TY - JOUR
T1 - Genetic candidate variants in two multigenerational families with childhood apraxia of speech
AU - Peter, Beate
AU - Wijsman, Ellen M.
AU - Nato, Alejandro Q.
AU - University of Washington Center for Mendelian Genomics, of Washington Center for Mendelian Genomics
AU - Matsushita, Mark M.
AU - Chapman, Kathy L.
AU - Stanaway, Ian B.
AU - Wolff, John
AU - Oda, Kaori
AU - Gabo, Virginia B.
AU - Raskind, Wendy H.
AU - Bamshad, M.
AU - Nickerson, D.
AU - Shendure, J.
N1 - Funding Information:
The authors are deeply grateful to the participants whose time and effort made this study possible. The following funding sources are gratefully acknowledged: American Speech-Language-Hearing Foundation New Century Scholars Research Grant (B. Peter), NIDCD T32DC00033 (B. Peter), NIDCD R03DC010886 (B. Peter), R01HD054562 (W. H. Raskind), and R01MH094293 (E. Wijsman). SNP genotyping and exome sequencing were provided by the University of Washington Center for Mendelian Genomics (UW CMG) and was funded by the National Human Genome Research Institute and NIH grant 1U54HG006493 to the three UW CMG members, Drs. M. Bamshad, D. Nickerson, and J. Shendure. Ian Stanaway was supported under grants from the Environmental Health Sciences of the National Institutes of Health (T32ES015459 and 5P01 ES009601) and the EPA (RD-83451401). Many thanks to Drs. E. Thompson and E. Blue for help with MORGAN program implementation and to Drs. Bamshad, Nickerson, and Shendure for helpful consultation.
Publisher Copyright:
© 2016 Peter et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2016/4
Y1 - 2016/4
N2 - Childhood apraxia of speech (CAS) is a severe and socially debilitating form of speech sound disorder with suspected genetic involvement, but the genetic etiology is not yet well understood. Very few known or putative causal genes have been identified to date, e.g., FOXP2 and BCL11A. Building a knowledge base of the genetic etiology of CAS will make it possible to identify infants at genetic risk and motivate the development of effective very early intervention programs. We investigated the genetic etiology of CAS in two large multigenerational families with familial CAS. Complementary genomic methods included Markov chain Monte Carlo linkage analysis, copy-number analysis, identity-by-descent sharing, and exome sequencing with variant filtering. No overlaps in regions with positive evidence of linkage between the two families were found. In one family, linkage analysis detected two chromosomal regions of interest, 5p15.1-p14.1, and 17p13.1-q11.1, inherited separately from the two founders. Single-point linkage analysis of selected variants identified CDH18 as a primary gene of interest and additionally, MYO10, NIPBL, GLP2R, NCOR1, FLCN, SMCR8, NEK8, and ANKRD12, possibly with additive effects. Linkage analysis in the second family detected five regions with LOD scores approaching the highest values possible in the family. A gene of interest was C4orf21 (ZGRF1) on 4q25-q28.2. Evidence for previously described causal copy-number variations and validated or suspected genes was not found. Results are consistent with a heterogeneous CAS etiology, as is expected in many neurogenic disorders. Future studies will investigate genome variants in these and other families with CAS.
AB - Childhood apraxia of speech (CAS) is a severe and socially debilitating form of speech sound disorder with suspected genetic involvement, but the genetic etiology is not yet well understood. Very few known or putative causal genes have been identified to date, e.g., FOXP2 and BCL11A. Building a knowledge base of the genetic etiology of CAS will make it possible to identify infants at genetic risk and motivate the development of effective very early intervention programs. We investigated the genetic etiology of CAS in two large multigenerational families with familial CAS. Complementary genomic methods included Markov chain Monte Carlo linkage analysis, copy-number analysis, identity-by-descent sharing, and exome sequencing with variant filtering. No overlaps in regions with positive evidence of linkage between the two families were found. In one family, linkage analysis detected two chromosomal regions of interest, 5p15.1-p14.1, and 17p13.1-q11.1, inherited separately from the two founders. Single-point linkage analysis of selected variants identified CDH18 as a primary gene of interest and additionally, MYO10, NIPBL, GLP2R, NCOR1, FLCN, SMCR8, NEK8, and ANKRD12, possibly with additive effects. Linkage analysis in the second family detected five regions with LOD scores approaching the highest values possible in the family. A gene of interest was C4orf21 (ZGRF1) on 4q25-q28.2. Evidence for previously described causal copy-number variations and validated or suspected genes was not found. Results are consistent with a heterogeneous CAS etiology, as is expected in many neurogenic disorders. Future studies will investigate genome variants in these and other families with CAS.
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U2 - 10.1371/journal.pone.0153864
DO - 10.1371/journal.pone.0153864
M3 - Article
C2 - 27120335
AN - SCOPUS:84966375756
SN - 1932-6203
VL - 11
JO - PloS one
JF - PloS one
IS - 4
M1 - e0153864
ER -