A Functional Genetic Link between Distinct Developmental Language Disorders

Abstract

BACKGROUND-Rare mutations affecting the FOXP2 transcription factor cause a monogenic speech and language disorder. We hypothesized that neural pathways downstream of FOXP2 influence more common phenotypes, such as specific language impairment.

Shining a light on CNTNAP2: complex functions to complex disorders

“…27 Significant association was identified for quantitative measures of expressive and receptive language ability as well as scores of non-word repetition (which are thought to relate to phonological working memory and therefore language-related processing ability) with a cluster of SNPs within introns 13-14 ( Figure 1a). 20,24 Non-word repetition was similarly associated with one of these intron 13 variants (rs2710102) in a cohort of dyslexia probands. 25 Strong evidence for a connection between CNTNAP2 and ASD has also emerged.…”

“…Intron 1 contains a regulatory element bound by the FOXP2 transcription factor. 20 Finally, an autistic patient was identified carrying a deletion of an putative upstream promoter region, which resulted in reduced expression levels. 21 Thus, although these deletions do not interrupt the protein product, they may affect regulatory elements to produce altered functional levels of CNTNAP2.…”

“…CNTNAP2 variants are associated with complex disorders Genome-wide association studies have also linked CNTNAP2 to complex neurological disorders, including language impairment, autism, dyslexia, schizophrenia, and depression 18,20,[22][23][24][25][26] (Table 2), although causal variants have not yet been identified. Convincing evidence has linked common variants (ie, single nucleotide polymorphisms; SNPs) in the CNTNAP2 region with the most common form of language disorder in children: specific language impairment (SLI).…”

ATP2C2andDYX1C1are putative modulators of dyslexia‐related MMR

“…Linkage studies pointed at nine chromosomal regions (termed DYX1 to 9) and subsequent association studies identified several dyslexia‐related genes within these regions, for example, DYX1C1 , DCDC2 , KIAA0319 , and ROBO1 . Moreover, associations with genes outside these regions such as CMIP , CNTNAP2, and FOXP2 have also been repeatedly reported (Peter et al., 2011; Scerri et al., 2011; Vernes et al., 2008). A frequent comorbidity of dyslexia is specific language impairment (SLI).…”

“…Thus, it is plausible to consider candidate single‐nucleotide polymorphisms (SNPs) reported to be associated with SLI also as relevant candidate SNPs for dyslexia and dyslexia‐related processes. Genes with already reported associations to both, SLI and dyslexia, include FOXP2 (Lai, Fisher, Hurst, Vargha‐Khadem, & Monaco, 2001; Wilcke et al., 2012), KIAA0319 (Cope et al., 2005; Newbury et al., 2011), CNTNAP2 (Newbury et al., 2011; Peter et al., 2011; Vernes et al., 2008), and CMIP (Newbury et al., 2009; Scerri et al., 2011). …”