Whole exome sequencing identifies rare coding variants in novel human-mouse ortholog genes in African individuals diagnosed with non-syndromic hearing impairment

Physiologically, the human and murine hearing systems are very similar, justifying the extensive use of mice in experimental models for hearing impairment (HI). About 340 murine HI genes have been reported; however, whether variants in all human-mouse ortholog genes contribute to HI has been rarely investigated. In humans, nearly 120 HI genes have been identified to date, with GJB2 and GJB6 variants accounting for half of congenital HI cases, of genetic origin, in populations of European and Asian ancestries, but not in most African populations. The contribution of variants in other known genes of HI among the populations of African ancestry is poorly studied and displays the lowest pick-up rate. We used whole exome sequencing (WES) to investigate pathogenic and likely pathogenic (PLP) variants in 34 novel human-mouse orthologs HI genes, in 40 individuals from Cameroon and South Africa diagnosed with non-syndromic hearing impairment (NSHI), and compared the data to WES data of 129 ethnically matched controls. In addition, protein modeling for selected PLP gene variants, gene enrichment, and network analyses were performed. A total of 4/38 murine genes, d6wsu163e, zfp719, grp152 and minar2, had no human orthologs. WES identified three rare PLP variants in 3/34 human-mouse orthologs genes in three unrelated Cameroonian patients, namely: OCM2, c.227G>C p.(Arg76Thr) and LRGI1, c.1657G>A p.(Gly533Arg) in a heterozygous state, and a PLP variant MCPH1, c.2311C>G p.(Pro771Ala) in a homozygous state. In silico functional analyses suggest that these human-mouse ortholog genes functionally co-expressed interactions with well-established HI genes: GJB2 and GJB6. The study found one homozygous variant in MCPH1, likely to explain HI in one patient, and suggests that human-mouse ortholog variants could contribute to the understanding of the physiology of hearing in humans. Impact statement Despite, human and murine hearing system being very similar, the contribution of variants in relevant mouse-ortholog genes to hearing impairment (HI) has not been fully investigated. The contribution of variants in the known non-syndromic hearing impairment (NSHI) genes among Africans is poorly studied, suggesting that the novel gene(s) and mutations are yet to be discovered in NSHI in the African populations. Using whole exome sequencing (WES), this study identified rare candidate pathogenic and likely pathogenic (PLP) variants in 3/34 novel human-mouse ortholog genes in 3/40 individuals, with one homozygous variant, MCPH1, c.2311C>G p.(Pro771Ala), likely to explain HI in one patient. In silico functional analyses suggest that these human-mouse ortholog genes could contribute to the understanding of the physiology of hearing in humans and thus the variants identified in those genes deserve additional investigations.

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Combining whole exome sequencing with in silico analysis and clinical data to identify candidate variants in pediatric left ventricular noncompaction

International Journal of Cardiology ◽

10.1016/j.ijcard.2021.11.001 ◽

2021 ◽

Author(s):

John Collyer ◽

Fuyi Xu ◽

Undral Munkhsaikhan ◽

Neely F. Alberson ◽

Buyan-Ochir Orgil ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Clinical Data ◽

In Silico ◽

In Silico Analysis ◽

Left Ventricular ◽

Left Ventricular Noncompaction ◽

Ventricular Noncompaction ◽

Whole Exome ◽

Silico Analysis

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Whole exome sequencing identifies a novel mutation in ASPM and ultra-rare mutation in CDK5RAP2 causing Primary microcephaly in consanguineous Pakistani families

Pakistan Journal of Medical Sciences ◽

10.12669/pjms.38.1.4464 ◽

2021 ◽

Vol 38 (1) ◽

Author(s):

Ehtisham ul Haq Makhdoom ◽

Haseeb Anwar ◽

Shahid Mahmood Baig ◽

Ghulam Hussain

Keyword(s):

Intellectual Disability ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Novel Mutation ◽

Speech Impairment ◽

Primary Microcephaly ◽

Rare Mutation ◽

Homozygous Variant ◽

Whole Exome ◽

Pakistani Families

Background & Objectives: Primary Microcephaly (MCPH) is a rare neurogenetic disease, manifesting congenitally reduced head circumference and non-progressive intellectual disability (ID). To date, twenty-eight genes with biallelic mutations have been reported for this disorder. The study aimed for molecular genetic characterization of Pakistani families segregating MCPH. Methods: We studied two unrelated consanguineous families (family A and B) presenting >2 patients with diagnostic symptoms of MCPH, born to asymptomatic parents. We employed whole-exome sequencing (WES) of probands to find putative causal mutations. The candidate variants were further confirmed and analyzed for co-segregation by Sanger sequencing of all available members of each family. This study was conducted at Government College University, Faisalabad, Pakistan, and Cologne Center for Genomics (CCG), University of Cologne, Germany; during 2017-2020. Results: We identified a novel homozygous variant c.10097_10098delGA, p.(Gly3366Glufs*19) in exon 26 of ASPM gene in family A which presents with moderate intellectual disability, speech impairment, visual abnormalities, seizures, and ptyalism. Family B was found to segregate nonsense, homozygous variant c.448C>T p.(Arg150*) in CDK5RAP2. The patients also exhibited mild to severe seizures without ptyalism that has not been previously reported in patients with mutations in the CDK5RAP2 gene. Conclusion: We report a novel mutation in ASPM and ultra-rare mutation in the CDK5RAP2 gene, both causing primary microcephaly. The study expands the mutational spectrum of the ASPM gene to 212, and also adds to the clinical spectrum of CDK5RAP2 mutations. It also demonstrated the utility of WES in the investigation and genetic diagnosis of genetically heterogeneous disorders like MCPH. These findings would aid in diagnostic and preventive strategies including carrier screening, cascade testing, and genetic counselling. doi: https://doi.org/10.12669/pjms.38.1.4464 How to cite this:Makhdoom EH, Anwar H, Baig SM, Hussain G. Whole exome sequencing identifies a novel mutation in ASPM and ultra-rare mutation in CDK5RAP2 causing Primary microcephaly in consanguineous Pakistani families. Pak J Med Sci. 2022;38(1):---------. doi: https://doi.org/10.12669/pjms.38.1.4464 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Homozygous TRPV4 mutation causes congenital distal spinal muscular atrophy and arthrogryposis

