A Novel Pathogenic Variant in the CABP2 Gene Causes Severe Nonsyndromic Hearing Loss in a Consanguineous Iranian Family

2019 ◽  
Vol 24 (5) ◽  
pp. 258-263 ◽  
Author(s):  
Mahbobeh Koohiyan ◽  
Mohammad Reza Noori-Daloii ◽  
Morteza Hashemzadeh-Chaleshtori ◽  
Mansoor Salehi ◽  
Hamidreza Abtahi ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Missense Variant ◽  
Pedigree Analysis ◽  
Gjb2 Gene ◽  
Genetic Linkage Analysis ◽  
Complex Process ◽  
Whole Exome ◽  
The Family ◽  
Iranian Family ◽  
Molecular Interpretation

Background and Objectives: Hereditary hearing loss (HL) can originate from mutations in one of many genes involved in the complex process of hearing. CABP2 mutations have been reported to cause moderate HL. Here, we report the whole exome sequencing (WES) of a proband presenting with prelingual, severe HL in an Iranian family. Methods: A comprehensive family history was obtained, and clinical evaluations and pedigree analysis were performed in the family with 2 affected members. After excluding mutations in the GJB2 gene and 7 other most common autosomal recessive nonsyndromic HL (ARNSHL) genes via Sanger sequencing and genetic linkage analysis in the family, WES was utilized to find the possible etiology of the disease. Results: WES results showed a novel rare variant (c.311G>A) in the CABP2gene.This missense variant in the exon 4 of the CABP2gene meets the criteria of being pathogenic according to the American College of Medical Genetics and Genomics (ACMG) interpretation guidelines. Conclusions: Up to now, 3 mutations have been reported for the CABP2gene to cause moderate ARNSHL in different populations. Our results show that CABP2variantsalso cause severe ARNSHL, adding CABP2to the growing list of genes that exhibit phenotypic heterogeneity. Expanding our understanding of the mutational spectrum of HL genes is an important step in providing the correct clinical molecular interpretation and diagnosis for patients.

scholarly journals Identification of a Novel Frameshift Mutation in the TECTA Gene in an Iranian Family With Autosomal Nonsyndromic Hearing Loss

2021 ◽  
Author(s):  
Javad Mohammadi-Asl ◽  
Nader Saki ◽  
Majid Karimi ◽  
Farideh Ghanbari Mardasi
Keyword(s):  
Hearing Loss ◽  
Genetic Factors ◽  
Frameshift Mutation ◽  
Nonsyndromic Hearing Loss ◽  
Whole Exome ◽  
The Family ◽  
Iranian Family ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing ◽  
Mutation Databases

Hearing loss (HL) is one of the most frequent birth defects, and genetic factors contribute to the pathogenesis of the disorder in about half of the patients. In the present study, we performed whole-exome sequencing (WES) based on Next-generation sequencing (NGS) in an Iranian family with hereditary HL. Then, Sanger sequencing was used to verify the segregation of the variant recognized in affected family members. A novel homozygous frameshift variation, c.649-650insC, in TECTA was found in the family, which might lead to a truncated TECTA protein (p. Asn218Gln fsX31). Our findings propose that the homozygous TECTA-p.N218QfsX31 mutation is the pathogenic variant for ARNSHL. To the best of our knowledge, this mutation has not been described in patients with the HL phenotype and so far has not to be reported in any of the mutation databases. Our data expand the spectrum of mutations in the TECTA gene in nonsyndromic hearing loss.

Whole exome sequencing identifies both nuclear and mitochondrial variations in an Iranian family with non-syndromic hearing loss

Mitochondrion ◽  
2019 ◽  
Vol 46 ◽  
pp. 321-325 ◽  
Author(s):  
Somayeh Khatami ◽  
Hassan Rokni-Zadeh ◽  
Neda Mohsen-Pour ◽  
Alireza Biglari ◽  
Majid Changi-Ashtiani ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Whole Exome ◽  
Iranian Family ◽  
Syndromic Hearing Loss

A COL4A5 Missense Variant in a Han-Chinese Family with X-linked Alport Syndrome

2019 ◽  
Vol 19 (10) ◽  
pp. 758-765
Author(s):  
Yuan Wu ◽  
Yi Guo ◽  
Jinzhong Yuan ◽  
Hongbo Xu ◽  
Yong Chen ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Sanger Sequencing ◽  
Alport Syndrome ◽  
Genetic Defect ◽  
Missense Variant ◽  
Han Chinese ◽  
Chinese Family ◽  
Chain Gene ◽  
Renal Disorder ◽  
The Family

