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 Missense Variant in LOXHD1 is Associated With Canine Nonsyndromic Hearing Loss

2021 ◽  
Author(s):  
Marjo K Hytönen ◽  
Julia E Niskanen ◽  
Meharji Arumilli ◽  
Casey A 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

Abstract Hearing loss is a common sensory deficit both in 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 mixed-breed dogs, of which the majority showed Rottweiler ancestry. Low allele frequencies in these populations, 2.6 % and 0.04 %, respectively, 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 the hearing disorder from the population.

scholarly journals A biallelic variant in CLRN2 causes non-syndromic hearing loss in humans

2021 ◽  
Author(s):  
Barbara Vona ◽  
Neda Mazaheri ◽  
Sheng-Jia Lin ◽  
Lucy A. Dunbar ◽  
Reza Maroofian ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Amino Acid ◽  
Rna Splicing ◽  
Stop Codon ◽  
Missense Variant ◽  
Homozygosity Mapping ◽  
Deafness Gene ◽  
Expression Studies ◽  
Hearing Function

AbstractDeafness, the most frequent sensory deficit in humans, is extremely heterogeneous with hundreds of genes involved. Clinical and genetic analyses of an extended consanguineous family with pre-lingual, moderate-to-profound autosomal recessive sensorineural hearing loss, allowed us to identify CLRN2, encoding a tetraspan protein, as a new deafness gene. Homozygosity mapping followed by exome sequencing identified a 14.96 Mb locus on chromosome 4p15.32p15.1 containing a likely pathogenic missense variant in CLRN2 (c.494C > A, NM_001079827.2) segregating with the disease. Using in vitro RNA splicing analysis, we show that the CLRN2 c.494C > A variant leads to two events: (1) the substitution of a highly conserved threonine (uncharged amino acid) to lysine (charged amino acid) at position 165, p.(Thr165Lys), and (2) aberrant splicing, with the retention of intron 2 resulting in a stop codon after 26 additional amino acids, p.(Gly146Lysfs*26). Expression studies and phenotyping of newly produced zebrafish and mouse models deficient for clarin 2 further confirm that clarin 2, expressed in the inner ear hair cells, is essential for normal organization and maintenance of the auditory hair bundles, and for hearing function. Together, our findings identify CLRN2 as a new deafness gene, which will impact future diagnosis and treatment for deaf patients.

scholarly journals A Nonsense Variant in Hephaestin Like 1 (HEPHL1) Is Responsible for Congenital Hypotrichosis in Belted Galloway Cattle

Genes ◽  
2021 ◽  
Vol 12 (5) ◽  
pp. 643
Author(s):  
Thibaud Kuca ◽  
Brandy M. Marron ◽  
Joana G. P. Jacinto ◽  
Julia M. Paris ◽  
Christian Gerspach ◽  
...  
Keyword(s):  
Genome Wide Association Study ◽  
Homozygosity Mapping ◽  
Mendelian Inheritance ◽  
Large Animal Model ◽  
Large Animal ◽  
Loss Of Function ◽  
Protein Coding ◽  
Positional Candidate ◽  
Genome Wide ◽  
A Genome

Genodermatosis such as hair disorders mostly follow a monogenic mode of inheritance. Congenital hypotrichosis (HY) belong to this group of disorders and is characterized by abnormally reduced hair since birth. The purpose of this study was to characterize the clinical phenotype of a breed-specific non-syndromic form of HY in Belted Galloway cattle and to identify the causative genetic variant for this recessive disorder. An affected calf born in Switzerland presented with multiple small to large areas of alopecia on the limbs and on the dorsal part of the head, neck, and back. A genome-wide association study using Swiss and US Belted Galloway cattle encompassing 12 cases and 61 controls revealed an association signal on chromosome 29. Homozygosity mapping in a subset of cases refined the HY locus to a 1.5 Mb critical interval and subsequent Sanger sequencing of protein-coding exons of positional candidate genes revealed a stop gain variant in the HEPHL1 gene that encodes a multi-copper ferroxidase protein so-called hephaestin like 1 (c.1684A>T; p.Lys562*). A perfect concordance between the homozygous presence of this most likely pathogenic loss-of-function variant and the HY phenotype was found. Genotyping of more than 700 purebred Swiss and US Belted Galloway cattle showed the global spread of the mutation. This study provides a molecular test that will permit the avoidance of risk matings by systematic genotyping of relevant breeding animals. This rare recessive HEPHL1-related form of hypotrichosis provides a novel large animal model for similar human conditions. The results have been incorporated in the Online Mendelian Inheritance in Animals (OMIA) database (OMIA 002230-9913).

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 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 A 50-kb deletion disrupting the RSPO2 gene is associated with tetradysmelia in Holstein Friesian cattle

2020 ◽  
Vol 52 (1) ◽  
Author(s):  
Doreen Becker ◽  
Rosemarie Weikard ◽  
Christoph Schulze ◽  
Peter Wohlsein ◽  
Christa Kühn
Keyword(s):  
Limb Development ◽  
Bos Taurus ◽  
Genetic Disorder ◽  
Homozygosity Mapping ◽  
Large Animal Model ◽  
Pathological Examination ◽  
Large Animal ◽  
Whole Genome ◽  
Nucleotide Polymorphisms ◽  
Holstein Friesian

