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.
Highlights
In 2009, Verheij et al.[1] reported overlapping interstitial microdeletions of chromosome 8q24 in two patients who had colobomata, congenital heart defects, limb abnormalities, developmental delay and seizures (MIM 615583)
A further patient with a missense variant in PUF602 and a foetus with an 8q24.3 deletion encompassing PUF60 occurring in association with an atrioventricular septal defect, a hypoplastic aortic arch, facial dysmorphism and other anomalies[3] strongly implicated this single gene as the cause of the phenotype
Her phenotype is consistent with respect to developmental delay, short stature and cardiac involvement
Summary
In 2009, Verheij et al.[1] reported overlapping interstitial microdeletions of chromosome 8q24 in two patients who had colobomata, congenital heart defects, limb abnormalities, developmental delay and seizures (MIM 615583). Dauber et al.[2] later described five patients who had microdeletions of 8q24.3 and similar phenotypes including ocular colobomata, microcephaly, developmental delay, short stature, craniofacial, cardiac and renal defects. All five patients had in common a 78-kb deleted region containing three genes: SCRIB, NRBP2 and PUF60. A further patient with a missense variant in PUF602 and a foetus with an 8q24.3 deletion encompassing PUF60 occurring in association with an atrioventricular septal defect, a hypoplastic aortic arch, facial dysmorphism and other anomalies[3] strongly implicated this single gene as the cause of the phenotype. The clinical features we observed in these patients and those previously published suggest that there is an emerging PUF60-related phenotype, this is variable and may be difficult to recognize
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