Background: Alport syndrome (AS) is an inherited familial nephropathy, characterized by progressive hematuric nephritis, bilateral sensorineural hypoacusis and ocular abnormalities. X-linked AS (XLAS) is the major AS form and is clinically heterogeneous, and it is associated with defects in the collagen type IV alpha 5 chain gene (COL4A5). Objective: The purpose of this research is to detect the genetic defect responsible for renal disorder in a 3-generation Han-Chinese pedigree. Methods: Detailed family history and clinical data of the family members were collected and recorded. Whole exome sequencing (WES) was applied in the proband to screen potential genetic variants, and then Sanger sequencing was used to verify the variant within the family. Two hundred unrelated ethnically matched normal individuals (male/female: 100/100, age 37.5 ± 5.5 years) without renal disorder were recruited as controls. Results: Three patients (I:1, II:1 and II:2) presented microscopic hematuria and proteinuria, and the patient I:1 developed uremia and end stage renal disease (ESRD) by age 55 and showed sensorineural hearing loss. Patient II:2 developed mild left ear hearing loss. Cataracts were present in patients I:1 and II:1. A COL4A5 gene missense variant, c.2156G>A (p.G719E), located in the Gly-X-Y repeats of exon 28, was identified to co-segregate with the renal disorder in this family. The variant was absent in 200 ethnically matched controls. Conclusion: By conducting WES and Sanger sequencing, a COL4A5 missense variant, c.2156G>A (p.G719E), was identified to co-segregate with the renal disorder, and it is possible that this variant is the genetic cause of the disorder in this family. Our study may extend the mutation spectrum of XLAS and may be useful for genetic counseling of this family. Further functional studies associated with genetic deficiency are warranted in the following research.

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 Case Report: Investigation and molecular genetic diagnosis of familial hypomagnesaemia: a case report

F1000Research ◽  
2019 ◽  
Vol 8 ◽  
pp. 666
Author(s):  
Jamie Willows ◽  
Maryam Al Badi ◽  
Chloe Richardson ◽  
Noel Edwards ◽  
Sarah Rice ◽  
...  
Keyword(s):  
Case Report ◽  
Molecular Genetic ◽  
Genetic Diagnosis ◽  
Missense Variant ◽  
Consanguineous Family ◽  
Affected Child ◽  
Whole Exome ◽  
The Family ◽  
Domain Interactions ◽  
Molecular Genetic Diagnosis

Genetic mutations causing familial hypomagnesaemia syndromes are well-recognised.  Affected patients can present with severe symptoms of hypomagnesaemia, such as seizures or cardiac arrhythmia.  We report an affected child, from a consanguineous family, who presented in the first weeks of life with seizures secondary to hypomagnesaemia, without other associated clinical features.  We performed whole exome sequencing in the affected child and segregation analysis within the family, which revealed a novel homozygous missense mutation in TRPM6, which was confirmed as a heterozygous allele in both parents and two younger siblings who had transient hypomagnesaemia. Using in silico modelling, we provide evidence that the missense variant p.(K1098E) in TRPM6 is pathogenic, as it disrupts stabilising TRP domain interactions. Management of familial hypomagnesaemia relies on prompt recognition, early magnesium replacement and lifelong monitoring.

scholarly journals Novel variants identified in CKAP2L in two siblings with Filippi Syndrome

2021 ◽  
pp. mcs.a006130
Author(s):  
Ryan J Patrick ◽  
Jill M Weimer ◽  
Laura Davis-Keppen ◽  
Megan L Landsverk
Keyword(s):  
Intellectual Disability ◽  
Autosomal Recessive ◽  
Missense Variant ◽  
Facial Features ◽  
Loss Of Function ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
The Family ◽  
Novel Variants ◽  
In Trans

Pathogenic variants in CKAP2L have previously been reported in Filippi Syndrome (FS), a rare autosomal recessive, craniodigital syndrome characterized by microcephaly, syndactyly, short stature, intellectual disability, and dysmorphic facial features. To date, fewer than ten patients with pathogenic variants in CKAP2L associated with FS have been reported. All of the previously reported probands have presumed loss-of-function variants (frameshift, canonical splice site, starting methionine) and all but one have been homozygous for a pathogenic variant. Here we describe two brothers who presented with microcephaly, micrognathia, syndactyly, dysmorphic features, and intellectual disability. Whole exome sequencing of the family identified a missense variant, c.2066G>A (p.Arg689His), in trans with a frameshift variant, c.1169_1173del (p.Ile390LysfsTer4), in CKAP2L. To our knowledge, these are the first patients with FS to be reported with a missense variant in CKAP2L and only the second family to be reported with two variants in trans.