10.1101/402388 ◽

2018 ◽

Author(s):

Jose Velilla ◽

Michael Mario Marchetti ◽

Agnes Toth-Petroczy ◽

Claire Grosgogeat ◽

Alexis H Bennett ◽

...

Keyword(s):

Spinal Muscular Atrophy ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

In Silico ◽

Muscular Atrophy ◽

Structural Modeling ◽

Recessive Mutation ◽

Homozygous Mutation ◽

Functional Studies ◽

Whole Exome

AbstractObjectiveThe objective of this study is to identify the genetic cause of disease in a congenital form of congenital spinal muscular atrophy and arthrogryposis (CSMAA).MethodsA 2-year-old boy was diagnosed with arthrogryposis multiplex congenita, severe skeletal abnormalities, torticollis, vocal cord paralysis and diminished lower limb movement. Whole exome sequencing was performed on the proband and family members. In silico modeling of protein structure and heterologous protein expression and cytotoxicity assays were performed to validate pathogenicity of the identified variant.ResultsWhole exome sequencing revealed a homozygous mutation in the TRPV4 gene (c.281C>T; p.S94L). The identification of a recessive mutation in TRPV4 extends the spectrum of mutations in recessive forms of the TRPV4-associated disease. p.S94L and other previously identified TRPV4 variants in different protein domains were compared in structural modeling and functional studies. In silico structural modeling suggests that the p.S94L mutation is in the disordered N-terminal region proximal to important regulatory binding sites for phosphoinositides and for PACSIN3, which could lead to alterations in trafficking and/or channel sensitivity. Functional studies by western blot and immunohistochemical analysis show that p.S94L reduces TRPV4 protein stability because of increased cytotoxicity and therefore involves a gain-of-function mechanism.ConclusionThis study identifies a novel homozygous mutation in TRPV4 as a cause of the recessive form of congenital spinal muscular atrophy and arthrogryposis.

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Whole Exome Sequencing and in silico Determination of the Magnitude of Alloreactive Antigen Presentation on HLA DRB1 in Allogeneic Stem Cell Transplant Recipients

Biology of Blood and Marrow Transplantation ◽

10.1016/j.bbmt.2016.12.339 ◽

2017 ◽

Vol 23 (3) ◽

pp. S199-S200

Author(s):

Ali Raied Salman ◽

Vishal N. Koparde ◽

Charles E. Hall ◽

David J. Kobulnicky ◽

Allison F. Scalora ◽

...

Keyword(s):

Stem Cell ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

In Silico ◽

Stem Cell Transplant ◽

Cell Transplant ◽

Allogeneic Stem Cell Transplant ◽

Transplant Recipients ◽

Whole Exome

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In Silico Derivation of HLA-Specific Alloreactivity Potential from Whole Exome Sequencing of Stem Cell Transplant Donor-Recipient Pairs

Biology of Blood and Marrow Transplantation ◽

10.1016/j.bbmt.2013.12.454 ◽

2014 ◽

Vol 20 (2) ◽

pp. S269-S270 ◽

Cited By ~ 1

Author(s):

Maximilian Jameson-Lee ◽

Vishal N. Koparde ◽

Juliana K. Sampson ◽

Allison F. Scalora ◽

Haniya Khalid ◽

...

Keyword(s):

Stem Cell ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

In Silico ◽

Stem Cell Transplant ◽

Cell Transplant ◽

Whole Exome

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A Novel BBS9 Mutation Identified via Whole-Exome Sequencing in a Chinese Family with Bardet-Biedl Syndrome

BioMed Research International ◽

10.1155/2021/4514967 ◽

2021 ◽

Vol 2021 ◽

pp. 1-5

Author(s):

Yue Zhang ◽

Manhong Xu ◽

Minglian Zhang ◽

Guoxing Yang ◽

Xiaorong Li

Keyword(s):

Mental Retardation ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Sanger Sequencing ◽

Chinese Family ◽

Cone Dystrophy ◽

Bardet Biedl Syndrome ◽

Homozygous Variant ◽

Whole Exome

Bardet-Biedl syndrome (BBS) is a genetically heterogeneous disorder characterized by polydactyly, obesity, rod-cone dystrophy, and mental retardation. Twenty-one genes have been identified as causing BBS. This study collected a BBS pedigree from two patients and performed whole-exome sequencing on one patient. We identified a novel homozygous variant c.1114C>T (p.Q372X) in the BBS9 of the two siblings. This variant was confirmed and completely cosegregated with the disease of this family by Sanger sequencing. We report a novel homozygous variant c.1114C>T in the BBS9 gene in a Chinese family.

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