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

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.

Post-transcriptional regulation of BRG1 by FIRΔexon2 in gastric cancer

“…FGF8 splicing variant analysis by up-or downregulated FIR or FIRΔexon2 in cancer cells FIR complete knockout C57BL/6 mice (FIR −/− ) was embryonic lethal before E9.5; strongly suggests that FIR is crucial for development 27 . Recently, the germ line mutations or deletions in the RNA recognition motifs (RRMs) of the PUF60 gene were reported in Verheij or CHARGE syndrome 12,[29][30][31] . In CHARGE syndrome patients, protein interactions are spoiled in alternative splicing of FGF8 mRNA pre-mRNA processing in neural development due to dysfunction among BRG1, SWI/SNF and CHD7.…”

Clinical characterization of aPUF60variant in a patient with Dubowitz‐like syndrome

“…The authors also thank Sarah Sawyer (Children' Tsukahara and Opitz (1996): review of 141 cases. b Low et al (2017):12 patients described.…”

“…disease, ocular coloboma, renal and spinal anomalies. Patients have been described with either single-site variants or deletions involving the PUF60 gene (Dauber et al, 2013;El Chehadeh et al, 2016;Graziano et al, 2017;Low et al, 2017;Moccia et al, 2018;Santos-Simarro et al, 2017;Zhao et al, 2018). Of those, seven patients were described in the DECIPHER database (Firth et al, 2009) with 8q24.3 microdeletion syndrome or Verheij syndrome (MIM# 615583).…”

Novel diagnosis and therapy for hepatoma targeting HBV-related carcinogenesis through alternative splicing of FIR (PUF60)/FIRΔexon2

“…Rare disease CHARGE syndrome [59] Phenotypic variability of genetic diseases [59] Verheji syndrome [59,60] developmental delay, intelllectual disability, microcephaly, craniofacial, renal and cardiac defects [58,59] Eye coloboma and complex cardiac malformations [59,61] atrioventricular septal defect and hypoplastic aortic arch, facial dysmorphism, microretrognathia, dysmorphic ears, clinodactyly of the 5th digit on both hands, mild rocker bottom feet and abnormal third sacral vertebra [61,62] microcephaly, short stature, intellectual disability, and heart defects with a de novo c.505C > T variant leading to a p.His169Tyr change in PUF60. (PUF60 deficiency) [63][64][65] Figure 5.…”

“…FIR: FUBP1-interacting repressor; WD: W (Typ) D (Asp) syndrome patients were present in 15 of 28 individuals (53.6%), whereas 4 (14.3%) individuals had other pathogenic variants such as RERE, KMT2D, EP300, or FIR/PUF60 [59] . A two base pair deletion was identified in the PUF60 gene, which is one of three genes in the critical region of the 8q24.3 microdeletion syndrome (Verheij syndrome) that shows intellectual disability [60] . In 2013, patients with microdeletions of chromosome 8q24.3 including FIR/PUF60 were found to have developmental delay, microcephaly, craniofacial, renal and cardiac defects were found in six patients with variants in FIR/PUF60 [61] .…”