Genetic Candidate Variants in Two Multigenerational Families with Childhood Apraxia of Speech

Abstract

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.

Sequential processing deficit as a shared persisting biomarker in dyslexia and childhood apraxia of speech

“…As mentioned, the cerebellum plays a crucial role not only in motor coordination but also in linguistic and cognitive functions, including reading. Our recent discoveries of CAS candidate genes that are highly expressed in the cerebellum (Peter et al, 2016) are consistent with the hypothesis that variations in different or multiple genes converge on the cerebellum, causing downstream difficulty with processing complex sequential information across domains. If so, a sequential processing deficit represents a shared biomarker of genetic etiology for dyslexia and CAS.…”

“…A study of a large multigenerational family with familial CAS led to the insight that sequential processing deficits can be observed across a wide range of task types, not only in oral and hand motor tasks but also during nonword decoding, spelling, and nonword repetition (Peter, Button, Stoel-Gammon, Chapman, & Raskind, 2013). In this family, CDH18 and eight other genes were identified as genes of interest (Peter et al, 2016), further supporting the view that sequential processing deficits have a genetic etiology. Interestingly, most of the identified genes in this family and the only candidate gene in another family with familial CAS (Peter et al, 2016) are highly expressed in the cerebellum.…”

“…In this family, CDH18 and eight other genes were identified as genes of interest (Peter et al, 2016), further supporting the view that sequential processing deficits have a genetic etiology. Interestingly, most of the identified genes in this family and the only candidate gene in another family with familial CAS (Peter et al, 2016) are highly expressed in the cerebellum.…”

“…Further, all adults in the phCAS group had at least two biological relatives with a current CAS diagnosis and a family history of CAS. In two of these families, candidate genes have already been identified and the family members who participated in this study were carriers of the genetic variants, a CDH18 mutation on chromosome 5 in one family (Peter et al, 2016) and a heterozygously deleted IGF2R – AIRN - SLC22A2 – SLC22A3 gene cluster on chromosome 6 in another family (Peter et al, 2017). In an additional family, a different candidate region on chromosome 6 was identified (Peter et al, 2012).…”

A Diagnostic Marker to Discriminate Childhood Apraxia of Speech From Speech Delay: I. Development and Description of the Pause Marker

“…Perceptual and acoustic data analyses in the present study used the methods in these articles and additional reference databases of speakers with typical speech and SD to study genetic and neurodevelopmental substrates of pediatric speech and MSD (e.g., Laffin et al, 2012;Peter et al, 2016;Raca et al, 2013;Rice et al;Shriberg, Paul, Black, & van Santen, 2011;Shriberg, Potter, & Strand, 2011;Worthey et al, 2013). Since the two 2010 methodological reports and the latter substantive articles, extensions of the SDCS have been developed to finalize the speech and motor speech classifications.…”