Börjeson-Forssman-Lehman Syndrome (BFLS) is a rare X-linked recessive syndrome characterized by intellectual disability, developmental delay, obesity, epilepsy, swelling of the subcutaneous tissues of the face, large but not deformed ears, hypogonadism, and gynecomastia. Pathogenic mutations in PHD finger protein 6 (PHF6) have been reported to cause BFLS. In this study, we describe two male siblings with mild intellectual disability, global developmental delay, short stature, microcephaly, and nyctalopia. Whole exome sequencing of the affected siblings and the parents identified a missense variant (c.413C > G) in the PHF6 gene, which leads to alteration of a serine residue at position 138 to cysteine. This mutation is located in a highly conserved region. Sanger sequencing confirmed the segregation of this mutation in the family in an X-linked recessive fashion. Multiple mass spectrometry-based proteomic studies have reported phosphorylation at serine 138 that describes the possible role of serine 138 in signaling. This novel variant in PHF6 gene helped in establishing a diagnosis of BFLS.
Keywords: Alternative splicing; Brain development; Hypogonadism; NuRD complex; Nucleolar; Obesity; Transcription regulation.