Novel candidate genes and regions for childhood apraxia of speech identified by array comparative genomic hybridization

1] University of Wisconsin-Madison, Madison, Wisconsin, USA [2] Wisconsin State Laboratory of Hygiene, Madison, Wisconsin, USA.
Genetics in medicine: official journal of the American College of Medical Genetics (Impact Factor: 7.33). 07/2012; 14(11). DOI: 10.1038/gim.2012.72
Source: PubMed


The goal of this study was to identify new candidate genes and genomic copy-number variations associated with a rare, severe, and persistent speech disorder termed childhood apraxia of speech. Childhood apraxia of speech is the speech disorder segregating with a mutation in FOXP2 in a multigenerational London pedigree widely studied for its role in the development of speech-language in humans.

A total of 24 participants who were suspected to have childhood apraxia of speech were assessed using a comprehensive protocol that samples speech in challenging contexts. All participants met clinical-research criteria for childhood apraxia of speech. Array comparative genomic hybridization analyses were completed using a customized 385K Nimblegen array (Roche Nimblegen, Madison, WI) with increased coverage of genes and regions previously associated with childhood apraxia of speech.

A total of 16 copy-number variations with potential consequences for speech-language development were detected in 12 or half of the 24 participants. The copy-number variations occurred on 10 chromosomes, 3 of which had two to four candidate regions. Several participants were identified with copy-number variations in two to three regions. In addition, one participant had a heterozygous FOXP2 mutation and a copy-number variation on chromosome 2, and one participant had a 16p11.2 microdeletion and copy-number variations on chromosomes 13 and 14.

Findings support the likelihood of heterogeneous genomic pathways associated with childhood apraxia of speech.

