2. Academic Validation
  3. Dominant variants in the splicing factor PUF60 cause a recognizable syndrome with intellectual disability, heart defects and short stature

Dominant variants in the splicing factor PUF60 cause a recognizable syndrome with intellectual disability, heart defects and short stature

  • Eur J Hum Genet. 2016 Jan;25(1):43-51. doi: 10.1038/ejhg.2016.133.
Salima El Chehadeh 1 2,  Wilhelmina S Kerstjens-Frederikse 3,  Julien Thevenon 4 5,  Paul Kuentz 4 5 6,  Ange-Line Bruel 5,  Christel Thauvin-Robinet 4 5,  Candace Bensignor 7,  Hélène Dollfus 8 9,  Vincent Laugel 9 10,  Jean-Baptiste Rivière 4 5 6,  Yannis Duffourd 4,  Caroline Bonnet 11,  Matthieu P Robert 12 13,  Rodica Isaiko 14,  Morgane Straub 14,  Catherine Creuzot-Garcher 14,  Patrick Calvas 15,  Nicolas Chassaing 15,  Bart Loeys 16,  Edwin Reyniers 16,  Geert Vandeweyer 16,  Frank Kooy 16,  Miroslava Hančárová 17,  Marketa Havlovicová 17,  Darina Prchalová 17,  Zdenek Sedláček 17,  Christian Gilissen 18,  Rolph Pfundt 18,  Jolien S Klein Wassink-Ruiter 3,  Laurence Faivre 4 5
Affiliations

Affiliations

  • 1 FHU TRANSLAD, Centre de Référence Maladies Rares <> de l'Est, Centre de Génétique, CHU de Dijon, Dijon, France. salima.elchehadeh@chru-strasbourg.fr.
  • 2 Service de génétique médicale, Institut de génétique médicale d'Alsace (IGMA), Centre de Référence Maladies Rares <> de l'Est, Hôpitaux Universitaires de Strasbourg, Hôpital de Hautepierre, Strasbourg, France. salima.elchehadeh@chru-strasbourg.fr.
  • 3 Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
  • 4 FHU TRANSLAD, Centre de Référence Maladies Rares <> de l'Est, Centre de Génétique, CHU de Dijon, Dijon, France.
  • 5 EA 4271, Génétique et Anomalies du Développement (GAD), Université de Bourgogne, Dijon, France.
  • 6 Laboratoire de Biologie Moléculaire, Plateau Technique de Biologie, CHU de Dijon, Dijon, France.
  • 7 Service de Pédiatrie, Hôpital d'enfants, CHU de Dijon, Dijon, France.
  • 8 Service de génétique médicale, Institut de génétique médicale d'Alsace (IGMA), Centre de Référence Maladies Rares <> de l'Est, Hôpitaux Universitaires de Strasbourg, Hôpital de Hautepierre, Strasbourg, France.
  • 9 U1112 Laboratoire de Génétique Médicale, Faculté de médecine, Université de Strasbourg, Strasbourg, France.
  • 10 Service de Neuropédiatrie, Hôpitaux Universitaires de Strasbourg, Hôpital de Hautepierre, Strasbourg, France.
  • 11 Service de Cardiopédiatrie, Hôpital d'enfants, CHU de Dijon, Dijon, France.
  • 12 Service d'Ophtalmologie, APHP, Hôpital Universitaire Necker-Enfants Malades, Paris, France.
  • 13 COGNAC-G, UMR 8257: CNRS-IRBA-Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
  • 14 Service d'Ophtalmologie, Hôpital Civil, CHU de Dijon, Dijon, France.
  • 15 Service de Génétique Médicale, & UMR1056 INSERM-UPS, Hôpital de Purpan, CHU de Toulouse, Toulouse, France.
  • 16 Centre of Medical Genetics, University Hospital of Antwerp, Antwerpen-Edegem, Belgium.
  • 17 Department of Biology and Medical Genetics, Charles University 2nd Faculty of Medicine and University Hospital Motol, Prague, Czech Republic.
  • 18 Department of Human Genetics, Radboud Institute for Molecular Life Sciences and Donders Centre for Neuroscience, Radboud University Medical Center, Nijmegen, The Netherlands.
PMID: 27804958 DOI: 10.1038/ejhg.2016.133
Abstract

Verheij syndrome, also called 8q24.3 microdeletion syndrome, is a rare condition characterized by ante- and postnatal growth retardation, microcephaly, vertebral anomalies, joint laxity/dislocation, developmental delay (DD), cardiac and renal defects and dysmorphic features. Recently, PUF60 (Poly-U Binding Splicing Factor 60 kDa), which encodes a component of the spliceosome, has been discussed as the best candidate gene for the Verheij syndrome phenotype, regarding the cardiac and short stature phenotype. To date, only one patient has been reported with a de novo variant in PUF60 that probably affects function (c.505C>T leading to p.(His169Tyr)) associated with DD, microcephaly, craniofacial and cardiac defects. Additional patients were required to confirm the pathogenesis of this association and further delineate the clinical spectrum. Here we report five patients with de novo heterozygous variants in PUF60 identified using whole exome Sequencing. Variants included a splice-site variant (c.24+1G>C), a frameshift variant (p.(Ile136Thrfs*31)), two nonsense variants (p.(Arg448*) and p.(Lys301*)) and a missense change (p.(Val483Ala)). All six patients with a PUF60 variant (the five patients of the present study and the unique reported patient) have the same core facial gestalt as 8q24.3 microdeletions patients, associated with DD. Other findings include feeding difficulties (3/6), cardiac defects (5/6), short stature (5/6), joint laxity and/or dislocation (5/6), vertebral anomalies (3/6), bilateral microphthalmia and irido-retinal coloboma (1/6), bilateral optic nerve hypoplasia (2/6), renal anomalies (2/6) and branchial arch defects (2/6). These results confirm that PUF60 is a major driver for the developmental, craniofacial, skeletal and cardiac phenotypes associated with the 8q24.3 microdeletion.

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