Identification of FOXP1 deletions in three unrelated patients with mental retardation and significant speech and language deficits

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.

Figure 1

FOXP1 deletions in patients with MR. (A) Schematic presentation of the position and size of the deleted regions (grey bars) at chromosome 3p14.1 in three patients with MR and in a control individual. Only the FOXP1 gene (NM_032682, minus strand) is affected. The coding exons are indicated by larger vertical lines compared to the non-coding exons. (B) Results of fluorescence in situ hybridization (FISH) shown for patient 3 and his parents. The positions of the BAC clones RP11-215K24 and RP11-154H23 flanking the deletion, as well as CTD-3121O8 located within the deletion (green signals) are given in Figure 1A. BAC clone RP11-778D09 was used as a reference probe located on chromosome 3q27 (red signals). The white arrow indicates the missing signal for clone CTD-3121O8 on one of the patient's chromosomes 3 while the signal is present in both chromosomes of the parents. (C) Breakpoint characterization by sequencing of junction fragments amplified by PCR on genomic DNA of the patients. In patient 1, the distal breakpoint was located at position 70,807,767, the proximal breakpoint at position 71,305,965 with a deletion size of 498,198 bp. In patient 2, the two breakpoints were located within a microhomology of three nucleotides (AGA) at the telomeric side at position 70,778,067-70,778,070 and the centromeric side at 71,437,354-71,437,357 resulting in a deletion size of 659,287 bp. For patient 3, the telomeric breakpoint is located at position 70,341,246-70,341,247 and the centromeric breakpoint at position 71,388,173-71,388,174 with a deletion size of 1,046,927 bp. All positions are given according to hg18, UCSC Human Genome March 2006.

Figure 2

Facial Phenotype of patients 2 and 3. Consistent facial features of patients showing broad and prominent forehead, frontal hair upsweep, and a short nose. (A) Patient 2, at the age of 4 years and 3 months. (B) Patient 3, at the age of 6 years, had in addition sparse lateral eye brows and down-slanting palpebral fissures.