Dataset Information

Detection and quantification of a KIF11 mosaicism in a subject presenting familial exudative vitreoretinopathy with microcephaly.

ABSTRACT: Familial exudative vitreoretinopathy (FEVR) is an inherited retinal disorder, which is primarily characterized by abnormal development of retinal vasculature. In this study, we reported a subject presenting the clinical features of FEVR as well as microcephaly. Screening of the KIF11 gene in this patient revealed a novel heterozygous protein-truncating variant (c.2717del, p.(L906*), NM_004523.3). Segregation analysis in the unaffected parents using Sanger sequencing suggested the variant to be present in a mosaic state in the unaffected mother. KIF11 exon 19 which harbors the variant was amplified from the proband and her father, as well as three different tissues of the mother, followed by amplicon-based deep sequencing. This analysis revealed that the variant is present in different tissues of the mother at various rates, i.e. in blood (16.9%), saliva (20.7%), or skin biopsy-derived fibroblast cells (6.6%). These data demonstrate the importance of deep sequencing in unaffected parents upon detection of a genetic defect in isolated cases to detect possible mosaicisms, enabling a more reliable recurrence risk assessment and thereby improve genetic counseling.

SUBMITTER: Karjosukarso DW

PROVIDER: S-EPMC6244075 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Detection and quantification of a KIF11 mosaicism in a subject presenting familial exudative vitreoretinopathy with microcephaly.

Karjosukarso Dyah W DW Cremers Frans P M FPM van Nouhuys C Erik CE Collin Rob W J RWJ

European journal of human genetics : EJHG 20180904 12

Familial exudative vitreoretinopathy (FEVR) is an inherited retinal disorder, which is primarily characterized by abnormal development of retinal vasculature. In this study, we reported a subject presenting the clinical features of FEVR as well as microcephaly. Screening of the KIF11 gene in this patient revealed a novel heterozygous protein-truncating variant (c.2717del, p.(L906*), NM_004523.3). Segregation analysis in the unaffected parents using Sanger sequencing suggested the variant to be p ...[more]

PMID: 30181612

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Project description:BackgroundFamilial exudative vitreoretinopathy (FEVR) is a genetic eye disorder that leads to abnormal development of retinal blood vessels, resulting in vision impairment. This study aims to identify pathogenic variants by targeted exome sequencing in 9 independent pedigrees with FEVR and characterize the novel pathogenic variants by molecular dynamics simulation.MethodsClinical data were collected from 9 families with FEVR. The causative genes were screened by targeted next-generation sequencing (TGS) and verified by Sanger sequencing. In silico analyses (SIFT, Polyphen2, Revel, MutationTaster, and GERP + +) were carried out to evaluate the pathogenicity of the variants. Molecular dynamics was simulated to predict protein conformation and flexibility transformation alterations on pathogenesis. Furthermore, molecular docking techniques were employed to explore the interactions and binding properties between LRP5 and DKK1 proteins relevant to the disease.ResultsA 44% overall detection rate was achieved with four variants including c.4289delC: p.Pro1431Argfs*8, c.2073G > T: p.Trp691Cys, c.1801G > A: p.Gly601Arg in LRP5 and c.633 T > A: p.Tyr211* in TSPAN12 in 4 unrelated probands. Based on in silico analysis and ACMG standard, two of them, c.4289delC: p.Pro1431Argfs*8 and c.2073G > T: p.Trp691Cys of LRP5 were identified as novel pathogenic variants. Based on computational predictions using molecular dynamics simulations and molecular docking, there are indications that these two variants might lead to alterations in the secondary structure and spatial conformation of the protein, potentially impacting its rigidity and flexibility. Furthermore, these pathogenic variants are speculated to potentially influence hydrogen bonding interactions and could result in an increased binding affinity with the DKK1 protein.ConclusionsTwo novel genetic variants of the LRP5 gene were identified, expanding the range of mutations associated with FEVR. Through molecular dynamics simulations and molecular docking, the potential impact of these variants on protein structure and their interactions with the DKK1 protein has been explored. These findings provide further support for the involvement of these variants in the pathogenesis of the disease.

Dataset Information

Detection and quantification of a KIF11 mosaicism in a subject presenting familial exudative vitreoretinopathy with microcephaly.

Publications

Detection and quantification of a KIF11 mosaicism in a subject presenting familial exudative vitreoretinopathy with microcephaly.

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