Heterozygous variants in ACTL6A, encoding a component of the BAF complex, are associated with intellectual disability

Ronit Marom, Mahim Jain, Lindsay C. Burrage, I. Wen Song, Brett H. Graham, Chester W. Brown, Servi J.C. Stevens, Alexander P.A. Stegmann, Andrew T. Gunter, Julie D. Kaplan, Ralitza M Gavrilova, Marwan Shinawi, Jill A. Rosenfeld, Yangjin Bae, Alyssa A. Tran, Yuqing Chen, James T. Lu, Richard A. Gibbs, Christine Eng, Yaping YangJustine Rousseau, Bert B.A. de Vries, Philippe M. Campeau, Brendan Lee

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Pathogenic variants in genes encoding components of the BRG1-associated factor (BAF) chromatin remodeling complex have been associated with intellectual disability syndromes. We identified heterozygous, novel variants in ACTL6A, a gene encoding a component of the BAF complex, in three subjects with varying degrees of intellectual disability. Two subjects have missense variants affecting highly conserved amino acid residues within the actin-like domain. Missense mutations in the homologous region in yeast actin were previously reported to be dominant lethal and were associated with impaired binding of the human ACTL6A to β-actin and BRG1. A third subject has a splicing variant that creates an in-frame deletion. Our findings suggest that the variants identified in our subjects may have a deleterious effect on the function of the protein by disturbing the integrity of the BAF complex. Thus, ACTL6A gene mutation analysis should be considered in patients with intellectual disability, learning disabilities, or developmental language disorder.

Original languageEnglish (US)
JournalHuman Mutation
DOIs
StateAccepted/In press - 2017

Fingerprint

Intellectual Disability
Actins
Gene Components
Language Development Disorders
Chromatin Assembly and Disassembly
Learning Disorders
Missense Mutation
Genes
Yeasts
Amino Acids
Mutation
Proteins

Keywords

  • ACTL6A
  • BAF complex
  • Intellectual disability
  • Speech delay

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Marom, R., Jain, M., Burrage, L. C., Song, I. W., Graham, B. H., Brown, C. W., ... Lee, B. (Accepted/In press). Heterozygous variants in ACTL6A, encoding a component of the BAF complex, are associated with intellectual disability. Human Mutation. https://doi.org/10.1002/humu.23282

Heterozygous variants in ACTL6A, encoding a component of the BAF complex, are associated with intellectual disability. / Marom, Ronit; Jain, Mahim; Burrage, Lindsay C.; Song, I. Wen; Graham, Brett H.; Brown, Chester W.; Stevens, Servi J.C.; Stegmann, Alexander P.A.; Gunter, Andrew T.; Kaplan, Julie D.; Gavrilova, Ralitza M; Shinawi, Marwan; Rosenfeld, Jill A.; Bae, Yangjin; Tran, Alyssa A.; Chen, Yuqing; Lu, James T.; Gibbs, Richard A.; Eng, Christine; Yang, Yaping; Rousseau, Justine; de Vries, Bert B.A.; Campeau, Philippe M.; Lee, Brendan.

In: Human Mutation, 2017.

Research output: Contribution to journalArticle

Marom, R, Jain, M, Burrage, LC, Song, IW, Graham, BH, Brown, CW, Stevens, SJC, Stegmann, APA, Gunter, AT, Kaplan, JD, Gavrilova, RM, Shinawi, M, Rosenfeld, JA, Bae, Y, Tran, AA, Chen, Y, Lu, JT, Gibbs, RA, Eng, C, Yang, Y, Rousseau, J, de Vries, BBA, Campeau, PM & Lee, B 2017, 'Heterozygous variants in ACTL6A, encoding a component of the BAF complex, are associated with intellectual disability', Human Mutation. https://doi.org/10.1002/humu.23282
Marom, Ronit ; Jain, Mahim ; Burrage, Lindsay C. ; Song, I. Wen ; Graham, Brett H. ; Brown, Chester W. ; Stevens, Servi J.C. ; Stegmann, Alexander P.A. ; Gunter, Andrew T. ; Kaplan, Julie D. ; Gavrilova, Ralitza M ; Shinawi, Marwan ; Rosenfeld, Jill A. ; Bae, Yangjin ; Tran, Alyssa A. ; Chen, Yuqing ; Lu, James T. ; Gibbs, Richard A. ; Eng, Christine ; Yang, Yaping ; Rousseau, Justine ; de Vries, Bert B.A. ; Campeau, Philippe M. ; Lee, Brendan. / Heterozygous variants in ACTL6A, encoding a component of the BAF complex, are associated with intellectual disability. In: Human Mutation. 2017.
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abstract = "Pathogenic variants in genes encoding components of the BRG1-associated factor (BAF) chromatin remodeling complex have been associated with intellectual disability syndromes. We identified heterozygous, novel variants in ACTL6A, a gene encoding a component of the BAF complex, in three subjects with varying degrees of intellectual disability. Two subjects have missense variants affecting highly conserved amino acid residues within the actin-like domain. Missense mutations in the homologous region in yeast actin were previously reported to be dominant lethal and were associated with impaired binding of the human ACTL6A to β-actin and BRG1. A third subject has a splicing variant that creates an in-frame deletion. Our findings suggest that the variants identified in our subjects may have a deleterious effect on the function of the protein by disturbing the integrity of the BAF complex. Thus, ACTL6A gene mutation analysis should be considered in patients with intellectual disability, learning disabilities, or developmental language disorder.",
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AU - Tran, Alyssa A.

AU - Chen, Yuqing

AU - Lu, James T.

AU - Gibbs, Richard A.

AU - Eng, Christine

AU - Yang, Yaping

AU - Rousseau, Justine

AU - de Vries, Bert B.A.

AU - Campeau, Philippe M.

AU - Lee, Brendan

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N2 - Pathogenic variants in genes encoding components of the BRG1-associated factor (BAF) chromatin remodeling complex have been associated with intellectual disability syndromes. We identified heterozygous, novel variants in ACTL6A, a gene encoding a component of the BAF complex, in three subjects with varying degrees of intellectual disability. Two subjects have missense variants affecting highly conserved amino acid residues within the actin-like domain. Missense mutations in the homologous region in yeast actin were previously reported to be dominant lethal and were associated with impaired binding of the human ACTL6A to β-actin and BRG1. A third subject has a splicing variant that creates an in-frame deletion. Our findings suggest that the variants identified in our subjects may have a deleterious effect on the function of the protein by disturbing the integrity of the BAF complex. Thus, ACTL6A gene mutation analysis should be considered in patients with intellectual disability, learning disabilities, or developmental language disorder.

AB - Pathogenic variants in genes encoding components of the BRG1-associated factor (BAF) chromatin remodeling complex have been associated with intellectual disability syndromes. We identified heterozygous, novel variants in ACTL6A, a gene encoding a component of the BAF complex, in three subjects with varying degrees of intellectual disability. Two subjects have missense variants affecting highly conserved amino acid residues within the actin-like domain. Missense mutations in the homologous region in yeast actin were previously reported to be dominant lethal and were associated with impaired binding of the human ACTL6A to β-actin and BRG1. A third subject has a splicing variant that creates an in-frame deletion. Our findings suggest that the variants identified in our subjects may have a deleterious effect on the function of the protein by disturbing the integrity of the BAF complex. Thus, ACTL6A gene mutation analysis should be considered in patients with intellectual disability, learning disabilities, or developmental language disorder.

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