Abstract Background Tetradysmelia is a rare genetic disorder that is characterized by an extremely severe reduction of all limb parts distal of the scapula and pelvic girdle. We studied a Holstein Friesian backcross family with 24 offspring, among which six calves displayed autosomal recessive tetradysmelia. In order to identify the genetic basis of the disorder, we genotyped three affected calves, five dams and nine unaffected siblings using a Bovine Illumina 50 k BeadChip and sequenced the whole genome of the sire. Results Pathological examination of four tetradysmelia cases revealed a uniform and severe dysmelia of all limbs. Applying a homozygosity mapping approach, we identified a homozygous region of 10.54 Mb on chromosome 14 (Bos taurus BTA14). Only calves that were diagnosed with tetradysmelia shared a distinct homozygous haplotype for this region. We sequenced the whole genome of the cases’ sire and searched for heterozygous single nucleotide polymorphisms (SNPs) and small variants on BTA14 that were uniquely present in the sire and absent from 3102 control whole-genome sequences of the 1000 Bull Genomes Project, but none were identified in the 10.54-Mb candidate region on BTA14. Therefore, we subsequently performed a more comprehensive analysis by also considering structural variants and detected a 50-kb deletion in the targeted chromosomal region that was in the heterozygous state in the cases’ sire. Using PCR, we confirmed that this detected deletion segregated perfectly within the family with tetradysmelia. The deletion spanned three exons of the bovine R-spondin 2 (RSPO2) gene, which encode three domains of the respective protein. R-spondin 2 is a secreted ligand of leucine-rich repeats containing G protein-coupled receptors that enhance Wnt signalling and is involved in a broad range of developmental processes during embryogenesis. Conclusions We identified a 50-kb deletion on BTA14 that disrupts the coding sequence of the RSPO2 gene and is associated with bovine tetradysmelia. To our knowledge, this is the first reported candidate causal mutation for tetradysmelia in a large animal model. Since signalling pathways involved in limb development are conserved across species, the observed inherited defect may serve as a model to further elucidate fundamental pathways of limb development.

scholarly journals A novel missense variant in the DIAPH1 gene in a Korean family with autosomal dominant nonsyndromic hearing loss

2016 ◽  
Vol 91 (5) ◽  
pp. 289-292 ◽  
Author(s):  
Tae-Hun Kang ◽  
Jeong-In Baek ◽  
Borum Sagong ◽  
Hong-Joon Park ◽  
Chan Ik Park ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Autosomal Dominant ◽  
Missense Variant ◽  
Nonsyndromic Hearing Loss ◽  
Korean Family ◽  
I Gene

scholarly journals Whole Exome Sequencing and Homozygosity Mapping Identify Mutation in the Cell Polarity Protein GPSM2 as the Cause of Nonsyndromic Hearing Loss DFNB82

2010 ◽  
Vol 87 (1) ◽  
pp. 90-94 ◽  
Author(s):  
Tom Walsh ◽  
Hashem Shahin ◽  
Tal Elkan-Miller ◽  
Ming K. Lee ◽  
Anne M. Thornton ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Cell Polarity ◽  
Homozygosity Mapping ◽  
Nonsyndromic Hearing Loss ◽  
Whole Exome

scholarly journals A Novel Heterozygous Missense Variant (c.667G>T;p.Gly223Cys) in USH1C That Interferes With Cadherin-Related 23 and Harmonin Interaction Causes Autosomal Dominant Nonsyndromic Hearing Loss

2020 ◽  
Vol 40 (3) ◽  
pp. 224-231 ◽  
Author(s):  
Ju Sun Song ◽  
Amel Bahloul ◽  
Christine Petit ◽  
Sang Jin Kim ◽  
Il Joon Moon ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Autosomal Dominant ◽  
Missense Variant ◽  
Nonsyndromic Hearing Loss

scholarly journals Benefits of Exome Sequencing in Children with Suspected Isolated Hearing Loss

Genes ◽  
2021 ◽  
Vol 12 (8) ◽  
pp. 1277
Author(s):  
Roxane Van Heurck ◽  
Maria Teresa Carminho-Rodrigues ◽  
Emmanuelle Ranza ◽  
Caterina Stafuzza ◽  
Lina Quteineh ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Exome Sequencing ◽  
Autosomal Dominant ◽  
Diagnostic Yield ◽  
Autosomal Recessive Inheritance ◽  
Nonsyndromic Hearing Loss ◽  
Whole Exome ◽  
Syndromic Hearing Loss ◽  
Children With Hearing Loss

Purpose: Hearing loss is characterized by an extensive genetic heterogeneity and remains a common disorder in children. Molecular diagnosis is of particular benefit in children, and permits the early identification of clinically-unrecognized hearing loss syndromes, which permits effective clinical management and follow-up, including genetic counselling. Methods: We performed whole-exome sequencing with the analysis of a panel of 189 genes associated with hearing loss in a prospective cohort of 61 children and 9 adults presenting mainly with isolated hearing loss. Results: The overall diagnostic rate using exome sequencing was 47.2% (52.5% in children; 22% in adults). In children with confirmed molecular results, 17/32 (53.2%) showed autosomal recessive inheritance patterns, 14/32 (43.75%) showed an autosomal dominant condition, and one case had X-linked hearing loss. In adults, the two patients showed an autosomal dominant inheritance pattern. Among the 32 children, 17 (53.1%) had nonsyndromic hearing loss and 15 (46.7%) had syndromic hearing loss. One adult was diagnosed with syndromic hearing loss and one with nonsyndromic hearing loss. The most common causative genes were STRC (5 cases), GJB2 (3 cases), COL11A1 (3 cases), and ACTG1 (3 cases). Conclusions: Exome sequencing has a high diagnostic yield in children with hearing loss and can reveal a syndromic hearing loss form before other organs/systems become involved, allowing the surveillance of unrecognized present and/or future complications associated with these syndromes.

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