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

Frederike L Harms; Alexander J M Dingemans; Maja Hempel; Rolph Pfundt; Tatjana Bierhals; Christian Casar; Christian Müller; Jikke-Mien F Niermeijer; Jan Fischer; Arne Jahn; Christoph Hübner; Silvia Majore; Emanuele Agolini; Antonio Novelli; Jasper van der Smagt; Robert Ernst; Ellen van Binsbergen; Grazia M S Mancini; Marjon van Slegtenhorst; Tahsin Stefan Barakat; Emma L Wakeling; Arveen Kamath; Lilian Downie; Lynn Pais; Susan M White; Bert B A de Vries; Kerstin Kutsche

doi:10.1016/j.gim.2023.100927

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

Genet Med. 2023 Oct;25(10):100927. doi: 10.1016/j.gim.2023.100927. Epub 2023 Jul 6.

Authors

Frederike L Harms¹, Alexander J M Dingemans², Maja Hempel³, Rolph Pfundt², Tatjana Bierhals¹, Christian Casar⁴, Christian Müller⁴, Jikke-Mien F Niermeijer⁵, Jan Fischer⁶, Arne Jahn⁶, Christoph Hübner⁷, Silvia Majore⁸, Emanuele Agolini⁹, Antonio Novelli⁹, Jasper van der Smagt¹⁰, Robert Ernst¹⁰, Ellen van Binsbergen¹⁰, Grazia M S Mancini¹¹, Marjon van Slegtenhorst¹¹, Tahsin Stefan Barakat¹², Emma L Wakeling¹³, Arveen Kamath¹⁴, Lilian Downie¹⁵, Lynn Pais¹⁶, Susan M White¹⁵, Bert B A de Vries¹⁷, Kerstin Kutsche¹⁸

Affiliations

¹ Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
² Department of Human Genetics, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, The Netherlands.
³ Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Institute of Human Genetics, University Hospital Heidelberg, Heidelberg, Germany.
⁴ Bioinformatics Core, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
⁵ Department of Neurology, Elisabeth-TweeSteden Hospital, Tilburg, The Netherlands.
⁶ Institute for Clinical Genetics, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany.
⁷ Department of Neuropaediatrics, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
⁸ Division of Medical Genetics, Department of Experimental Medicine, San Camillo-Forlanini Hospital, Sapienza University, Rome, Italy.
⁹ Laboratory of Medical Genetics, Translational Cytogenomics Research Unit, Bambino Gesù Children Hospital, IRCCS, Rome, Italy.
¹⁰ Department of Genetics, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.
¹¹ Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
¹² Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, The Netherlands; Discovery Unit, Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
¹³ North East Thames Regional Genetic Service, Great Ormond Street Hospital for Children, NHS Foundation Trust, London, United Kingdom.
¹⁴ All Wales Medical Genomics Service/ Pennaeth Labordy Genomeg Cymru Gyfan, University Hospital of Wales, Heath Park, Cardiff, United Kingdom.
¹⁵ Victorian Clinical Genetics Service, Murdoch Children's Research Institute, VIC; Department of Paediatrics, University of Melbourne, Melbourne, Australia.
¹⁶ Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA.
¹⁷ Department of Human Genetics, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, The Netherlands. Electronic address: Bert.deVries@radboudumc.nl.
¹⁸ Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. Electronic address: kkutsche@uke.de.

PMID: 37422718
DOI: 10.1016/j.gim.2023.100927

Abstract

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.

Keywords: Craniofacial spliceosomopathies; Exome; Loss of function; Nager syndrome; Negative autoregulation.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Craniofacial Abnormalities*
Humans
Hypospadias* / genetics
Male
RNA Splicing
RNA Splicing Factors / genetics
RNA-Binding Proteins / genetics
Trans-Activators / genetics
Transcription Factors / genetics
Transcription Factors / metabolism

Substances

RNA Splicing Factors
Transcription Factors
PHF5A protein, human
Trans-Activators
RNA-Binding Proteins
SF3B4 protein, human

Abstract

Publication types

MeSH terms

Substances

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