Bi-Allelic Novel Variants in CLIC5 Identified in a Cameroonian Multiplex Family with Non-Syndromic Hearing Impairment

DNA samples from five members of a multiplex non-consanguineous Cameroonian family, segregating prelingual and progressive autosomal recessive non-syndromic sensorineural hearing impairment, underwent whole exome sequencing. We identified novel bi-allelic compound heterozygous pathogenic variants in CLIC5. The variants identified, i.e., the missense [NM_016929.5:c.224T>C; p.(L75P)] and the splicing (NM_016929.5:c.63+1G>A), were validated using Sanger sequencing in all seven available family members and co-segregated with hearing impairment (HI) in the three hearing impaired family members. The three affected individuals were compound heterozygous for both variants, and all unaffected individuals were heterozygous for one of the two variants. Both variants were absent from the genome aggregation database (gnomAD), the Single Nucleotide Polymorphism Database (dbSNP), and the UK10K and Greater Middle East (GME) databases, as well as from 122 apparently healthy controls from Cameroon. We also did not identify these pathogenic variants in 118 unrelated sporadic cases of non-syndromic hearing impairment (NSHI) from Cameroon. In silico analysis showed that the missense variant CLIC5-p.(L75P) substitutes a highly conserved amino acid residue (leucine), and is expected to alter the stability, the structure, and the function of the CLIC5 protein, while the splicing variant CLIC5-(c.63+1G>A) is predicted to disrupt a consensus donor splice site and alter the splicing of the pre-mRNA. This study is the second report, worldwide, to describe CLIC5 involvement in human hearing impairment, and thus confirms CLIC5 as a novel non-syndromic hearing impairment gene that should be included in targeted diagnostic gene panels.

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A novel variant in DXML2 gene is associated with autosomal dominant non-syndromic hearing impairment (DFNA71) in a Cameroonian family

Experimental Biology and Medicine ◽

10.1177/1535370221999746 ◽

2021 ◽

pp. 153537022199974

Author(s):

Edmond Wonkam-Tingang ◽

Isabelle Schrauwen ◽

Kevin K Esoh ◽

Thashi Bharadwaj ◽

Liz M Nouel-Saied ◽

...

Keyword(s):

Hearing Impairment ◽

Autosomal Dominant ◽

Family Members ◽

Missense Variant ◽

Novel Variant ◽

Sensorineural Hearing Impairment ◽

History Of ◽

Syndromic Hearing Impairment ◽

Congenital Hearing Impairment ◽

Apparently Healthy

Approximately half of congenital hearing impairment cases are inherited, with non-syndromic hearing impairment (NSHI) being the most frequent clinical entity of genetic hearing impairment cases. A family from Cameroon with NSHI was investigated by performing exome sequencing using DNA samples obtained from three family members, followed by direct Sanger sequencing in additional family members and controls participants. We identified an autosomal dominantly inherited novel missense variant [NM_001174116.2:c.918G>T; p.(Q306H)] in DMXL2 gene (MIM:612186) that co-segregates with mild to profound non-syndromic sensorineural hearing impairment . The p.(Q306H) variant which substitutes a highly conserved glutamine residue is predicted deleterious by various bioinformatics tools and is absent from several genome databases. This variant was also neither found in 121 apparently healthy controls without a family history of hearing impairment , nor 112 sporadic NSHI cases from Cameroon. There is one previous report of a large Han Chinese NSHI family that segregates a missense variant in DMXL2. The present study provides additional evidence that DMXL2 is involved in hearing impairment etiology, and we suggest DMXL2 should be considered in diagnostic hearing impairment panels.

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Audiological features in Serbian patients with hearing impairment identified with c.35delG in the GJB2 gene

Srpski arhiv za celokupno lekarstvo ◽

10.2298/sarh201117098d ◽

2021 ◽

pp. 98-98

Author(s):

Bojana Dobric ◽

Danijela Radivojevic ◽

Jovana Jecmenica ◽

Vassos Neocleous ◽

Pavlos Fanis ◽

...

