TY - JOUR
T1 - De novo mutations in FOXP1 in cases with intellectual disability, autism, and language impairment
AU - Hamdan, Fadi F.
AU - Daoud, Hussein
AU - Rochefort, Daniel
AU - Piton, Amélie
AU - Gauthier, Julie
AU - Langlois, Mathieu
AU - Foomani, Gila
AU - Dobrzeniecka, Sylvia
AU - Krebs, Marie Odile
AU - Joober, Ridha
AU - Lafrenire, Ronald G.
AU - Lacaille, Jean Claude
AU - Mottron, Laurent
AU - Drapeau, Pierre
AU - Beauchamp, Miriam H.
AU - Phillips, Michael S.
AU - Fombonne, Eric
AU - Rouleau, Guy A.
AU - Michaud, Jacques L.
N1 - Funding Information:
This work was supported by grants from the Canadian Institute of Health Research (CIHR) (J.L.M., G.A.R., J.-C.L.), Réseau de Génétique Médicale Appliquée (RMGA) / Fonds de la Recherche en Santé du Québec (FRSQ) (J.L.M. and M.S.P.), Genome Canada and Genome Quebec, and cofunding by Université de Montréal for the Synapse to Diseases (S2D) project (G.A.R. and P.D.). J.L.M. is the recipient of a Clinical Investigatorship Award of the CIHR (Institute of Genetics) and a Senior Scientist Award from FRSQ. E.F. holds the CIHR-funded Canada Research Chair in Child Psychiatry. H.D. is a recipient of a CIHR postdoctoral fellowship award. We thank the patients and their parents for participating in this study. We are grateful for the dedicated work of members of the S2D team (CHUM Research Center, Montreal), including Management (Claude Marineau), Bioinformatics (Edouard Henrion, Ousmane Diallo, and Dan Spiegelman), and the Genetic Screening divisions (Annie Levert, Annie Raymond, Pascal Thibodeau, Sandra Laurent, and Karine Lachapelle). We are thankful for the efforts of the members of McGill University and Génome Québec Innovation Centre Sequencing (Pierre Lepage, Sébastien Brunet, and Hao Fan Yam) and Bioinformatics (Louis Létourneau and Louis Dumond Joseph) groups.
PY - 2010/11/12
Y1 - 2010/11/12
N2 - Heterozygous mutations in FOXP2, which encodes a forkhead transcription factor, have been shown to cause developmental verbal dyspraxia and language impairment. FOXP2 and its closest homolog, FOXP1, are coexpressed in brain regions that are important for language and cooperatively regulate developmental processes, raising the possibility that FOXP1 may also be involved in developmental conditions that are associated with language impairment. In order to explore this possibility, we searched for mutations in FOXP1 in patients with intellectual disability (ID; mental retardation) and/or autism spectrum disorders (ASD). We first performed array-based genomic hybridization on sporadic nonsyndromic ID (NSID) (n = 30) or ASD (n = 80) cases. We identified a de novo intragenic deletion encompassing exons 4-14 of FOXP1 in a patient with NSID and autistic features. In addition, sequencing of all coding exons of FOXP1 in sporadic NSID (n = 110) or ASD (n = 135) cases, as well as in 570 controls, revealed the presence of a de novo nonsense mutation (c.1573C>T [p.R525X]) in the conserved forkhead DNA-binding domain in a patient with NSID and autism. Luciferase reporter assays showed that the p.R525X alteration disrupts the activity of the protein. Formal assessments revealed that both patients with de novo mutations in FOXP1 also show severe language impairment, mood lability with physical aggressiveness, and specific obsessions and compulsions. In conclusion, both FOXP1 and FOXP2 are associated with language impairment, but decrease of the former has a more global impact on brain development than that of the latter.
AB - Heterozygous mutations in FOXP2, which encodes a forkhead transcription factor, have been shown to cause developmental verbal dyspraxia and language impairment. FOXP2 and its closest homolog, FOXP1, are coexpressed in brain regions that are important for language and cooperatively regulate developmental processes, raising the possibility that FOXP1 may also be involved in developmental conditions that are associated with language impairment. In order to explore this possibility, we searched for mutations in FOXP1 in patients with intellectual disability (ID; mental retardation) and/or autism spectrum disorders (ASD). We first performed array-based genomic hybridization on sporadic nonsyndromic ID (NSID) (n = 30) or ASD (n = 80) cases. We identified a de novo intragenic deletion encompassing exons 4-14 of FOXP1 in a patient with NSID and autistic features. In addition, sequencing of all coding exons of FOXP1 in sporadic NSID (n = 110) or ASD (n = 135) cases, as well as in 570 controls, revealed the presence of a de novo nonsense mutation (c.1573C>T [p.R525X]) in the conserved forkhead DNA-binding domain in a patient with NSID and autism. Luciferase reporter assays showed that the p.R525X alteration disrupts the activity of the protein. Formal assessments revealed that both patients with de novo mutations in FOXP1 also show severe language impairment, mood lability with physical aggressiveness, and specific obsessions and compulsions. In conclusion, both FOXP1 and FOXP2 are associated with language impairment, but decrease of the former has a more global impact on brain development than that of the latter.
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U2 - 10.1016/j.ajhg.2010.09.017
DO - 10.1016/j.ajhg.2010.09.017
M3 - Article
C2 - 20950788
AN - SCOPUS:78249268820
SN - 0002-9297
VL - 87
SP - 671
EP - 678
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 5
ER -