Identification and functional characterization ofde novo FOXP1variants provides novel insights into the etiology of neurodevelopmental disorder

Abstract

De novo disruptions of the neural transcription factor FOXP1 are a recently discovered, rare cause of sporadic intellectual disability (ID). We report three new cases of FOXP1-related disorder identified through clinical whole-exome sequencing. Detailed phenotypic assessment confirmed that global developmental delay, autistic features, speech/language deficits, hypotonia and mild dysmorphic features are core features of the disorder. We expand the phenotypic spectrum to include sensory integration disorder and hypertelorism. Notably, the etiological variants in these cases include two missense variants within the DNA-binding domain of FOXP1. Only one such variant has been reported previously. The third patient carries a stop-gain variant. We performed functional characterization of the three missense variants alongside our stop-gain and two previously described truncating/frameshift variants. All variants severely disrupted multiple aspects of protein function. Strikingly, the missense variants had similarly severe effects on protein function as the truncating/frameshift variants. Our findings indicate that a loss of transcriptional repression activity of FOXP1 underlies the neurodevelopmental phenotype in FOXP1-related disorder. Interestingly, the three novel variants retained the ability to interact with wild-type FOXP1, suggesting these variants could exert a dominant-negative effect by interfering with the normal FOXP1 protein. These variants also retained the ability to interact with FOXP2, a paralogous transcription factor disrupted in rare cases of speech and language disorder. Thus, speech/language deficits in these individuals might be worsened through deleterious effects on FOXP2 function. Our findings highlight that de novo FOXP1 variants are a cause of sporadic ID and emphasize the importance of this transcription factor in neurodevelopment.

Functional characterization of rare FOXP2 variants in neurodevelopmental disorder

“…Heterodimerization among certain FOXP proteins may therefore be an important mechanism for differential regulation of target genes in different neuronal subtypes. Of note, heterozygous disruption of FOXP1 results in a severe neurodevelopmental phenotype that includes language deficits, potentially reflecting dysregulation of some of the same target genes impacted by FOXP2 disruption [30, 31]. …”

“…Variants which abolish both transcriptional regulatory activity and protein dimerization, such as the p.R328* and p.Q390Vfs*7 variants, may act as null alleles, resulting in haploinsufficiency of FOXP2 . In contrast, variants which show a loss of transcriptional regulatory activity but retain the ability to dimerize, like the p.R553H variant, may additionally interfere with the functioning of wild-type protein, as has been suggested for comparable variants in FOXP1 [31]. Variants producing these dominant-negative effects might result in a more severe phenotype.…”

“…The probability of recurrence for this particular variant is elevated because it involves mutation of a CpG site. Indeed, pathological mutation events have been observed at the equivalent CpG site in the FOX proteins FOXC2, FOXE1, FOXF1, FOXL2, and FOXP1 [31, 54–57]. The second probable new case of FOXP2 -related speech/language disorder in DECIPHER presented with delayed speech and language development, delayed fine motor development, strabismus and tall stature and carries a novel de novo stop-gain variant, p.R564*, truncating the FOXP2 protein within the FOX domain.…”

Next-generation DNA sequencing identifies novel gene variants and pathways involved in specific language impairment

“…Mutations of the FOXP2 transcription factor (Forkhead box, P2, OMIM*605317) are known to lead to developmental syndromes involving verbal dyspraxia, or childhood apraxia of speech, accompanied by problems with many aspects of language2728. FOXP1 (Forkhead box P1, OMIM*605515), a paralogue of FOXP2 , has similarly been implicated in neurodevelopmental disorder2930, along with some of its transcriptional targets, most notably, CNTNAP2 (Contactin-associated protein-like 2, OMIM*604569)3132. Rare variants of the FOXP2 target SRPX2 (Sushi-repeat-containing protein, X-linked, 2, OMIM*300642)33 have been identified in epileptic aphasias34, as have mutations of GRIN2A (Glutamate receptor, ionotropic, N-methyl-D-aspartate, subunit 2A, OMIM*138253)353637.…”

Pathogenic missense mutation pattern of forkhead box genes in neurodevelopmental disorders

“…FOXP1:p.R514H lost the transcriptional repression activity (Sollis et al, ; Vernes et al, ). Both variants can mislocalize and aggregate wild type FOXP1 and FOXP2 in the nucleus and cytoplasm (Estruch, Graham, Chinnappa, Deriziotis, & Fisher, ; Sollis et al, ). Another equal position in FOXG1, Arg230His, was reported to affect the affinity of FOXG1 for DNA (Takahashi et al, ).…”