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.

Centre of Medical Genetics University Hospital of Antwerp Antwerpen Edegem Belgium

COGNAC G UMR 8257 CNRS IRBA Université Paris Descartes Sorbonne Paris Cité Paris France

Department of Biology and Medical Genetics Charles University 2nd Faculty of Medicine and University Hospital Motol Prague Czech Republic

Department of Genetics University of Groningen University Medical Center Groningen Groningen The Netherlands

Department of Human Genetics Radboud Institute for Molecular Life Sciences and Donders Centre for Neuroscience Radboud University Medical Center Nijmegen The Netherlands

EA 4271 Génétique et Anomalies du Développement Université de Bourgogne Dijon France

FHU TRANSLAD Centre de Référence Maladies Rares <<Anomalies du développement et syndromes malformatifs>> de l'Est Centre de Génétique CHU de Dijon Dijon France

Laboratoire de Biologie Moléculaire Plateau Technique de Biologie CHU de Dijon Dijon France

Service d'Ophtalmologie APHP Hôpital Universitaire Necker Enfants Malades Paris France

Service d'Ophtalmologie Hôpital Civil CHU de Dijon Dijon France

Service de Cardiopédiatrie Hôpital d'enfants CHU de Dijon Dijon France

Service de Génétique Médicale and UMR1056 INSERM UPS Hôpital de Purpan CHU de Toulouse Toulouse France

Service de génétique médicale Institut de génétique médicale d'Alsace Centre de Référence Maladies Rares <<Anomalies du développement et syndromes malformatifs>> de l'Est Hôpitaux Universitaires de Strasbourg Hôpital de Hautepierre Strasbourg France

Service de Neuropédiatrie Hôpitaux Universitaires de Strasbourg Hôpital de Hautepierre Strasbourg France

Service de Pédiatrie Hôpital d'enfants CHU de Dijon Dijon France

U1112 Laboratoire de Génétique Médicale Faculté de médecine Université de Strasbourg Strasbourg France

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