Keyword(s):

Hearing Loss ◽

Hearing Impairment ◽

Autosomal Recessive ◽

Gjb2 Gene ◽

Compound Heterozygous ◽

Heterozygous State ◽

Phenotype Correlation ◽

Pathogenic Variants ◽

Environmental Causes ◽

35Delg Mutation

Introduction/Objective. Hearing impairment (HI) is the most common sensorineural disorder with an incidence of 1/700-1000 newborns. Variants in the GJB2 gene are the major cause of autosomal recessive nonsyndromic sensorineural hearing loss (ARNSHL). The degree of HI in patients with detected mutations in GJB2 gene ranges from mild to profound. The aim of this study was to determine possible genotype-phenotype association between audiometric characteristics and detected genotypes in ARNSHL patients from Serbia. Methods. Ninety-two patients with ARNSHL underwent genetic analysis with PCR-ARMS and sequencing of the GJB2 gene. Audiological analyses were obtained in all patients using a combination of several methods to estimate the degree of hearing loss. Results. Audiological analysis performed in the 92 probands showed moderate to profound range of hearing loss. All identified pathogenic variants accounted for 42.39% of the mutant alleles (78/184 alleles), with the c.35delG mutation being the most frequent (30.43%). Genotype-phenotype correlation in an isolated group of 37 patients bearing c.35delG in the homozygous, compound heterozygous or heterozygous state. In this group the majority of patients (30/37, 81.08%) exhibited severe to profound hearing deficit. Conclusion. Association between genotype and the degree of hearing impairment in patients analyzed in this study demonstrated that patients with bi-allelic truncating mutations i.e. c.35delG, associate with the more severe hearing loss when compared with those identified with only one affected allele. The various degrees of hearing impairment observed in heterozygous patients could be explained by the presence of an undetected second mutation or other modifier genes or environmental causes.

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Novel MFSD8 Variants in a Chinese Family with Nonsyndromic Macular Dystrophy

Journal of Ophthalmology ◽

10.1155/2021/6684045 ◽

2021 ◽

Vol 2021 ◽

pp. 1-5

Author(s):

Qin Xiang ◽

Yanna Cao ◽

Hongbo Xu ◽

Zhijian Yang ◽

Liang Tang ◽

...

Keyword(s):

Family Members ◽

Major Facilitator Superfamily ◽

Chinese Family ◽

Macular Dystrophy ◽

Compound Heterozygous ◽

The Novel ◽

Pathogenic Variants ◽

Compound Heterozygous Variants ◽

Major Facilitator ◽

Mfsd8 Gene

Purpose. To identify the molecular etiology of a Chinese family with nonsyndromic macular dystrophy. Methods. Ophthalmic examinations were performed, and genomic DNA was extracted from available family members. Whole exome sequencing of two members (the proband and her unaffected mother) and Sanger sequencing in available family members were performed to screen potential pathogenic variants. Results. Novel compound heterozygous variants, c.1066C>T (p.Pro356Ser) and c.1102+2T>C, in the major facilitator superfamily domain containing 8 gene (MFSD8) were suspected to be involved in this family’s macular dystrophy phenotype. The novel c.1066C>T variant in the MFSD8 gene probably resulted in substitution of serine for proline at the 356th residue and was predicted to be “uncertain significance” through in silico analyses. The novel c.1102+2T>C variant in the MFSD8 gene was likely to affect the splicing form and predicted to be “pathogenic.” Conclusion. The novel compound heterozygous variants, c.1066C>T (p.Pro356Ser) and c.1102+2T>C, in the MFSD8 gene are likely responsible for the isolated macular dystrophy phenotype in this family. This study enlarged the MFSD8 gene mutant spectrum and might provide more accurate genetic counseling for this family.

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Compound heterozygous inheritance of two novel COQ2 variants results in familial coenzyme Q deficiency

Orphanet Journal of Rare Diseases ◽

10.1186/s13023-020-01600-8 ◽

2020 ◽

Vol 15 (1) ◽

Author(s):

Aliaa H. Abdelhakim ◽

Avinash V. Dharmadhikari ◽

Sara D. Ragi ◽

Jose Ronaldo Lima de Carvalho ◽

Christine L. Xu ◽

...

Keyword(s):

Coenzyme Q ◽

Clinical Manifestations ◽

Missense Variant ◽

Neurological Involvement ◽

Cone Dystrophy ◽

Compound Heterozygous ◽

Pathogenic Variants ◽

Whole Exome ◽

Compound Heterozygous Variants ◽

End Stage

Abstract Background Primary coenzyme Q10 deficiency is a rare disease that results in diverse and variable clinical manifestations. Nephropathy, myopathy and neurologic involvement are commonly associated, however retinopathy has also been observed with certain pathogenic variants of genes in the coenzyme Q biosynthesis pathway. In this report, we describe a novel presentation of the disease that includes nephropathy and retinopathy without neurological involvement, and which is the result of a compound heterozygous state arising from the inheritance of two recessive potentially pathogenic variants, previously not described. Materials and methods Retrospective report, with complete ophthalmic examination, multimodal imaging, electroretinography, and whole exome sequencing performed on a family with three affected siblings. Results We show that affected individuals in the described family inherited two heterozygous variants of the COQ2 gene, resulting in a frameshift variant in one allele, and a predicted deleterious missense variant in the second allele (c.288dupC,p.(Ala97Argfs*56) and c.376C > G,p.(Arg126Gly) respectively). Electroretinography results were consistent with rod-cone dystrophy in the affected individuals. All affected individuals in the family exhibited the characteristic retinopathy as well as end-stage nephropathy, without evidence of any neurological involvement. Conclusions We identified two novel compound heterozygous variants of the COQ2 gene that result in primary coenzyme Q deficiency. Targeted sequencing of coenzyme Q biosynthetic pathway genes may be useful in diagnosing oculorenal clinical presentations syndromes not explained by more well known syndromes (e.g., Senior-Loken and Bardet-Biedl syndromes).

