Background Disruptions of the FOXP2 gene, encoding a forkhead transcription factor, are the first known monogenic cause of a speech and language disorder. So far, mainly chromosomal rearrangements such as translocations or larger deletions affecting FOXP2 have been reported. Intragenic deletions or convincingly pathogenic point mutations in FOXP2 have up to date only been reported in three families. We thus aimed at a further characterisation of the mutational and clinical spectrum.
Methods Chromosomal microarray testing, trio exome sequencing, multigene panel sequencing and targeted sequencing of FOXP2 were performed in individuals with variable developmental disorders, and speech and language deficits.
Results We identified four different truncating mutations, two novel missense mutations within the forkhead domain and an intragenic deletion in FOXP2 in 14 individuals from eight unrelated families. Mutations occurred de novo in four families and were inherited from an affected parent in the other four. All index patients presented with various manifestations of language and speech impairment. Apart from two individuals with normal onset of speech, age of first words was between 4 and 7 years. Articulation difficulties such as slurred speech, dyspraxia, stuttering and poor pronunciation were frequently noted. Motor development was normal or only mildly delayed. Mild cognitive impairment was reported for most individuals.
Conclusions By identifying intragenic deletions or mutations in 14 individuals from eight unrelated families with variable developmental delay/cognitive impairment and speech and language deficits, we considerably broaden the mutational and clinical spectrum associated with aberrations in FOXP2.
- developmental delay
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Contributors MSR, AR, UM, TAB, KEC, AR, MS, KS, DG, PJ, DDD Study, MK, HR, US-M, PB, SB-W, JK, AR and CZ provided clinical and mutational data. MSR and CZ wrote the manuscript, AR, UM, TAB, KEC, AR, MS and KS wrote the respective case reports. All coauthors read and agreed with the text.
Funding CZ was supported by a grant from the German Research Foundation (DFG, ZW184/1-2) and by the IZKF (Interdisziplinäres Zentrum für Klinische Forschung, E26) Erlangen. TAB acknowledges funding from the National Institute of Health Research, UK. The DDD study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health and the Wellcome Trust Sanger Institute (grant number WT098051). The views expressed in this publication are those of the author(s) and not necessarily those of the Wellcome Trust or the Department of Health. The study has UK Research Ethics Committee approval (10/H0305/83, granted by the Cambridge South REC, and GEN/284/12 granted by the Republic of Ireland REC). The research team acknowledges the support of the National Institute for Health Research, through the Comprehensive Clinical Research Network.
Competing interests None declared.
Ethics approval Institutional review boards of the Medical Faculty of the Friedrich-Alexander-University Erlangen-Nürnberg.
Provenance and peer review Not commissioned; externally peer reviewed.