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Eur J Hum Genet. 2017 May;25(5):552-559. doi: 10.1038/ejhg.2017.27. Epub 2017 Mar 22.

PUF60 variants cause a syndrome of ID, short stature, microcephaly, coloboma, craniofacial, cardiac, renal and spinal features.

Author information

1
Department of Clinical Genetics, St Michaels Hospital, Bristol, UK.
2
School of Clinical Sciences, University of Bristol, Bristol, UK.
3
MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
4
Institute of Human Genetics, University of Leipzig Hospitals and Clinics, Leipzig, Germany.
5
Institute of Medical Genetics, University Hospital of Wales, Cardiff, UK.
6
Service de Génétique Médicale, Hôpital de Hautepierre, Strasbourg, France.
7
Bristol Regional Genetics Laboratory, Southmead Hospital, Bristol, UK.
8
Northern Genetics Service, Newcastle upon Tyne Hospitals, Newcastle, UK.
9
Department of Clinical Genetics, Great Ormond Street Hospital, London, UK.
10
Department of Molecular and Medical Genetics, Oregon Health and Sciences University, Portland, OR, USA.
11
Centre de Génétique, CHU Dijon Bourgogne-Hôpital François Mitterrand, Dijon, France.
12
Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
13
Genetics and Metabolism, Pediatric Subspecialties, Carle Physicians Group, Urbana, IL, USA.
14
Northern Ireland Regional Genetics Service, Belfast City Hospital, Belfast, UK.
15
SW Thames Regional Genetics Service, St Georges University Hospital Trust, London, UK.
16
West Midlands Regional Genetics Service, Birmingham, UK.
17
Service de Génétique Médicale, Hôpital Arnaud de Villeneuve, CHRU de Montpellier, Montpellier, France.
18
Wellcome Trust Sanger Institute, Cambridge, UK.

Abstract

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.

PMID:
28327570
PMCID:
PMC5392357
DOI:
10.1038/ejhg.2017.27
[Indexed for MEDLINE]
Free PMC Article

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