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Disparities in discovery of pathogenic variants for autosomal recessive non-syndromic hearing impairment by ancestry

European Journal of Human Genetics ◽

10.1038/s41431-019-0417-2 ◽

2019 ◽

Vol 27 (9) ◽

pp. 1456-1465 ◽

Cited By ~ 5

Author(s):

Imen Chakchouk ◽

Di Zhang ◽

Zhihui Zhang ◽

Laurent C. Francioli ◽

Regie Lyn P. Santos-Cortez ◽

...

Keyword(s):

Hearing Impairment ◽

Autosomal Recessive ◽

Pathogenic Variants ◽

Syndromic Hearing Impairment

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Persistent Hypoglycemia with Polycystic Kidneys: A Rare Combination – A Case Report

Biomedicine Hub ◽

10.1159/000511389 ◽

2020 ◽

Vol 5 (3) ◽

pp. 1-6

Author(s):

Priya Prasher ◽

Katherine Redmond ◽

Hillarey Stone ◽

James Bailes ◽

Edward Nehus ◽

...

Keyword(s):

Case Report ◽

Promoter Region ◽

Molecular Genetic ◽

Missense Variant ◽

Compound Heterozygous ◽

Molecular Genetic Testing ◽

Coding Region ◽

Polycystic Kidney ◽

Homozygous State ◽

Pathogenic Variants

We present the case of an infant referred to our NICU born at 39 weeks’ gestation with persistent hypoglycemia with elevated insulin levels (HI) requiring diazoxide to maintain normoglycemia. Additionally, polycystic kidney disease (PKD) was detected by ultrasound. Molecular genetic testing revealed pathogenic variants in the <i>PMM2</i>gene, i.e., a variant in the promoter region and a missense variant in the coding region. The precoding variant was recently described in 11 European families with similar phenotypes, either in a homozygous state or as compound heterozygous with a pathogenic coding variant. In neonates with HI associated with PKD, this rare recessive disorder should be considered.

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

BMC Medical Genomics ◽

10.1186/s12920-021-01052-4 ◽

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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A Novel Missense Variant in the ESRRB Gene Causing Nonsyndromic Hearing Loss: In Silico Analyses of a Case

10.21203/rs.3.rs-698699/v1 ◽

2021 ◽

Author(s):

Tohid Ghasemnejad ◽

Mahmoud Shekari Khaniani ◽

Jafar Nouri Nojadeh ◽

Sima Mansoori Derakhshan

Keyword(s):

Hearing Loss ◽

In Silico ◽

Standard Procedure ◽

In Silico Analysis ◽

Missense Variant ◽

12S Rrna ◽

Pathogenic Variants ◽

Genetic Hearing Loss ◽

Syndromic Hearing Loss ◽

Silico Analysis

Abstract Background: Genetic hearing loss (GHL) is a common heterogeneous disorder that can affect all ages, ethnicities, and genders. The most common form of hearing loss (HL) is autosomal recessive non-syndromic hearing loss (ARNSHL) and in most cases specific genotype-phenotype correlation is indistinguishable. This study aimed to identify the genetic cause of hearing loss in an Iranian Azeri Turkish ethnicity family with consanguine marriage which is negative for GJB2, GJB6 and mitochondrially encoded 12S RRNA (MT-RNR1) deleterious mutations.Methods: Targeted genome sequencing was applied for the detection of possible genetic causes of HL in this family. Co-segregation and in silico analysis of variant was performed by standard procedure.Results: A missense variant, c.499G>A, was identified in the ESRRB gene. Healthy and affected members of the family confirmed co-segregation of the variant with ARNSHL in the pedigree and then the pathogenicity of the variant was confirmed by in silico analysis and ACMG Guidelines. Conclusion: We report a novel missense variant in the ESRRB gene which seems to be a pathogenic variant. The result of this study suggests that the genetic background of hearing loss patients plays important role in the pathogenicity; moreover, targeted genomic capture is a powerful method that can discover pathogenic variants in heterogeneous disorders.