A Novel Missense Mutation in NALCN cause CLIFAHDD Syndrome and Prenatal Diagnosis in China

2020 ◽  
Author(s):  
Yuping Li ◽  
Chenglong Zhou ◽  
Yangran Chen ◽  
Haihong Shi ◽  
Qiang Chen ◽  
...  
Keyword(s):  
Bioinformatics Analysis ◽  
Clinical Symptoms ◽  
Missense Variant ◽  
Pathogenic Mutation ◽  
Foot Deformities ◽  
Gene Diagnosis ◽  
Rare Mutations ◽  
Whole Exome ◽  
The Family ◽  
Novel Variant

Abstract Background : CLIFAHDD is caused by mutation in NALCN and characterized by facial malformation, hypotonia, and developmental delay. Recently rare mutations in NALCN associated with of CLIFAHDD syndrome have been reported. Methods : Whole exome sequencing (WES) was applied to a diagnosis suspected CLIFAHDD syndrome proband based on clinical symptoms. Blood samples were taken from the parents of the proband for co-segregation analysis using Sanger sequencing. In addition, prenatal gene diagnosis was performed to the family. Finally bioinformatics analysis was utilized to predict the pathogenesis of novel variant. Result : We reported a 24-hour-old proband with a novel missense variant c.3016G>T (p.Val1006Phe) in NALCN by WES. The proband showed clinical symptoms of head abnormalities, neck shortage, thumbs adduction, positional foot deformities and elbows contracture. Prenatal diagnosis revealed that the proband’s sibling did not carry c.3016G>T. Conclusion : Our findings indicate c.3016G>T is a novel pathogenic mutation, while extending new phenotype CLIFAHDD syndrome and enriching the mutation spectrum of the NALCN gene.

Spectrum and frequencies of non GJB2 gene mutations in Czech patients with early non‐syndromic hearing loss detected by gene panel NGS and whole‐exome sequencing

2020 ◽  
Vol 98 (6) ◽  
pp. 548-554
Author(s):  
Dana Safka Brozkova ◽  
Simona Poisson Marková ◽  
Anna Uhrová Mészárosová ◽  
Ján Jenčík ◽  
Vlasta Čejnová ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Gene Mutations ◽  
Gene Panel ◽  
Gjb2 Gene ◽  
Whole Exome ◽  
Syndromic Hearing Loss

Identification and Clinical Implications of a Novel MYO15A Variant in a Consanguineous Iranian Family by Targeted Exome Sequencing

2019 ◽  
Vol 24 (1) ◽  
pp. 25-31 ◽  
Author(s):  
Narges Zarepour ◽  
Mahbobeh Koohiyan ◽  
Afsaneh Taghipour-Sheshdeh ◽  
Fatemeh Nemati-Zargaran ◽  
Nader Saki ◽  
...  
Keyword(s):  
Pedigree Analysis ◽  
Genetic Linkage Analysis ◽  
Clinical Evaluations ◽  
Sequencing Technologies ◽  
The Family ◽  
New Strategy ◽  
Genetics And Genomics ◽  
Next Generation Sequencing Ngs ◽  
Very High ◽  
Generation Sequencing

Background and Objectives: Hereditary hearing loss (HL) is known by a very high genetic heterogeneity, which makes a molecular diagnosis problematic. Next-generation sequencing (NGS) is a new strategy that can overcome this problem. Method: A comprehensive family history was obtained, and clinical evaluations and pedigree analysis were performed in the family with 3 affected members. After excluding mutations in the GJB2 and 7 other most common autosomal recessive nonsyndromic HL genes via Sanger sequencing and genetic linkage analysis in the family, we applied the Otogenetics deafness NGS panel in the proband of this family. Results: NGS results showed a novel rare variant (c.7720C>T) in the MYO15A gene. This nonsense variant in the exon 40 of the MYO15A gene fulfills the criteria of being categorized as pathogenic according to the American College of Medical Genetics and Genomics guideline. Conclusions: New DNA sequencing technologies could lead to identification of the disease causing variants in highly heterogeneous disorders such as HL.

scholarly journals Identification of an unknown frameshift variant of NOG in a Han Chinese family with proximal symphalangism

2020 ◽  
Vol 40 (6) ◽  
Author(s):  
Zhuang-Zhuang Yuan ◽  
Fang Yu ◽  
Jie-Yuan Jin ◽  
Zi-Jun Jiao ◽  
Ju-Yu Tang ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Conductive Hearing Loss ◽  
Genetic Diagnosis ◽  
Chinese Patient ◽  
Chinese Family ◽  
Autosomal Dominant Disorder ◽  
Genetic Lesion ◽  
Whole Exome ◽  
The Family ◽  
Conductive Hearing

Abstract Proximal symphalangism (SYM1) is an autosomal dominant disorder manifested by ankylosis of the proximal interphalangeal joints of fingers, carpal and tarsal bone fusion, and conductive hearing loss in some cases. Herein, we clinically diagnosed a Chinese patient with fusions of the bilateral proximal interphalangeal joints in the 2–5 digits without conductive hearing loss. Family history investigation revealed that his mother and grandfather also suffered from SYM1. Whole exome sequencing was performed to detect the genetic lesion of the family. The candidate gene variants were validated by Sanger sequencing. By data filtering, co-segregation analysis and bioinformatics analysis, we highly suspected that an unknown heterozygous frameshift variant (c.635_636insG, p.Q213Pfs*57) in NOG was responsible for the SYM1 in the family. This variant was predicted to be deleterious and resulted in a prolonged protein. This finding broadened the spectrum of NOG mutations associated with SYM1 and contributed to genetic diagnosis and counseling of families with SYM1.

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