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Whole Exome Sequencing Identified a Novel Biallelic SMARCAL1 Mutation in the Extremely Rare Disease SIOD

Schimke immuno-osseous dysplasia (SIOD) is an extremely rare autosomal recessive pleiotropic disease. Although biallelic mutations in SMARCAL1 gene have been reported to be the genetic etiology of SIOD, its molecular diagnosis has been challenging in a relatively proportion of cases due to the extre...

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Autores principales: Jin, Jing, Wu, Keke, Liu, Zhenwei, Chen, Xiaomin, Jiang, Shan, Wang, Zhen, Li, Weixing
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6591458/
https://www.ncbi.nlm.nih.gov/pubmed/31275356
http://dx.doi.org/10.3389/fgene.2019.00565
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author Jin, Jing
Wu, Keke
Liu, Zhenwei
Chen, Xiaomin
Jiang, Shan
Wang, Zhen
Li, Weixing
author_facet Jin, Jing
Wu, Keke
Liu, Zhenwei
Chen, Xiaomin
Jiang, Shan
Wang, Zhen
Li, Weixing
author_sort Jin, Jing
collection PubMed
description Schimke immuno-osseous dysplasia (SIOD) is an extremely rare autosomal recessive pleiotropic disease. Although biallelic mutations in SMARCAL1 gene have been reported to be the genetic etiology of SIOD, its molecular diagnosis has been challenging in a relatively proportion of cases due to the extreme rarity. Here, we made a definitive SIOD diagnosis of a 5-year-old girl with an extremely mild phenotype by applying whole exome sequencing (WES). As a result, a novel maternal mutation (c.2141+5G > A) confirmed to create a novel splice donor site combined with a known paternal mutation (c.1933C > T; p.Arg645Cys) were detected. In addition, previous reported SIOD cases showed excessive enrichment for mutations in the helicase ATP-binding and C-terminal domains of SMARCAL1. Similarly, the novel mutation we identified caused a mutant protein truncated in the SMARCAL1 C-terminus. Interestingly, based on the phenotypic profile, compared to reported cases, the patient in our study exhibited milder symptoms with renal dysfunctions limited to asymptomatic proteinuria, but no neurological signs or recurrent infections. Moreover, we identified 73 SMARCAL1-interacting genes, which formed a significant interconnected interaction network with roles in disease-related pathways such as double-strand break repair via homologous recombination, DNA repair, and replication fork processing. Notably, the top 15 SMARCAL1-interacting genes all showed a similar renal temporal expression pattern. Altogether, to our knowledge, the case in this study is the first case diagnosed originally based on a genetic test via WES rather than a characteristic phenotype. The identification of the novel allelic mutation (c.2141+5G > A) extends the phenotypic spectrum of SMARCAL1 mutations and the following bioinformatics analysis presents additional genetic evidence to illustrate the role of SMARCAL1 in SIOD.
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spelling pubmed-65914582019-07-02 Whole Exome Sequencing Identified a Novel Biallelic SMARCAL1 Mutation in the Extremely Rare Disease SIOD Jin, Jing Wu, Keke Liu, Zhenwei Chen, Xiaomin Jiang, Shan Wang, Zhen Li, Weixing Front Genet Genetics Schimke immuno-osseous dysplasia (SIOD) is an extremely rare autosomal recessive pleiotropic disease. Although biallelic mutations in SMARCAL1 gene have been reported to be the genetic etiology of SIOD, its molecular diagnosis has been challenging in a relatively proportion of cases due to the extreme rarity. Here, we made a definitive SIOD diagnosis of a 5-year-old girl with an extremely mild phenotype by applying whole exome sequencing (WES). As a result, a novel maternal mutation (c.2141+5G > A) confirmed to create a novel splice donor site combined with a known paternal mutation (c.1933C > T; p.Arg645Cys) were detected. In addition, previous reported SIOD cases showed excessive enrichment for mutations in the helicase ATP-binding and C-terminal domains of SMARCAL1. Similarly, the novel mutation we identified caused a mutant protein truncated in the SMARCAL1 C-terminus. Interestingly, based on the phenotypic profile, compared to reported cases, the patient in our study exhibited milder symptoms with renal dysfunctions limited to asymptomatic proteinuria, but no neurological signs or recurrent infections. Moreover, we identified 73 SMARCAL1-interacting genes, which formed a significant interconnected interaction network with roles in disease-related pathways such as double-strand break repair via homologous recombination, DNA repair, and replication fork processing. Notably, the top 15 SMARCAL1-interacting genes all showed a similar renal temporal expression pattern. Altogether, to our knowledge, the case in this study is the first case diagnosed originally based on a genetic test via WES rather than a characteristic phenotype. The identification of the novel allelic mutation (c.2141+5G > A) extends the phenotypic spectrum of SMARCAL1 mutations and the following bioinformatics analysis presents additional genetic evidence to illustrate the role of SMARCAL1 in SIOD. Frontiers Media S.A. 2019-06-18 /pmc/articles/PMC6591458/ /pubmed/31275356 http://dx.doi.org/10.3389/fgene.2019.00565 Text en Copyright © 2019 Jin, Wu, Liu, Chen, Jiang, Wang and Li. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Genetics
Jin, Jing
Wu, Keke
Liu, Zhenwei
Chen, Xiaomin
Jiang, Shan
Wang, Zhen
Li, Weixing
Whole Exome Sequencing Identified a Novel Biallelic SMARCAL1 Mutation in the Extremely Rare Disease SIOD
title Whole Exome Sequencing Identified a Novel Biallelic SMARCAL1 Mutation in the Extremely Rare Disease SIOD
title_full Whole Exome Sequencing Identified a Novel Biallelic SMARCAL1 Mutation in the Extremely Rare Disease SIOD
title_fullStr Whole Exome Sequencing Identified a Novel Biallelic SMARCAL1 Mutation in the Extremely Rare Disease SIOD
title_full_unstemmed Whole Exome Sequencing Identified a Novel Biallelic SMARCAL1 Mutation in the Extremely Rare Disease SIOD
title_short Whole Exome Sequencing Identified a Novel Biallelic SMARCAL1 Mutation in the Extremely Rare Disease SIOD
title_sort whole exome sequencing identified a novel biallelic smarcal1 mutation in the extremely rare disease siod
topic Genetics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6591458/
https://www.ncbi.nlm.nih.gov/pubmed/31275356
http://dx.doi.org/10.3389/fgene.2019.00565
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