de novo PHF5A variants are associated with craniofacial abnormalities, developmental delay, and hypospadias.
PURPOSE: The SF3B splicing complex is composed of SF3B1-6 and PHF5A. We report a developmental disorder caused by de novo variants in PHF5A.METHODS: Clinical, genomic, and functional studies using subject-derived fibroblasts and a heterologous cellular system were performed.RESULTS: We studied nine subjects with congenital malformations, including preauricular tags and hypospadias, growth abnormalities, and developmental delay who had de novo heterozygous PHF5A variants, including four loss-of-function (LOF), three missense, one splice, and one start-loss variant. In subject-derived fibroblasts with PHF5A LOF variants, wild-type and variant PHF5A mRNAs had a 1:1 ratio and PHF5A mRNA levels were normal. Transcriptome sequencing revealed alternative promoter use and downregulated genes involved in cell cycle regulation. Subject and control fibroblasts had similar amounts of PHF5A with the predicted wild-type molecular weight and of SF3B1-3 and SF3B6. SF3B complex formation was unaffected in two subject cell lines.CONCLUSION: Our data suggest the existence of feedback mechanisms in fibroblasts with PHF5A LOF variants to maintain normal levels of SF3B components. These compensatory mechanisms in subject fibroblasts with PHF5A or SF3B4 LOF variants suggest disturbed autoregulation of mutated splicing factor genes in specific cell types, i.e. neural crest cells, during embryonic development rather than haploinsufficiency as pathomechanism.
|Year of Publication
Genetics in medicine : official journal of the American College of Medical Genetics