Phenotypic variability of CLDN14 mutations causing DFNB29 hearing loss in the Pakistani population

Abstract Background GLI3 is a transcriptional regulator of several genes involved in mammalian skeletal development. Mutations in the pleiotropic gene GLI3 may result in different inherited disorders including Greig cephalopolysyndactyly syndrome (GCPS). GCPS is characterized by mild to severe craniofacial and limb malformations. Methods and Results Here, we report clinical and molecular study of 3 families with GCPS originated in different regions of Pakistan. Sanger sequencing revealed two novel variants including a frameshift [c. 3790_3791InsC, p.(Gly1236Argfs*11)] and a missense [c.1692A>G, p.(His536Arg)], and one previously reported variant [c.1965_1966delAT, p.(His627Glufs*48)] located in 2 different domains of the GLI3. Conclusion This study not only expanded spectrum of the mutations in the GLI3 but also highlighted phenotypic variability in the GCPS patients. This will facilitate diagnosis and genetic counseling of families with same and related disorders in the Pakistani population.

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Phenotypic variability of non-syndromic hearing loss in patients heterozygous for both c.35delG of GJB2 and the 342-kb deletion involving GJB6

Hearing Research ◽

10.1016/s0378-5955(03)00346-0 ◽

2004 ◽

Vol 188 (1-2) ◽

pp. 42-46 ◽

Cited By ~ 19

Author(s):

Hanno Bolz ◽

Götz Schade ◽

Stefanie Ehmer ◽

Christian Kothe ◽

Markus Hess ◽

...

Keyword(s):

Hearing Loss ◽

Phenotypic Variability ◽

Syndromic Hearing Loss

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

Genes ◽

10.3390/genes11121474 ◽

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.

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Novel Mutations in CLPP, LARS2, CDH23, and COL4A5 Identified in Familial Cases of Prelingual Hearing Loss

Genes ◽

10.3390/genes11090978 ◽

2020 ◽

Vol 11 (9) ◽

pp. 978

Author(s):

Saba Zafar ◽

Mohsin Shahzad ◽

Rafaqat Ishaq ◽

Ayesha Yousaf ◽

Rehan S. Shaikh ◽

...

Keyword(s):

Hearing Loss ◽

Novel Mutations ◽

Hearing Disorders ◽

Low Frequencies ◽

Pakistani Population ◽

3 Dimensional ◽

Pathogenic Variants ◽

Uncertain Significance ◽

Novel Alleles ◽

In Silico Analyses

We report the underlying genetic causes of prelingual hearing loss (HL) segregating in eight large consanguineous families, ascertained from the Punjab province of Pakistan. Exome sequencing followed by segregation analysis revealed seven potentially pathogenic variants, including four novel alleles c.257G>A, c.6083A>C, c.89A>G, and c.1249A>G of CLPP, CDH23, COL4A5, and LARS2, respectively. We also identified three previously reported HL-causing variants (c.4528C>T, c.35delG, and c.1219T>C) of MYO15A, GJB2, and TMPRSS3 segregating in four families. All identified variants were either absent or had very low frequencies in the control databases. Our in silico analyses and 3-dimensional (3D) molecular modeling support the deleterious impact of these variants on the encoded proteins. Variants identified in MYO15A, GJB2, TMPRSS3, and CDH23 were classified as “pathogenic” or “likely pathogenic”, while the variants in CLPP and LARS2 fall in the category of “uncertain significance” based on the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) variant pathogenicity guidelines. This paper highlights the genetic diversity of hearing disorders in the Pakistani population and reports the identification of four novel mutations in four HL families.

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Erbliche Hörstörungen des Menschen – die Bedeutung genetischer Ansätze für Medizin und grundlagenwissenschaftliches Verständnis

e-Neuroforum ◽

10.1515/nf-2014-0305 ◽

2014 ◽

Vol 20 (3) ◽

Author(s):

Christian Kubisch

Keyword(s):

Hearing Loss ◽

Hearing Impairment ◽

Social Environment ◽

Clinical Medicine ◽

Age Of Onset ◽

Phenotypic Variability ◽

Molecular Physiology ◽

Hereditary Hearing Loss ◽

Monogenic Diseases ◽

Scientific Results

AbstractHereditary hearing loss in humans - the importance of genetic approaches for clinical medicine and basic scienceHereditary hearing loss belongs to the most common monogenic diseases in humans and, depending on the severity of symptoms and age of onset, the dysfunction of one of the main sensory systems can lead to major problems for the affected individual and his/her social environment. The diagnostic workup of hearing impairment is complicated by a pronounced phenotypic variability and extensive genetic heterogeneity. Nevertheless, many forms of monogenic hearing impairment have been elucidated during the last years by genetic approaches. In addition to improved counseling and medical management of patients and families, these scientific results have contributed significantly to the identification of functionally relevant molecules of the inner ear and have thus helped to better understand the molecular physiology of hearing and pathophysiology of hearing impairment.

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High level of intrafamilial phenotypic variability of non-syndromic hearing loss in a Lur family due to delE120 mutation in GJB2 gene

International Journal of Pediatric Otorhinolaryngology ◽

10.1016/j.ijporl.2010.06.005 ◽

2010 ◽

Vol 74 (9) ◽

pp. 1089-1091 ◽

Cited By ~ 13

Author(s):

Nejat Mahdieh ◽

Hamideh Bagherian ◽

Atefeh Shirkavand ◽

Maryam Sharafi ◽

Sirous Zeinali

Keyword(s):

Hearing Loss ◽

Phenotypic Variability ◽

Gjb2 Gene ◽

Syndromic Hearing Loss ◽

High Level ◽

Intrafamilial Phenotypic Variability

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Intra-familial phenotypic variability in a Moroccan family with hearing loss and palmoplantar keratoderma (PPK)

Current Research in Translational Medicine ◽

10.1016/j.retram.2016.01.011 ◽

2016 ◽

Vol 64 (2) ◽

pp. 61-64 ◽

Cited By ~ 1

Author(s):

A. Bousfiha ◽

A. Bakhchane ◽

S. Elrharchi ◽

H. Dehbi ◽

M. Kabine ◽

...

