Abstract
Mental retardation affects 2-3% of the population and shows a high heritability. Neurodevelopmental disorders that include pronounced impairment in language and speech skills occur less frequently. For most cases, the molecular basis of mental retardation with or without speech and language disorder is unknown due to the heterogeneity of underlying genetic factors. We have used molecular karyotyping on 1523 patients with mental retardation to detect copy number variations (CNVs) including deletions or duplications. These studies revealed three heterozygous overlapping deletions solely affecting the forkhead box P1 (FOXP1) gene. All three patients had moderate mental retardation and significant language and speech deficits. Since our results are consistent with a de novo occurrence of these deletions, we considered them as causal although we detected a single large deletion including FOXP1 and additional genes in 4104 ancestrally matched controls. These findings are of interest with regard to the structural and functional relationship between FOXP1 and FOXP2. Mutations in FOXP2 have been previously related to monogenic cases of developmental verbal dyspraxia. Both FOXP1 and FOXP2 are expressed in songbird and human brain regions that are important for the developmental processes that culminate in speech and language. ©2010 Wiley-Liss, Inc.
Highlights
Mental retardation (MR) is defined as a significant impairment of cognitive and adaptive functions with an onset before the age of 18 years (Ropers, 2008)
Approval for the study was obtained by the ethical review boards of the participating institutions and informed written consent was obtained from all participants
This is the first report of 3p14.1 deletions that solely affect the forkhead box P1 (FOXP1) gene in three unrelated patients with moderate mental retardation in combination with a significant impairment of speech and language abilities
Summary
Mental retardation (MR) is defined as a significant impairment of cognitive and adaptive functions with an onset before the age of 18 years (Ropers, 2008). It has been shown that the causes of the disorder include environmental and genetic factors (Inlow and Restifo, 2004), still for most cases, the pathological basis remains unexplained. Due to the heterogeneity of the underlying genetic factors, the identification of MR candidate genes still remains difficult to date. CNVs have been shown as the underlying cause or susceptibility factors for a variety of autism spectrum disorders and conditions associated with MR (Berkel, et al, 2010; Marshall, et al, 2008; Sebat, et al, 2007; Zweier, et al, 2010). Array-based comparative genomic hybridization has enabled the detection of interstitial submicroscopic copy number alterations in about 10 % of patients with MR (de Vries, et al, 2005). We present the identification of overlapping heterozygous deletions affecting the FOXP1 (MIM# 605515) gene in three unrelated patients with MR and significant speech and language disorder
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