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

Karen J. Low, Morad Ansari, Rami Abou Jamra, Angus Clarke, Salima El Chehadeh, David R. Fitzpatrick, Mark Greenslade, Alex Henderson, Jane Hurst, Kory Keller, Paul Kuentz, Trine Prescott, Franziska Roessler, Kaja K. Selmer, Michael C. Schneider, Fiona Stewart, Katrina Tatton-Brown, Julien Thevenon, Magnus D. Vigeland, Julie VogtMarjolaine Willems, Jonathan Zonana, D. D.D. Study, Sarah F. Smithson*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

37 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)552-559
Number of pages8
JournalEuropean Journal of Human Genetics
Issue number5
Publication statusPublished - 1 May 2017


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