FOXP2 is not a major susceptibility gene for autism or specific language impairment

Abstract

The FOXP2 gene, located on human 7q31 (at the SPCH1 locus), encodes a transcription factor containing a polyglutamine tract and a forkhead domain. FOXP2 is mutated in a severe monogenic form of speech and language impairment, segregating within a single large pedigree, and is also disrupted by a translocation in an isolated case. Several studies of autistic disorder have demonstrated linkage to a similar region of 7q (the AUTS1 locus), leading to the proposal that a single genetic factor on 7q31 contributes to both autism and language disorders. In the present study, we directly evaluate the impact of the FOXP2 gene with regard to both complex language impairments and autism, through use of association and mutation screening analyses. We conclude that coding-region variants in FOXP2 do not underlie the AUTS1 linkage and that the gene is unlikely to play a role in autism or more common forms of language impairment.

Figure 1

Autism and language studies of chromosome 7q. The chromosome 7 ideogram shows the order and map distance of markers used in various studies. Blackened boxes show approximate positions of regions highlighted by linkage studies. Unblackened boxes represent approximate positions of breakpoints in cytogenetic studies. Each MLS shown was obtained in the region highlighted for the appropriate linkage study. The methods of LOD estimation varied between studies. Note that the SPCH1 linkage has been directly attributed to the FOXP2 gene.

Figure 2

Schematic of FOXP2 (adapted with permission from Lai et al. [2001]). Numbers in black indicate exon numbers. Numbers in grey indicate intron numbers as used in table 3. All exons are shown to scale. Introns are shown to scale with each other, and the sizes of all introns >5 kb are given in brackets (in kb). Positions of all microsatellites and SNPs used for association analysis are indicated by arrows, and distances (in kb) are given from the nearest coding exon. Exons 5 and 6 contain a polyglutamine encoding tract; exons 12–14 contain the forkhead (fox) domain; exons 3a and 3b are alternatively spliced; the KE mutation is found in exon 14; the CS translocation breakpoint is between exon 3b and exon 4.

Figure 3

FOXP2 exon 6. A, Family 43 pedigree. Both the mother and father have no reported history of language problems. Child 1 is clinically normal, child 2 is clinically affected, and child 3 has a reported language delay but is too young to test formally. B, The CAGCAG insertion in FOXP2 exon 6. The boxed area represents the possible site for CAGCAG insertion. Underlined bases represent primers for exon 5. Exonic sequence is represented by capital letters; intronic sequence is represented by lowercase letters.