A de novo FOXP1 variant in a patient with autism, intellectual disability and severe speech and language impairment

Abstract

FOXP1 (forkhead box protein P1) is a transcription factor involved in the development of several tissues, including the brain. An emerging phenotype of patients with protein-disrupting FOXP1 variants includes global developmental delay, intellectual disability and mild to severe speech/language deficits. We report on a female child with a history of severe hypotonia, autism spectrum disorder and mild intellectual disability with severe speech/language impairment. Clinical exome sequencing identified a heterozygous de novo FOXP1 variant c.1267_1268delGT (p.V423Hfs*37). Functional analyses using cellular models show that the variant disrupts multiple aspects of FOXP1 activity, including subcellular localization and transcriptional repression properties. Our findings highlight the importance of performing functional characterization to help uncover the biological significance of variants identified by genomics approaches, thereby providing insight into pathways underlying complex neurodevelopmental disorders. Moreover, our data support the hypothesis that de novo variants represent significant causal factors in severe sporadic disorders and extend the phenotype seen in individuals with FOXP1 haploinsufficiency.

Autism genetics – an overview

“…On the other hand, WES of affected and unaffected individuals has proven to be a powerful approach and has already led to the identification of more than 150 novel candidate genes for ASD . Compared to GWAS, WES provides new opportunities for sporadic cases and has the capacity to detect de novo mutations and variations with incomplete penetrance.…”

“…De novo loss‐of‐function variants in the fork head box P1 ( FOXP1 ) gene have been identified in independent studies of individuals with ASD . Mice with constitutive heterozygous deletion of Foxp1 had reduced ultrasonic vocalizations .…”

Mapping the distribution of language related genes FoxP1, FoxP2, and CntnaP2 in the brains of vocal learning bat species

“…FOXP2 mutations were identified as a monogenic cause of speech and language disorder in an extended pedigree (known as the “KE family”) and has since been found in numerous similarly affected but unrelated individuals (Morgan, Fisher, Scheffer, & Hildebrand, ). The FOXP1 gene is closely related to FOXP2 and mutations in this gene have also been found in children with language impairments, although unlike individuals with FOXP2 mutations, these children usually display additional deficits including autism spectrum disorder, mild to moderate intellectual disabilities and motor impairments (Hamdan et al, ; Lozano, Vino, Lozano, Fisher, & Deriziotis, ; Sollis et al, ). Both FOXP2 and FOXP1 are members of the same protein family that act to regulate the expression of other genes in the genome, determining when and where they are switched on or off (Li, Weidenfeld, & Morrisey, ).…”

Expression of forkhead box transcription factor genes Foxp1 and Foxp2 during jaw development

“…In humans, mutations affecting FOXP1 and FOXP2 have been found in patients with language and speech defects, often accompanied by additional intellectual disability and/or autism spectrum disorder (Lai et al 2001, Feuk et al 2006, Zeesman et al 2006, Takahashi et al 2009, Horn et al 2010, Le Fevre et al 2013, Lozano et al 2015). Many of the patients also exhibited generalized functional deficiencies of the face and neck muscles (difficulties in chewing, swallowing, coughing, laughing), and characteristic facial features (triangular face, prominent forehead, short and broad nose, low set ears, downward slanting eyes, high-arched palate, wide-spaced teeth) (Feuk et al 2006, Zeesman et al 2006, Horn et al 2010, Le Fevre et al 2013, Lozano et al 2015).…”

“…Many of the patients also exhibited generalized functional deficiencies of the face and neck muscles (difficulties in chewing, swallowing, coughing, laughing), and characteristic facial features (triangular face, prominent forehead, short and broad nose, low set ears, downward slanting eyes, high-arched palate, wide-spaced teeth) (Feuk et al 2006, Zeesman et al 2006, Horn et al 2010, Le Fevre et al 2013, Lozano et al 2015). The language and mental defects clearly implicate problems in brain development, and the musculoskeletal phenotypes of the face may be secondary to the disruption in the motor control from the brain for the muscles.…”