Identification of novel FOXP1 variants in four unrelated patients with intellectual disability and speech impairment

Background To document the clinical phenotypes and identify the genetic causes of four unrelated children with intellectual disability and speech impairment. Methods Trio-based whole exome sequencing (Trios) was performed for four probands and their parents. Identified variants underwent pathogenicity assessment utilizing in silico protein structure prediction and RNA analysis. Results Trios revealed four novel de novo heterozygous FOXP1 variants: a frameshift variant c.1909dup (p.Glu637Glyfs * 10), two missense variants c.1568T>C (p.Phe523Ser) and c.1541G>T (p.Arg514Leu), and a splicing variant c.1653-34_1653-25delTTTAACTTTG, all confirmed by Sanger sequencing. Protein structure analysis predicted that the missense variants, located within the forkhead box (FOX) domain, are likely to impair protein function. RNA analysis demonstrated that the splicing variant c.1653-34_1653-25delTTTAACTTTG induced skipping of exons 18 and 19, resulting in an in-frame deletion of 64 amino acids (p.Asn511_Gln574del). Conclusion Our findings expand the mutational spectrum of FOXP1 and underscore the utility of in silico protein structure prediction and RNA analysis in the classification of variants of uncertain significance.