Pathogenic missense mutation pattern of forkhead box genes in neurodevelopmental disorders

Abstract

Background Forkhead box (FOX) proteins are a family of transcription factors. Mutations of three FOX genes, including FOXP1 , FOXP2 , and FOXG1, have been reported in neurodevelopmental disorders (NDDs). However, due to the lack of site‐specific statistical significance, the pathogenicity of missense mutations of these genes is difficult to determine. Methods DNA and RNA were extracted from peripheral blood lymphocytes. The mutation was detected by single‐molecule molecular inversion probe‐based targeted sequencing, and the variant was validated by Sanger sequencing. Real‐time quantitative PCR and western blot were performed to assay the expression of the mRNA and protein. To assess the pattern of disorder‐related missense mutations of NDD‐related FOX genes, we manually curated de novo and inherited missense or inframeshift variants within FOXP1 , FOXP2 , and FOXG1 that co‐segregated with phenotypes in NDDs. All variants were annotated by ANNOVAR. Results We detected a novel de novo missense mutation ( NM_001244815 : c.G1444A, p.E482K) of FOXP1 in a patient with intellectual disability and severe speech delay. Real‐time PCR and western blot revealed a dramatic reduction of mRNA and protein expression in patient‐derived lymphocytes, indicating a loss‐of‐function mechanism. We observed that the majority of the de novo or transmitted missense variants were located in the FOX domains, and 95% were classified as pathogenic mutations. However, 10 variants were located outside of the FOX domain and were classified as likely pathogenic or variants of uncertain significance. Conclusion Our study shows the pathogenicity of missense and inframeshift variants of NDD‐related FOX genes, which is important for clinical diagnosis and genetic counseling. Functional analysis is needed to determine the pathogenicity of the variants with uncertain clinical significance.

Individuals with FOXP1 syndrome present with a complex neurobehavioral profile with high rates of ADHD, anxiety, repetitive behaviors, and sensory symptoms

“…Neurodevelopmental symptoms in FOXP1 syndrome were first attributed to FOXP1 haploinsufficiency through the finding of full or partial deletions in affected individuals [ 3 , 6 ]. Subsequently, loss of function and missense variants in FOXP1 were described, confirming this relationship [ 7 – 11 ]. More recently, dominant negative missense variants have been implicated in the syndrome [ 10 ].…”

“…More recently, dominant negative missense variants have been implicated in the syndrome [ 10 ]. Individuals with FOXP1 syndrome (including individuals with mutations or deletion impacting the FOXP1 gene) typically present with intellectual disability, speech and language deficits, hypotonia, features of ASD, and mild dysmorphic features [ 3 , 7 , 8 , 11 ].…”

Forkhead box R1-mediated stress response linked to a case of human microcephaly and brain atrophy

“…Disruption in FOXG1 in humans leads to structural brain abnormalities including microcephaly and agenesis of the corpus callosum (Shoichet et al , 2005; Kortum et al ., 2011; Hettige & Ernst, 2019). In addition, human mutations in both FOXP1 and FOXP2 lead to severe speech and cognitive impairments (Lai et al , 2000; MacDermot et al ., 2005; Takahashi et al , 2009; Horn et al , 2010; Nudel & Newbury, 2013; Han et al ., 2019); where both genes have also been linked to autism spectrum disorders (Takahashi et al ., 2009; Mukamel et al , 2011; Bowers & Konopka, 2012b, a).…”

“…Human genetic analyses have shown several FOX genes have important biological functions associated with brain development; these include FOXG1 (potential determinant of forebrain size; Florian et al , 2012; Hettige & Ernst, 2019; Pringsheim et al , 2019) and FOXP2 (vocal learning; MacDermot et al , 2005; Fisher & Scharff, 2009; Nudel & Newbury, 2013). Further, mutations in FOXG1, FOXC2, FOXL2, FOXP1 and FOXP2 have profound effects on human brain development including microcephaly, intellectual impairments, and language disorders (D’Haene et al , 2010; Kortum et al , 2011; Butler et al , 2012; Seltzer & Paciorkowski, 2014; Han et al , 2019).…”

Novel FOXP1 pathogenic variants in two Indian subjects with syndromic intellectual disability

“…Haplo‐insufficiency of FOXP1 causes Mental retardation with language impairment with or without autistic features (OMIM#613670). Worldwide less than 50 subjects with monogenic defects in FOXP1 have been reported (Han et al, 2019; Meerschaut et al, 2017). We ascertained two boys from unrelated families harboring novel disease causing variants in FOXP1 .…”