Beate Peter

Replication of CNTNAP2 association with nonword repetition and support for FOXP2 association with timed reading and motor activities in a dyslexia family sample

Two functionally related genes, FOXP2 and CNTNAP2, influence language abilities in families with rare syndromic and common nonsyndromic forms of impaired language, respectively. We investigated whether these genes are associated with component phenotypes of dyslexia and measures of sequential motor ability. Quantitative transmission disequilibrium testing (QTDT) and linear association modeling were used to evaluate associations with measures of phonological memory (nonword repetition, NWR), expressive language (sentence repetition), reading (real word reading efficiency, RWRE; word attack, WATT), and timed sequential motor activities (rapid alternating place of articulation, RAPA; finger succession in the dominant hand, FS-D) in 188 family trios with a child with dyslexia. Consistent with a prior study of language impairment, QTDT in dyslexia showed evidence of CNTNAP2 single nucleotide polymorphism (SNP) association with NWR. For FOXP2, we provide the first evidence for SNP association with component phenotypes of dyslexia, specifically NWR and RWRE but not WATT. In addition, FOXP2 SNP associations with both RAPA and FS-D were observed. Our results confirm the role of CNTNAP2 in NWR in a dyslexia sample and motivate new questions about the effects of FOXP2 in neurodevelopmental disorders.

De novo microdeletion of BCL11A is associated with severe speech sound disorder.

In 10 cases of 2p15p16.1 microdeletions reported worldwide to date, shared phenotypes included growth retardation, craniofacial and skeletal dysmorphic traits, internal organ defects, intellectual disability, nonverbal or low verbal status, abnormal muscle tone, and gross motor delays. The size of the deletions ranged from 0.3 to 5.7 Mb, where the smallest deletion involved the BCL11A, PAPOLG, and REL genes. Here we report on an 11‐year‐old male with a heterozygous de novo 0.2 Mb deletion containing a single gene, BCL11A, and a phenotype characterized by childhood apraxia of speech and dysarthria in the presence of general oral and gross motor dyspraxia and hypotonia as well as expressive language and mild intellectual delays. BCL11A is situated within the dyslexia susceptibility candidate region 3 (DYX3) candidate region on chromosome 2. The present case is the first to involve a single gene within the microdeletion region and a phenotype restricted to a subset of the traits observed in other cases with more extensive deletions.

The Genetics of Reading Disabilities: From Phenotypes to Candidate Genes

This article provides an overview of (a) issues in definition and diagnosis of specific reading disabilities at the behavioral level that may occur in different constellations of developmental and phenotypic profiles (patterns); (b) rapidly expanding research on genetic heterogeneity and gene candidates for dyslexia and other reading disabilities; (c) emerging research on gene-brain relationships; and (d) current understanding of epigenetic mechanisms whereby environmental events may alter behavioral expression of genetic variations. A glossary of genetic terms (denoted by bold font) is provided for readers not familiar with the technical terms.

Timing errors in two children with suspected childhood apraxia of speech (sCAS) during speech and music‐related tasks

Impaired speech prosody has been identified as a critical feature of suspected childhood apraxia of speech (sCAS). Lexical stress productions of children with sCAS have been characterized as ‘excessive/equal/misplaced’. This investigation examines two potential explanations of this particular deficit, articulatory difficulty and impaired intrinsic timing. Two children with a diagnosis of sCAS (ages 4 years, 3 months and 9 years, 5 months) and two age‐matched controls were observed during three speech and three music tasks. Acoustic analysis revealed that in all tasks, the performance of the controls was more accurate than that of the children with sCAS. Timing structures and accuracy are discussed with respect to diagnostic status, age, speech and music tasks, and timing unit size.

Motor sequencing deficit as an endophenotype of speech sound disorder: a genome-wide linkage analysis in a multigenerational family.

Objectives The aim of this pilot study was to investigate a measure of motor sequencing deficit as a potential endophenotype of speech sound disorder (SSD) in a multigenerational family with evidence of familial SSD. Methods In a multigenerational family with evidence of a familial motor-based SSD, affectation status and a measure of motor sequencing during oral motor testing were obtained. To further investigate the role of motor sequencing as an endophenotype for genetic studies, parametric and nonparametric linkage analyses were carried out using a genome-wide panel of 404 microsatellites. Results In seven of the 10 family members with available data, SSD affectation status and motor sequencing status coincided. Linkage analysis revealed four regions of interest, 6p21, 7q32, 7q36, and 8q24, primarily identified with the measure of motor sequencing ability. The 6p21 region overlaps with a locus implicated in rapid alternating naming in a recent genome-wide dyslexia linkage study. The 7q32 locus contains a locus implicated in dyslexia. The 7q36 locus borders on a gene known to affect the component traits of language impairment. Conclusion The results are consistent with a motor-based endophenotype of SSD that would be informative for genetic studies. The linkage results in this first genome-wide study in a multigenerational family with SSD warrant follow-up in additional families and with fine mapping or next-generation approaches to gene identification.

