ascertained 56 small families mainly of Yoruba ethno-lingual ancestry in or near Ibadan, Nigeria, that had at least one individual with nonsyndromic, severe-to-profound, prelingual-onset, bilateral hearing loss not attributed to nongenetic factors. We performed a combination of exome and Sanger sequencing analyses to evaluate both nuclear and mitochondrial genomes. No biallelic pathogenic variants were identified in GJB2, a common cause of deafness in many populations. Potential causative variants were identified in genes associated with nonsyndromic hearing loss (CIB2, COL11A1, ILDR1, MYO15A, TMPRSS3, and WFS1), nonsyndromic hearing loss or Usher syndrome (CDH23, MYO7A, PCDH15, and USH2A), and other syndromic forms of hearing loss (CHD7, OPA1, and SPTLC1). Several rare mitochondrial variants, including m.1555A>G, were detected in the gene MT-RNR1 but not in control Yoruba samples. Overall, 20 (33%) of 60 independent cases of hearing loss in this cohort of families were associated with likely causal variants in genes reported to underlie deafness in other populations. None of these likely causal variants were present in more than one family, most were detected as compound heterozygotes, and 77% had not been previously associated with hearing loss. These results indicate an unusually high level of genetic heterogeneity of hearing loss in Ibadan, Nigeria and point to challenges for molecular genetic screening, counseling, and early intervention in this population.

scholarly journals A novel USH2A variant in a patient with hearing loss and prenatal diagnosis of a familial fetus: a case report

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Cong Zhou ◽  
Yuanyuan Xiao ◽  
Hanbing Xie ◽  
Shanling Liu ◽  
Jing Wang
Keyword(s):  
Hearing Loss ◽  
Prenatal Diagnosis ◽  
Usher Syndrome ◽  
Chinese Patient ◽  
Compound Heterozygous ◽  
Case Presentation ◽  
Pathogenic Variants ◽  
Compound Heterozygous Variants ◽  
Gene Panels

Abstract Background Usher syndrome (USH) is the most common cause of inherited deaf-blindness. The current study aimed to identify pathogenic variants in a Chinese patient with hearing loss and to report the identification of a novel p.(Phe1583Leufs*10) variant in USH2A, which met the needs of prenatal diagnosis of the patient's mother. Case presentation Genomic DNA obtained from a five-year-old girl with hearing loss was analyzed via the hearing loss-targeted gene panels. We identified the compound heterozygous variants c.8559-2A>G and c.4749delT in Usher syndrome type 2A (USH2A) gene as the underlying cause of the patient; the former variation has been reported in the literature, but not the latter. The parents of the girl were heterozygous carriers. The two variants were classified as pathogenic. Based on these findings, amniotic fluid samples were used for prenatal diagnosis of the couple's fetus, which was found to carry c.4749delT but not c.8559-2A>G variation. During the follow-up period of more than 9 months after the birth of the fetus, it was confirmed that the infant was healthy. Conclusions The results of the present study identified two compound heterozygous USH2A variants in a patient with hearing loss and reported a novel USH2A variant which expands the spectrum of USH2A variants in USH.

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