Keyword(s):

Hearing Loss ◽

Phenotypic Variability ◽

Palmoplantar Keratoderma ◽

Moroccan Family

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Pendred Syndrome in a large consanguineous Brazilian family caused by a homozygous mutation in the SLC26A4 gene

Arquivos Brasileiros de Endocrinologia & Metabologia ◽

10.1590/s0004-27302008000800015 ◽

2008 ◽

Vol 52 (8) ◽

pp. 1296-1303 ◽

Cited By ~ 7

Author(s):

Adriana Lofrano-Porto ◽

Gustavo B. Barra ◽

Paula P. Nascimento ◽

Patrícia G. G. Costa ◽

Érica C. Garcia ◽

...

Keyword(s):

Hearing Loss ◽

Phenotypic Variability ◽

Sensorineural Deafness ◽

Molecular Characteristics ◽

Homozygous Mutation ◽

Thyroid Function Tests ◽

Pendred Syndrome ◽

Slc26a4 Gene ◽

Organification Defect ◽

Temporal Bones

Pendred Syndrome (PS) is an autossomal recessive disorder characterized by sensorineural deafness, goiter and iodide organification defect. The hearing loss is associated with inner ear abnormalities, ranging from an isolated enlarged vestibular aqueduct (EVA) to a typical coclear dysplasia. Mutations in the gene that encodes pendrin (SLC26A4), a chloride/iodide transporter, have been shown to be associated with PS. We describe the clinical and molecular characteristics of a large consanguineous family harboring a mutation in the SLC26A4 gene. The proband was a 26-year-old deaf Brazilian woman who presented a bulky multinodular goiter and hypothyroidism since puberty. Five other siblings were deaf: one brother had a similar phenotype, three siblings also had goiters but normal thyroid function tests, and one brother had only a subtle thyroid enlargement. Other 4 siblings had no thyroid or hearing disorder. Parents were first degree cousins and had normal hearing. The mother was healthy, except for subclinical hypothyroidism; the father was deceased. A perchlorate test in the proband showed a discharge of 21% of the incorporated iodide 2h after the administration of 1g of KClO4. Audiological examinations showed profound hearing loss in all deaf subjects; CT and MRI of the temporal bones showed EVA in all of them. Genomic DNA was isolated from whole blood, from the 6 affected and 4 unaffected siblings, the mother and control. The coding region of the PDS gene (exons 2-21), including exon/intron boundaries, were amplified by PCR and sequenced. A single base-pair (T) deletion at position 1197 of exon 10 was detected in homozygous state in the 6 deaf siblings. The mother and 2 unaffected siblings were heterozygous for this mutation, which has been described by Everett et al. The 1197delT mutation is predicted to result in a frameshift and a truncated protein. The existence of PS phenocopies and intrafamilial phenotypic variability are well documented. The definite diagnosis requires molecular analysis. Our study illustrates the value and challenges of mutational analysis in selected patients with PS.

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Segregation of two variants suggests the presence of autosomal dominant and recessive forms of WFS1-related disease within the same family: expanding the phenotypic spectrum of Wolfram Syndrome

Journal of Medical Genetics ◽

10.1136/jmedgenet-2018-105782 ◽

2019 ◽

Vol 57 (2) ◽

pp. 121-123 ◽

Cited By ~ 2

Author(s):

Laina Lusk ◽

Emily Black ◽

Jaime Vengoechea

Keyword(s):

Hearing Loss ◽

Optic Atrophy ◽

Autosomal Dominant ◽

Phenotypic Variability ◽

Wolfram Syndrome ◽

Related Disease ◽

Uncertain Significance ◽

Similar Phenotype ◽

Biallelic Mutations ◽

Clinical Counselling

BackgroundWFS1 was initially described as causative agent of autosomal recessive (AR) Wolfram syndrome, a childhood-onset disorder involving diabetes, optic atrophy, hearing loss and neurodegenerative features. However, the discovery of autosomal dominant (AD) disorders caused by this gene has resulted in clinical counselling and result interpretation challenges.ObjectiveWe seek to report a family that appears to segregate dominant and recessive forms of WFS1-related disease.Methods/resultsA 19-year-old woman presented with progressive childhood sensorineural hearing loss and recent optic atrophy, with biallelic mutations in WFS1: c.2486T>C (likely pathogenic) and c.2470G>A (uncertain significance). Her A1C was normal. Her sister carried the same variants and had a similar phenotype. Their father carried c.2486T>C and was found to have mild–moderate hearing loss but no optic atrophy or neurological symptoms. The mother carried c.2470G>A and had a normal audiogram and ophthalmological exam. Providing anticipatory guidance for this family was difficult given the phenotypic variability of WFS1-related disorders and the uncertainty surrounding whether the inheritance pattern was AR or AD.ConclusionThe clinical correlation of the variants identified in this family suggests an AR Wolfram-like syndrome, without the typical diabetes mellitus or diabetes insipidus nor neurological decline. To our knowledge, this is a novel WFS1-related phenotype.

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