De novo PHF5A variants are associated with craniofacial abnormalities, developmental delay, and hypospadias

Research output: Contribution to journalResearch articleContributedpeer-review


  • Frederike L. Harms - , University of Hamburg (Author)
  • Alexander J.M. Dingemans - , Radboud University Nijmegen (Author)
  • Maja Hempel - , University of Hamburg, Heidelberg University  (Author)
  • Rolph Pfundt - , Radboud University Nijmegen (Author)
  • Tatjana Bierhals - , University of Hamburg (Author)
  • Christian Casar - , University of Hamburg (Author)
  • Christian Müller - , University of Hamburg (Author)
  • Jikke Mien F. Niermeijer - , ETZ Elisabeth - Tweesteden Ziekenhuis (Author)
  • Jan Fischer - , Institute of Clinical Genetics (Author)
  • Arne Jahn - , Institute of Clinical Genetics, University Hospital Carl Gustav Carus Dresden, Dresden University of Technology (Author)
  • Christoph Hübner - , Department of Paediatrics, Division of Neuropediatrics (Author)
  • Silvia Majore - , University of Rome La Sapienza (Author)
  • Emanuele Agolini - , IRCCS Ospedale pediatrico Bambino Gesù - Roma (Author)
  • Antonio Novelli - , IRCCS Ospedale pediatrico Bambino Gesù - Roma (Author)
  • Jasper van der Smagt - , Utrecht University (Author)
  • Robert Ernst - , Utrecht University (Author)
  • Ellen van Binsbergen - , Utrecht University (Author)
  • Grazia M.S. Mancini - , Erasmus University Rotterdam (Author)
  • Marjon van Slegtenhorst - , Erasmus University Rotterdam (Author)
  • Tahsin S. Barakat - , Erasmus University Rotterdam (Author)
  • Emma L. Wakeling - , Great Ormond Street Hospital for Children NHS Trust (Author)
  • Arveen Kamath - , University Hospital of Wales (Author)
  • Lilian Downie - , Murdoch Children's Research Institute, University of Melbourne (Author)
  • Lynn Pais - , Broad Institute of Harvard University and MIT (Author)
  • Susan M. White - , Murdoch Children's Research Institute, University of Melbourne (Author)
  • Bert B.A. de Vries - , Radboud University Nijmegen (Author)
  • Kerstin Kutsche - , University of Hamburg (Author)


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.


Original languageEnglish
Article number100927
JournalGenetics in medicine
Issue number10
Publication statusPublished - Oct 2023

External IDs

PubMed 37422718


ASJC Scopus subject areas


  • Craniofacial spliceosomopathies, Exome, Loss of function, Nager syndrome, Negative autoregulation, Hypospadias/genetics, Humans, Male, Trans-Activators/genetics, RNA-Binding Proteins/genetics, Transcription Factors/genetics, RNA Splicing, Craniofacial Abnormalities, RNA Splicing Factors/genetics