Central timing deficits in subtypes of primary speech disorders

Childhood apraxia of speech (CAS) is a proposed speech disorder subtype that interferes with motor planning and/or programming, affecting prosody in many cases. Pilot data (Peter & Stoel‐Gammon, ) were consistent with the notion that deficits in timing accuracy in speech and music‐related tasks may be associated with CAS. This study replicated and expanded earlier findings. Eleven children with speech disorders and age‐and gender‐matched controls participated in non‐word imitation, clapped rhythm imitation, and paced repetitive tapping tasks. Results suggest a central timing deficit, expressed in both the oral and the limb modality, and observable in two different types of timing measures, overall rhythmic structures and small‐scale durations. Associations among timing measures were strongest in the participants with speech disorders, who also showed lower timing accuracy than the controls in all measures. The number of observed CAS characteristics was associated with timing deficits.

Deficits in sequential processing manifest in motor and linguistic tasks in a multigenerational family with childhood apraxia of speech

The purpose of this study was to evaluate a global deficit in sequential processing as candidate endophenotypein a family with familial childhood apraxia of speech (CAS). Of 10 adults and 13 children in a three-generational family with speech sound disorder (SSD) consistent with CAS, 3 adults and 6 children had past or present SSD diagnoses. Two preschoolers with unremediated CAS showed a high number of sequencing errors during single-word production. Performance on tasks with high sequential processing loads differentiated between the affected and unaffected family members, whereas there were no group differences in tasks with low processing loads. Adults with a history of SSD produced more sequencing errors during nonword and multisyllabic real word imitation, compared to those without such a history. Results are consistent with a global deficit in sequential processing that influences speech development as well as cognitive and linguistic processing.

Evidence for a Familial Speech Sound Disorder Subtype in a Multigenerational Study of Oral and Hand Motor Sequencing Ability.

Purpose: To evaluate phenotypic expressions of speech sound disorder (SSD) in multigenerational families with evidence of familial forms of SSD. Method: Members of five multigenerational families (N = 36) produced rapid sequences of monosyllables and disyllables and tapped computer keys with repetitive and alternating movements. Results: Measures of repetitive and alternating motor speed were correlated within and between the two motor systems. Repetitive and alternating motor speeds increased in children and decreased in adults as a function of age. In two families with children who had severe speech deficits consistent with disrupted praxis, slowed alternating, but not repetitive, oral movements characterized most of the affected children and adults with a history of SSD, and slowed alternating hand movements were seen in some of the biologically related participants as well. Conclusion: Results are consistent with a familial motor-based SSD subtype with incomplete penetrance, motivating new clinical questions about motor-based intervention not only in the oral but also the limb system.

Associations among measures of sequential processing in motor and linguistics tasks in adults with and without a family history of childhood apraxia of speech: A replication study

The purpose of this study was to address the hypothesis that childhood apraxia of speech (CAS) is influenced by an underlying deficit in sequential processing that is also expressed in other modalities. In a sample of 21 adults from five multigenerational families, 11 with histories of various familial speech sound disorders, 3 biologically related adults from a family with familial CAS showed motor sequencing deficits in an alternating motor speech task. Compared with the other adults, these three participants showed deficits in tasks requiring high loads of sequential processing, including nonword imitation, nonword reading and spelling. Qualitative error analyses in real word and nonword imitations revealed group differences in phoneme sequencing errors. Motor sequencing ability was correlated with phoneme sequencing errors during real word and nonword imitation, reading and spelling. Correlations were characterized by extremely high scores in one family and extremely low scores in another. Results are consistent with a central deficit in sequential processing in CAS of familial origin.

Familial dyskinesia and facial myokymia (FDFM): Follow-up of a large family and linkage to chromosome 3p21-3q21.

We previously reported a five‐generation family manifesting an autosomal dominant disorder of facial myokymia and dystonic/choreic movements (FDFM). The dyskinetic episodes are initially paroxysmal but may become constant. With increasing age they may lessen or even disappear. The previous study excluded nine candidate genes chosen for their association with myokymia or chorea and two regions containing single or clustered ion channel genes. We now report identification by whole genome linkage analysis of a broad region on chromosome 3p21‐3q21 that segregates with the disease in all 10 affected members in three generations who participated in the study. GENEHUNTER‐MODSCORE Version 2.0.1 provided a maximum multipoint LOD score of 3.099. No other disorders primarily characterized by myokymia, dystonia, or chorea are known to map to this region. Identification of additional families with FDFM may narrow the critical region and facilitate the choice of candidate genes for further analysis.