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 9 subjects with congenital malformations, including preauricular tags and hypospadias, growth abnormalities, and developmental delay who had de novo heterozygous PHF5A variants, including 4 loss-of-function (LOF), 3 missense, 1 splice, and 1 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 2 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, that is, neural crest cells, during embryonic development rather than haploinsufficiency as pathomechanism. & COPY; 2023 by American College of Medical Genetics and Genomics. Published by Elsevier Inc.

Automated summary

In this study, we discovered that de novo variants in the PHF5A gene can cause developmental disorders. Through clinical, genomic, and functional studies, we identified various types of PHF5A variants in nine patients, including loss-of-function, missense, splice, and start-loss variants. Our findings suggest that the loss-of-function variants in PHF5A result in downregulation of genes involved in cell-cycle regulation, but compensatory mechanisms maintain normal levels of other SF3B complex components.