PUF60 variants cause a syndrome of ID, short stature, microcephaly, coloboma, craniofacial, cardiac, renal and spinal features.
PUF60 encodes a nucleic acid-binding protein, a component of multimeric complexes regulating RNA splicing and transcription. In 2013, patients with microdeletions of chromosome 8q24.3 including PUF60 were found to have developmental delay, microcephaly, craniofacial, renal and cardiac defects. Very similar phenotypes have been described in six patients with variants in PUF60, suggesting that it underlies the syndrome. We report 12 additional patients with PUF60 variants who were ascertained using exome sequencing: six through the Deciphering Developmental Disorders Study and six through similar projects. Detailed phenotypic analysis of all patients was undertaken. All 12 patients had de novo heterozygous PUF60 variants on exome analysis, each confirmed by Sanger sequencing: four frameshift variants resulting in premature stop codons, three missense variants that clustered within the RNA recognition motif of PUF60 and five essential splice-site (ESS) variant. Analysis of cDNA from a fibroblast cell line derived from one of the patients with an ESS variants revealed aberrant splicing. The consistent feature was developmental delay and most patients had short stature. The phenotypic variability was striking; however, we observed similarities including spinal segmentation anomalies, congenital heart disease, ocular colobomata, hand anomalies and (in two patients) unilateral renal agenesis/horseshoe kidney. Characteristic facial features included micrognathia, a thin upper lip and long philtrum, narrow almond-shaped palpebral fissures, synophrys, flared eyebrows and facial hypertrichosis. Heterozygote loss-of-function variants in PUF60 cause a phenotype comprising growth/developmental delay and craniofacial, cardiac, renal, ocular and spinal anomalies, adding to disorders of human development resulting from aberrant RNA processing/spliceosomal function.
Department of Clinical Genetics, St Michaels Hospital, Bristol, UK.|School of Clinical Sciences, University of Bristol, Bristol, UK.
Karen J
KJ
Low
MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
Morad
M
Ansari
Institute of Human Genetics, University of Leipzig Hospitals and Clinics, Leipzig, Germany.
Rami
R
Abou Jamra
Institute of Medical Genetics, University Hospital of Wales, Cardiff, UK.
Angus
A
Clarke
Service de Génétique Médicale, Hôpital de Hautepierre, Strasbourg, France.
Salima
S
El Chehadeh
MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
David R
DR
FitzPatrick
Bristol Regional Genetics Laboratory, Southmead Hospital, Bristol, UK.
Mark
M
Greenslade
Northern Genetics Service, Newcastle upon Tyne Hospitals, Newcastle, UK.
Alex
A
Henderson
Department of Clinical Genetics, Great Ormond Street Hospital, London, UK.
Jane
J
Hurst
Department of Molecular and Medical Genetics, Oregon Health and Sciences University, Portland, OR, USA.
Kory
K
Keller
Centre de Génétique, CHU Dijon Bourgogne-Hôpital François Mitterrand, Dijon, France.
Paul
P
Kuentz
Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
Trine
T
Prescott
Institute of Human Genetics, University of Leipzig Hospitals and Clinics, Leipzig, Germany.
Franziska
F
Roessler
Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
Kaja K
KK
Selmer
Genetics and Metabolism, Pediatric Subspecialties, Carle Physicians Group, Urbana, IL, USA.
Michael C
MC
Schneider
Northern Ireland Regional Genetics Service, Belfast City Hospital, Belfast, UK.
Fiona
F
Stewart
SW Thames Regional Genetics Service, St Georges University Hospital Trust, London, UK.
Katrina
K
Tatton-Brown
Centre de Génétique, CHU Dijon Bourgogne-Hôpital François Mitterrand, Dijon, France.
Julien
J
Thevenon
Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
Magnus D
MD
Vigeland
West Midlands Regional Genetics Service, Birmingham, UK.
Julie
J
Vogt
Service de Génétique Médicale, Hôpital Arnaud de Villeneuve, CHRU de Montpellier, Montpellier, France.
Marjolaine
M
Willems
Department of Molecular and Medical Genetics, Oregon Health and Sciences University, Portland, OR, USA.
Jonathan
J
Zonana
Wellcome Trust Sanger Institute, Cambridge, UK.
D D D
DD
Study
Department of Clinical Genetics, St Michaels Hospital, Bristol, UK.|School of Clinical Sciences, University of Bristol, Bristol, UK.
Sarah F
SF
Smithson
D000015:Abnormalities, Multiple / Q000175:diagnosis / Q000235:genetics*; D002478:Cells, Cultured; D002648:Child; D018388:Codon, Terminator / Q000235:genetics; D059472:Exome; D005260:Female; D006579:Heterozygote; D006801:Humans; D008607:Intellectual Disability / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D008831:Microcephaly / Q000175:diagnosis / Q000235:genetics*; D020125:Mutation, Missense; D010641:Phenotype; D000072260:RNA Splicing Factors / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics*; D013577:Syndrome
D018388:Codon, Terminator; D000072260:RNA Splicing Factors; D012097:Repressor Proteins; C410595:poly-U binding splicing factor 60KDa