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Biallelic VPS35L pathogenic variants cause 3C/Ritscher-Schinzel-like syndrome through dysfunction of retriever complex

Journal of Medical Genetics ◽

10.1136/jmedgenet-2019-106213 ◽

2019 ◽

Vol 57 (4) ◽

pp. 245-253 ◽

Cited By ~ 3

Author(s):

Kohji Kato ◽

Yasuyoshi Oka ◽

Hideki Muramatsu ◽

Filipp F Vasilev ◽

Takanobu Otomo ◽

...

Keyword(s):

Core Protein ◽

Early Stage ◽

Critical Role ◽

Missense Variant ◽

Compound Heterozygous ◽

Chondrodysplasia Punctata ◽

Loss Of Function ◽

Skeletal Malformation ◽

Endosomal Membrane ◽

Pathogenic Variants

Background3C/Ritscher-Schinzel syndrome is characterised by congenital cranio-cerebello-cardiac dysplasia, where CCDC22 and WASHC5 are accepted as the causative genes. In combination with the retromer or retriever complex, these genes play a role in endosomal membrane protein recycling. We aimed to identify the gene abnormality responsible for the pathogenicity in siblings with a 3C/Ritscher-Schinzel-like syndrome, displaying cranio-cerebello-cardiac dysplasia, coloboma, microphthalmia, chondrodysplasia punctata and complicated skeletal malformation.MethodsExome sequencing was performed to identify pathogenic variants. Cellular biological analyses and generation of knockout mice were carried out to elucidate the gene function and pathophysiological significance of the identified variants.ResultsWe identified compound heterozygous pathogenic variants (c.1097dup; p.Cys366Trpfs*28 and c.2755G>A; p.Ala919Thr) in the VPS35L gene, which encodes a core protein of the retriever complex. The identified missense variant lacked the ability to form the retriever complex, and the frameshift variant induced non-sense-mediated mRNA decay, thereby confirming biallelic loss of function of VPS35L. In addition, VPS35L knockout cells showed decreased autophagic function in nutrient-rich and starvation conditions, as well as following treatment with Torin 1. We also generated Vps35l−/− mice and demonstrated that they were embryonic lethal at an early stage, between E7.5 and E10.5.ConclusionsOur results suggest that biallelic loss-of-function variants in VPS35L underlies 3C/Ritscher-Schinzel-like syndrome. Furthermore, VPS35L is necessary for autophagic function and essential for early embryonic development. The data presented here provide a new insight into the critical role of the retriever complex in fetal development.

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Novel Pathogenic Variants in PJVK, the Gene Encoding Pejvakin, in Subjects with Autosomal Recessive Non-Syndromic Hearing Impairment and Auditory Neuropathy Spectrum Disorder

Genes ◽

10.3390/genes13010149 ◽

2022 ◽

Vol 13 (1) ◽

pp. 149

Author(s):

María Domínguez-Ruiz ◽

Montserrat Rodríguez-Ballesteros ◽

Marta Gandía ◽

Elena Gómez-Rosas ◽

Manuela Villamar ◽

...

Keyword(s):

Hearing Impairment ◽

Autosomal Recessive ◽

Auditory Neuropathy ◽

Spectrum Disorder ◽

Gene Encoding ◽

Auditory Neuropathy Spectrum Disorder ◽

Familial Cases ◽

Pathogenic Variants ◽

Cochlear Hearing Loss ◽

Syndromic Hearing Impairment

Pathogenic variants in the PJVK gene cause the DFNB59 type of autosomal recessive non-syndromic hearing impairment (AR-NSHI). Phenotypes are not homogeneous, as a few subjects show auditory neuropathy spectrum disorder (ANSD), while others show cochlear hearing loss. The numbers of reported cases and pathogenic variants are still small to establish accurate genotype-phenotype correlations. We investigated a cohort of 77 Spanish familial cases of AR-NSHI, in whom DFNB1 had been excluded, and a cohort of 84 simplex cases with isolated ANSD in whom OTOF variants had been excluded. All seven exons and exon-intron boundaries of the PJVK gene were sequenced. We report three novel DFNB59 cases, one from the AR-NSHI cohort and two from the ANSD cohort, with stable, severe to profound NSHI. Two of the subjects received unilateral cochlear implantation, with apparent good outcomes. Our study expands the spectrum of PJVK mutations, as we report four novel pathogenic variants: p.Leu224Arg, p.His294Ilefs*43, p.His294Asp and p.Phe317Serfs*20. We review the reported cases of DFNB59, summarize the clinical features of this rare subtype of AR-NSHI and discuss the involvement of PJVK in ANSD.

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