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Available from: Kathy Jakielski, May 03, 2014
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    • "CNTNAP2 is located downstream from and is regulated by FOXP2 (7q31), which has been linked to the occurrence of CAS in the oft-studied KE family [Lai, Fisher, Hurst, Vargha-Khadem, & Monaco, 2001; Vernes et al., 2008]. CNTNAP2 is closely related to FOXP2 and has been identified as a candidate gene for dyslexia, SLI, and autism [Laffin et al., 2012; Rodenas- Cuadrado, Ho, & Vernes, 2014]. To our knowledge, this is the first report to link variants in CNTNAP2 to CAS without comorbid reading, language, and cognitive impairments, which indicates that CNTNAP2 variants may be associated with deficits in speech production in the absence of comorbid reading, language, and cognitive impairments. "
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    ABSTRACT: Childhood apraxia of speech (CAS) is a debilitating pediatric speech disorder characterized by varying symptom profiles, comorbid deficits, and limited response to intervention. Specific Language Impairment (SLI) is an inherited pediatric language disorder characterized by delayed and/or disordered oral language skills including impaired semantics, syntax, and discourse. To date, the genes associated with CAS and SLI are not fully characterized. In the current study, we evaluated behavioral and genetic profiles of seven children with CAS and eight children with SLI, while ensuring all children were free of comorbid impairments. Deletions within CNTNAP2 were found in two children with CAS but not in any of the children with SLI. These children exhibited average to high performance on language and word reading assessments in spite of poor articulation scores. These findings suggest that genetic variation within CNTNAP2 may be related to speech production deficits. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part B Neuropsychiatric Genetics 06/2015; DOI:10.1002/ajmg.b.32325 · 3.42 Impact Factor
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    • "A number of distinct etiological mutations affecting this gene have been discovered, in different families and cases (Fisher and Scharff, 2009). These range from missense mutations (Lai et al., 2001; Laffin et al., 2012), non-sense mutations (MacDermot et al., 2005) and indels (Turner et al., 2013), to gross chromosomal abnormalities like translocations (Shriberg et al., 2006; Kosho et al., 2008) and deletions (Zeesman et al., 2006; Palka et al., 2012; Rice et al., 2012; Zilina et al., 2012). The most thoroughly studied FOXP2 disruption is a heterozygous missense mutation that co-segregates with speech and language disorder in 15 members of a three generation pedigree , known as the KE family (Fisher et al., 1998). "
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    ABSTRACT: The FOXP2 transcription factor is one of the most well-known genes to have been implicated in developmental speech and language disorders. Rare mutations disrupting the function of this gene have been described in different families and cases. In a large three-generation family carrying a missense mutation, neuroimaging studies revealed significant effects on brain structure and function, most notably in the inferior frontal gyrus, caudate nucleus, and cerebellum. After the identification of rare disruptive FOXP2 variants impacting on brain structure, several reports proposed that common variants at this locus may also have detectable effects on the brain, extending beyond disorder into normal phenotypic variation. These neuroimaging genetics studies used groups of between 14 and 96 participants. The current study assessed effects of common FOXP2 variants on neuroanatomy using voxel-based morphometry (VBM) and volumetric techniques in a sample of >1300 people from the general population. In a first targeted stage we analyzed single nucleotide polymorphisms (SNPs) claimed to have effects in prior smaller studies (rs2253478, rs12533005, rs2396753, rs6980093, rs7784315, rs17137124, rs10230558, rs7782412, rs1456031), beginning with regions proposed in the relevant papers, then assessing impact across the entire brain. In the second gene-wide stage, we tested all common FOXP2 variation, focusing on volumetry of those regions most strongly implicated from analyses of rare disruptive mutations. Despite using a sample that is more than 10 times that used for prior studies of common FOXP2 variation, we found no evidence for effects of SNPs on variability in neuroanatomy in the general population. Thus, the impact of this gene on brain structure may be largely limited to extreme cases of rare disruptive alleles. Alternatively, effects of common variants at this gene exist but are too subtle to be detected with standard volumetric techniques.
    Frontiers in Human Neuroscience 07/2014; 8:473. DOI:10.3389/fnhum.2014.00473 · 3.63 Impact Factor
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    • "All 10 participants were evaluated for FOXP2 mutation status by sequencing each of the seventeen FOXP2 coding exons [NCBI:NM_014491.3]. The exons were amplified by polymerase chain reaction (PCR) (AmpliTaq Gold PCR Master Mix; Applied Biosystems, Carlsbad, CA, USA) using oligos referenced elsewhere [29]. PCR amplification and amplicon size were verified by gel electrophoresis. "
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    ABSTRACT: Childhood apraxia of speech (CAS) is a rare, severe, persistent pediatric motor speech disorder with associated deficits in sensorimotor, cognitive, language, learning and affective processes. Among other neurogenetic origins, CAS is the disorder segregating with a mutation in FOXP2 in a widely studied, multigenerational London family. We report the first whole-exome sequencing (WES) findings from a cohort of 10 unrelated participants, ages 3 to 19 years, with well-characterized CAS. As part of a larger study of children and youth with motor speech sound disorders, 32 participants were classified as positive for CAS on the basis of a behavioral classification marker using auditory-perceptual and acoustic methods that quantify the competence, precision and stability of a speaker's speech, prosody and voice. WES of 10 randomly selected participants was completed using the Illumina Genome Analyzer IIx Sequencing System. Image analysis, base calling, demultiplexing, read mapping, and variant calling were performed using Illumina software. Software developed in-house was used for variant annotation, prioritization and interpretation to identify those variants likely to be deleterious to neurodevelopmental substrates of speech-language development. Among potentially deleterious variants, clinically reportable findings of interest occurred on a total of five chromosomes (Chr3, Chr6, Chr7, Chr9 and Chr17), which included six genes either strongly associated with CAS (FOXP1 and CNTNAP2) or associated with disorders with phenotypes overlapping CAS (ATP13A4, CNTNAP1, KIAA0319 and SETX). A total of 8 (80%) of the 10 participants had clinically reportable variants in one or two of the six genes, with variants in ATP13A4, KIAA0319 and CNTNAP2 being the most prevalent. Similar to the results reported in emerging WES studies of other complex neurodevelopmental disorders, our findings from this first WES study of CAS are interpreted as support for heterogeneous genetic origins of this pediatric motor speech disorder with multiple genes, pathways and complex interactions. We also submit that our findings illustrate the potential use of WES for both gene identification and case-by-case clinical diagnostics in pediatric motor speech disorders.
    Journal of Neurodevelopmental Disorders 10/2013; 5(1):29. DOI:10.1186/1866-1955-5-29 · 3.27 Impact Factor
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