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 H. Gavrilova; Marwan Shinawi; Jill A. Rosenfeld; Yangjin Bae; Alyssa A. Tran; Yuqing Chen; James T. Lu; Richard A. Gibbs; Christine Eng; Yaping Yang; Justine Rousseau; Bert B.A. de Vries; Philippe M. Campeau; Brendan Lee

doi:10.1002/humu.23282

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 H. 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

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18 Scopus citations

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 language	English
Pages (from-to)	1365-1371
Number of pages	7
Journal	Human mutation
Volume	38
Issue number	10
DOIs	https://doi.org/10.1002/humu.23282
State	Published - Oct 2017

Keywords

ACTL6A
BAF complex
intellectual disability
speech delay

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Marom, R., Jain, M., Burrage, L. C., Song, I. W., Graham, B. H., Brown, C. W., Stevens, S. J. C., Stegmann, A. P. A., Gunter, A. T., Kaplan, J. D., Gavrilova, R. H., Shinawi, M., Rosenfeld, J. A., Bae, Y., Tran, A. A., Chen, Y., Lu, J. T., Gibbs, R. A., Eng, C., ... Lee, B. (2017). Heterozygous variants in ACTL6A, encoding a component of the BAF complex, are associated with intellectual disability. Human mutation, 38(10), 1365-1371. https://doi.org/10.1002/humu.23282

@article{48f165c4c5f244dbb6abe77f6afaccbb,

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

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.",

keywords = "ACTL6A, BAF complex, intellectual disability, speech delay",

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

note = "Funding Information: We thank the patients and their families for their participation in our study. We also thank Brian Dawson for his help with preparation of figures for this manuscript. This project was supported by the Cytometry and Cell Sorting Core at Baylor College of Medicine with funding from the NIH (P30 AI036211, P30 CA125123, and S10 RR024574) and the expert assistance of Joel M. Sederstrom. The Department of Molecular and Human Genetics at Baylor College of Medicine receives revenue from clinical testing done at Baylor Genetics Laboratories. Publisher Copyright: {\textcopyright} 2017 Wiley Periodicals, Inc.",

year = "2017",

month = oct,

doi = "10.1002/humu.23282",

language = "English",

volume = "38",

pages = "1365--1371",

journal = "Human Mutation",

issn = "1059-7794",

number = "10",

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Marom, R, Jain, M, Burrage, LC, Song, IW, Graham, BH, Brown, CW, Stevens, SJC, Stegmann, APA, Gunter, AT, Kaplan, JD, Gavrilova, RH, 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, vol. 38, no. 10, pp. 1365-1371. https://doi.org/10.1002/humu.23282

TY - JOUR

T1 - Heterozygous variants in ACTL6A, encoding a component of the BAF complex, are associated with intellectual disability

AU - Marom, Ronit

AU - Jain, Mahim

AU - Burrage, Lindsay C.

AU - Song, I. Wen

AU - Graham, Brett H.

AU - Brown, Chester W.

AU - Stevens, Servi J.C.

AU - Stegmann, Alexander P.A.

AU - Gunter, Andrew T.

AU - Kaplan, Julie D.

AU - Gavrilova, Ralitza H.

AU - Shinawi, Marwan

AU - Rosenfeld, Jill A.

AU - Bae, Yangjin

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

N1 - Funding Information: We thank the patients and their families for their participation in our study. We also thank Brian Dawson for his help with preparation of figures for this manuscript. This project was supported by the Cytometry and Cell Sorting Core at Baylor College of Medicine with funding from the NIH (P30 AI036211, P30 CA125123, and S10 RR024574) and the expert assistance of Joel M. Sederstrom. The Department of Molecular and Human Genetics at Baylor College of Medicine receives revenue from clinical testing done at Baylor Genetics Laboratories. Publisher Copyright: © 2017 Wiley Periodicals, Inc.

PY - 2017/10

Y1 - 2017/10

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.

KW - ACTL6A

KW - BAF complex

KW - intellectual disability

KW - speech delay

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U2 - 10.1002/humu.23282

DO - 10.1002/humu.23282

M3 - Article

C2 - 28649782

AN - SCOPUS:85022185065

SN - 1059-7794

VL - 38

SP - 1365

EP - 1371

JO - Human Mutation

JF - Human Mutation

IS - 10

ER -

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

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