Genetic Candidate Variants in Two Multigenerational Families with Childhood Apraxia of Speech.
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.
Dpt. of Speech and Hearing Sciences, Arizona State University, Tempe, Arizona, United States of America.|Dpt. of Communication Sciences and Disorders, Saint Louis University, Saint Louis, Missouri, United States of America.|Dpt. of Speech and Hearing Sciences, University of Washington, Seattle, Washington, United States of America.
Beate
0000-0002-9083-8522
B
Peter
Div. of Medical Genetics, Dpt. of Medicine, University of Washington, Seattle, Washington, United States of America.|Dpt. of Biostatistics, University of Washington, Seattle, Washington, United States of America.
Ellen M
EM
Wijsman
Div. of Medical Genetics, Dpt. of Medicine, University of Washington, Seattle, Washington, United States of America.
Alejandro Q
AQ
Nato
Div. of Medical Genetics, Dpt. of Medicine, University of Washington, Seattle, Washington, United States of America.
Mark M
MM
Matsushita
Dpt. of Communication Sciences and Disorders, University of Utah, Salt Lake City, Utah, United States of America.
Kathy L
KL
Chapman
Dpt. of Environmental and Occupational Health, Environmental Toxicology, University of Washington, Seattle, Washington, United States of America.
Ian B
IB
Stanaway
Div. of Medical Genetics, Dpt. of Medicine, University of Washington, Seattle, Washington, United States of America.
John
J
Wolff
Div. of Medical Genetics, Dpt. of Medicine, University of Washington, Seattle, Washington, United States of America.
Kaori
K
Oda
Div. of Medical Genetics, Dpt. of Medicine, University of Washington, Seattle, Washington, United States of America.
Virginia B
VB
Gabo
Div. of Medical Genetics, Dpt. of Medicine, University of Washington, Seattle, Washington, United States of America.|Dpt. of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington, United States of America.
Wendy H
WH
Raskind
D001072:Apraxias / Q000235:genetics*; D056915:DNA Copy Number Variations / Q000235:genetics*; D059472:Exome / Q000235:genetics; D005260:Female; D008040:Genetic Linkage / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008126:Lod Score; D008297:Male; D010375:Pedigree; D012306:Risk; D013060:Speech / Q000502:physiology*