FOXP2 variants in 14 individuals with developmental speech and language disorders broaden the mutational and clinical spectrum

  title={FOXP2 variants in 14 individuals with developmental speech and language disorders broaden the mutational and clinical spectrum},
  author={Miriam S. Reuter and Angelika Riess and Ute Moog and Tracy A. Briggs and Kate E. Chandler and Anita Rauch and Miriam Stampfer and Katharina Steindl and Dieter Gl{\"a}ser and Pascal Joset and Mandy Krumbiegel and Harald Rabe and Uta Schulte-Mattler and Peter Bauer and Stefanie Beck-W{\"o}dl and J{\"u}rgen Kohlhase and Andr{\'e} Reis and Christiane Zweier},
  journal={Journal of Medical Genetics},
  pages={64 - 72}
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… 

Heterozygous variants that disturb the transcriptional repressor activity of FOXP4 cause a developmental disorder with speech/language delays and multiple congenital abnormalities

The findings show that heterozygous loss-of-function variants in FOXP4 are associated with an autosomal dominant neurodevelopmental disorder with speech/language delays, growth defects, and variable congenital abnormalities.

Equivalent missense variant in the FOXP2 and FOXP1 transcription factors causes distinct neurodevelopmental disorders

Detailed functional characterization of the two variants in cell model systems revealed very similar molecular consequences, including aberrant subcellular localization, disruption of transcription factor activity, and deleterious effects on protein interactions, highlighting divergent roles of FOXP2 and FOXP1 in neurodevelopment.

Functional characterization of rare FOXP2 variants in neurodevelopmental disorder

It is found that FOXP2 variants with reduced polyglutamine tracts did not exhibit altered behaviour in cellular assays, indicating that such tracts are non-essential for core aspects ofFOXP2 function, and that tract variation is unlikely to be a highly penetrant cause of speech/language disorder.

7q31.2q31.31 deletion downstream of FOXP2 segregating in a family with speech and language disorder

The close phenotypic overlap with FOXP2‐associated speech and language disorder rather suggests a positional effect on FoxP2 expression and function.

Indepth characterization of a cohort of individuals with missense and loss-of-function variants disrupting FOXP2

Background: Heterozygous disruptions of FOXP2 were the first identified molecular cause for severe speech disorder, childhood apraxia of speech (CAS), yet few cases have been reported, limiting

Exome Sequencing of Two Siblings with Sporadic Autism Spectrum Disorder and Severe Speech Sound Disorder Suggests Pleiotropic and Complex Effects

Analysis of whole-exome sequences in a nuclear family with two dually affected and one unaffected offspring suggests compound heterozygosity as a cause of ASD and CAS, pleiotropic gene effects, and potentially additional, complex genetic effects.

Prospective investigation of FOXP1 syndrome

This first study to prospectively examine the genotype-phenotype relationship in multiple individuals withFOXP1 syndrome, using a battery of standardized clinical assessments, identifies novel FOXP1 mutations associated with FOXP 1 syndrome, identifies recurrent mutations, and demonstrates significant clustering of missense mutations in the DNA-binding domain.

Genetic aetiologies for childhood speech disorder: novel pathways co-expressed during brain development

A diagnostic yield comparable to, or even higher, than other neurodevelopmental disorders with substantial de novo variant burden is confirmed, and data support the increasingly recognised overlaps between genes conferring risk for a range of neuro developmental disorders.

Do variants in the coding regions of FOXP2, a gene implicated in speech disorder, confer a risk for congenital amusia?

Congenital amusia is a lifelong disorder that compromises the normal development of musical abilities in 1.5-4% of the general population. There is a substantial genetic contribution to congenital

Genomics of speech and language disorders

There are multiple factors involved in speech and language. Investigating animal models, mainly through songbirds, have allowed a better understanding of the language process. Verbal dyspraxia,



Identification of FOXP2 truncation as a novel cause of developmental speech and language deficits.

Investigation of the entire coding region of FOXP2, including alternatively spliced exons, in 49 probands affected with verbal dyspraxia and the discovery of the first nonsense mutation in FoxP2 opens the door for detailed investigations of neurodevelopment in people carrying different etiological variants of the gene.

Small intragenic deletion in FOXP2 associated with childhood apraxia of speech and dysarthria

This is the first report of a small intragenic deletion of FOXP2 that is likely to be the cause of severe motor speech disorder associated with language and literacy problems.

Functional genetic analysis of mutations implicated in a human speech and language disorder.

It is hypothesize that expression of alternative isoforms of FOXP2 may provide mechanisms for post-translational regulation of transcription factor function, and explore the properties of different isoforms, resulting from alternative splicing in human brain.

Phenotype of FOXP2 haploinsufficiency in a mother and son

Clinical findings for two new individuals with a submicroscopic deletion of FOXP2, a transcription factor, are reported on: a boy with severe apraxia of speech and his currently moderately affected mother, which provide informative phenotypic information on FoxP2 haploinsufficiency.

A forkhead-domain gene is mutated in a severe speech and language disorder

It is suggested that the gene FOXP2, which encodes a putative transcription factor containing a polyglutamine tract and a forkhead DNA-binding domain, is involved in the developmental process that culminates in speech and language.

A chromosomal rearrangement in a child with severe speech and language disorder separates FOXP2 from a functional enhancer

It is shown that an element 2 kb downstream of this breakpoint with epigenetic characteristics of an enhancer drives reporter gene expression in human cell-lines, and displacement of this element by translocation may disturb gene expression, contributing to the observed language phenotype.

Mosaic 7q31 Deletion Involving FOXP2 Gene Associated With Language Impairment

It is suggested that children found with a deletion involving the FOXP2 region should be evaluated for CAS and that analysis of the FoxP2 gene including array comparative genomic hybridization should be considered in selected patients with CAS.

Speech and language impairment and oromotor dyspraxia due to deletion of 7q31 that involves FOXP2

It is proposed that this patient's communication disorder and oromotor deficiency are due to haploinsufficiency for FOXP2 and that her dysmorphism and developmental delay are a consequence of the absence of the other genes involved in the microdeletion.

Absence of a paternally inherited FOXP2 gene in developmental verbal dyspraxia.

The results indicate that absence of paternal FOXP2 is the cause of DVD in patients with SRS with maternal UPD7, and point to a role for differential parent-of-origin expression ofFOXP2 in human speech development.