Identification of FOXP2 Truncation as a Novel Cause of Developmental Speech and Language Deficits Kay D. MacDermot, Elena Bonora, Nuala Sykes, Anne-Marie.

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Identification of FOXP2 Truncation as a Novel Cause of Developmental Speech and Language Deficits Kay D. MacDermot, Elena Bonora, Nuala Sykes, Anne-Marie Coupe, Cecilia S.L. Lai, Sonja C. Vernes, Faraneh Vargha-Khadem, Fiona McKenzie, Robert L. Smith, Anthony P. Monaco, Simon E. Fisher The American Journal of Human Genetics Volume 76, Issue 6, Pages 1074-1080 (June 2005) DOI: 10.1086/430841 Copyright © 2005 The American Society of Human Genetics Terms and Conditions

Figure 1 Schematic of the human FOXP2 locus, which spans >600 kb of genomic DNA, showing sequence variants identified in subjects with verbal dyspraxia. Black shading indicates translated exons; “atg” and “tga” denote positions of initiation and termination codons. Known domains encoded by exons include polyglutamine tracts (Q40 and Q10), a zinc-finger motif (ZnF), a leucine zipper (LeuZ), the forkhead domain (FOX), and an acidic C-terminus (Acidic). Exons 3b and 4a are alternatively spliced coding exons yielding amino acid insertions, whereas alternatively spliced exons 2a, 2b, and 3a are predicted to be noncoding. Exons s1–s3 and 1 represent alternative 5′ UTR regions that have not been found in the same human transcript; the position of the 5′ end of exon 1 is based on currently available EST data. For more information on splicing and isoforms, see Lai et al. (2001) and Bruce and Margolis (2002). All known exons were screened for mutations, with the exception of two noncoding exons: s1 (5′ CpG-rich UTR) and 2a (alternatively spliced and untranslated). Coding variants are shown above the locus, with resulting codon and amino acid changes indicated. For reference, the KE mutation is also included. Noncoding variants are shown below the locus, with information regarding relative position (with respect to the exon in question) and frequency in probands (number of heterozygous probands/total probands screened). An asterisk (*) denotes intronic variants that correspond to those previously detected by Newbury et al. (2002), and rs numbers are indicated for polymorphisms also present in dbSNP. Locus schematic is adapted from Fisher et al. (2003). The American Journal of Human Genetics 2005 76, 1074-1080DOI: (10.1086/430841) Copyright © 2005 The American Society of Human Genetics Terms and Conditions

Figure 2 A, Amino acid sequence of main isoform of human FOXP2, showing all coding changes found thus far in individuals with developmental verbal dyspraxia (Lai et al. 2001; present study). Each change was absent from large numbers of control chromosomes, but only the R328X and R553H mutations are found in multiple affected members in families segregating developmental speech and language disorder. B, Nucleotide sequence of normal and expanded polyglutamine-encoding region identified in one of the probands in this study. The American Journal of Human Genetics 2005 76, 1074-1080DOI: (10.1086/430841) Copyright © 2005 The American Society of Human Genetics Terms and Conditions