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Identification of a Rare Novel KMT2C Mutation That Presents with Schizophrenia in a Multiplex Family

Schizophrenia is a complex genetic disorder involving many common variants with modest effects and rare mutations with high penetrance. Rare mutations associated with schizophrenia are highly heterogeneous and private for affected individuals and families. Identifying such mutations can help establi...

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Autores principales: Chen, Chia-Hsiang, Huang, Ailing, Huang, Yu-Shu, Fang, Ting-Hsuan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8707139/
https://www.ncbi.nlm.nih.gov/pubmed/34945726
http://dx.doi.org/10.3390/jpm11121254
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author Chen, Chia-Hsiang
Huang, Ailing
Huang, Yu-Shu
Fang, Ting-Hsuan
author_facet Chen, Chia-Hsiang
Huang, Ailing
Huang, Yu-Shu
Fang, Ting-Hsuan
author_sort Chen, Chia-Hsiang
collection PubMed
description Schizophrenia is a complex genetic disorder involving many common variants with modest effects and rare mutations with high penetrance. Rare mutations associated with schizophrenia are highly heterogeneous and private for affected individuals and families. Identifying such mutations can help establish the molecular diagnosis, elucidate the pathogenesis, and provide helpful genetic counseling for affected patients and families. We performed a whole-exome sequencing analysis to search for rare pathogenic mutations co-segregating with schizophrenia transmitted in a dominant inheritance in a two-generation multiplex family. We identified a rare missense mutation H1574R (Histidine1574Arginine, rs199796552) of KMT2C (lysine methyltransferase 2C) co-segregating with affected members in this family. The mutation is a novel deleterious mutation of KMT2C, not reported before in the literature. The KMT2C encodes a histone 3 lysine 4 (H3K4)-specific methyltransferase and involves epigenetic regulation of brain gene expression. Mutations of KMT2C have been found in neurodevelopmental disorders, such as Kleefstra syndrome, intellectual disability, and autism spectrum disorders. Our finding suggests that schizophrenia might be one of the clinical phenotype spectra of KMT2C mutations, and KMT2C might be a novel risk gene for schizophrenia. Nevertheless, the co-segregation of this mutation with schizophrenia in this family might also be due to chance; functional assays of this mutation are needed to address this issue.
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spelling pubmed-87071392021-12-25 Identification of a Rare Novel KMT2C Mutation That Presents with Schizophrenia in a Multiplex Family Chen, Chia-Hsiang Huang, Ailing Huang, Yu-Shu Fang, Ting-Hsuan J Pers Med Article Schizophrenia is a complex genetic disorder involving many common variants with modest effects and rare mutations with high penetrance. Rare mutations associated with schizophrenia are highly heterogeneous and private for affected individuals and families. Identifying such mutations can help establish the molecular diagnosis, elucidate the pathogenesis, and provide helpful genetic counseling for affected patients and families. We performed a whole-exome sequencing analysis to search for rare pathogenic mutations co-segregating with schizophrenia transmitted in a dominant inheritance in a two-generation multiplex family. We identified a rare missense mutation H1574R (Histidine1574Arginine, rs199796552) of KMT2C (lysine methyltransferase 2C) co-segregating with affected members in this family. The mutation is a novel deleterious mutation of KMT2C, not reported before in the literature. The KMT2C encodes a histone 3 lysine 4 (H3K4)-specific methyltransferase and involves epigenetic regulation of brain gene expression. Mutations of KMT2C have been found in neurodevelopmental disorders, such as Kleefstra syndrome, intellectual disability, and autism spectrum disorders. Our finding suggests that schizophrenia might be one of the clinical phenotype spectra of KMT2C mutations, and KMT2C might be a novel risk gene for schizophrenia. Nevertheless, the co-segregation of this mutation with schizophrenia in this family might also be due to chance; functional assays of this mutation are needed to address this issue. MDPI 2021-11-25 /pmc/articles/PMC8707139/ /pubmed/34945726 http://dx.doi.org/10.3390/jpm11121254 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Chen, Chia-Hsiang
Huang, Ailing
Huang, Yu-Shu
Fang, Ting-Hsuan
Identification of a Rare Novel KMT2C Mutation That Presents with Schizophrenia in a Multiplex Family
title Identification of a Rare Novel KMT2C Mutation That Presents with Schizophrenia in a Multiplex Family
title_full Identification of a Rare Novel KMT2C Mutation That Presents with Schizophrenia in a Multiplex Family
title_fullStr Identification of a Rare Novel KMT2C Mutation That Presents with Schizophrenia in a Multiplex Family
title_full_unstemmed Identification of a Rare Novel KMT2C Mutation That Presents with Schizophrenia in a Multiplex Family
title_short Identification of a Rare Novel KMT2C Mutation That Presents with Schizophrenia in a Multiplex Family
title_sort identification of a rare novel kmt2c mutation that presents with schizophrenia in a multiplex family
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8707139/
https://www.ncbi.nlm.nih.gov/pubmed/34945726
http://dx.doi.org/10.3390/jpm11121254
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