Dominant variants in the splicing factor PUF60 cause a recognizable syndrome with intellectual disability, heart defects and short stature

Abstract

International audienceVerheij syndrome, also called 8q24.3 microdeletion syndrome, is a rare condition characterized by ante- and postnatal growth retardation, microcephaly, vertebral anomalies, joint laxity/dislocation, developmental delay (DD), cardiac and renal defects and dysmorphic features. Recently, PUF60 (Poly-U Binding Splicing Factor 60 kDa), which encodes a component of the spliceosome, has been discussed as the best candidate gene for the Verheij syndrome phenotype, regarding the cardiac and short stature phenotype. To date, only one patient has been reported with a de novo variant in PUF60 that probably affects function (c.505C>T leading to p.(His169Tyr)) associated with DD, microcephaly, craniofacial and cardiac defects. Additional patients were required to confirm the pathogenesis of this association and further delineate the clinical spectrum. Here we report five patients with de novo heterozygous variants in PUF60 identified using whole exome sequencing. Variants included a splice-site variant (c.24+1G>C), a frameshift variant (p.(Ile136Thrfs*31)), two nonsense variants (p.(Arg448*) and p.(Lys301*)) and a missense change (p.(Val483Ala)). All six patients with a PUF60 variant (the five patients of the present study and the unique reported patient) have the same core facial gestalt as 8q24.3 microdeletions patients, associated with DD. Other findings include feeding difficulties (3/6), cardiac defects (5/6), short stature (5/6), joint laxity and/or dislocation (5/6), vertebral anomalies (3/6), bilateral microphthalmia and irido-retinal coloboma (1/6), bilateral optic nerve hypoplasia (2/6), renal anomalies (2/6) and branchial arch defects (2/6). These results confirm that PUF60 is a major driver for the developmental, craniofacial, skeletal and cardiac phenotypes associated with the 8q24.3 microdeletio

Exome sequencing reveals NAA15 and PUF60 as candidate genes associated with intellectual disability

“…Knockout of the PUF60 ortholog in C. elegans is embryonic lethal, while studies in Drosophila implicates a critical role for the PUF60 ortholog in alternative splicing affecting developmental regulation (MacMorris, Brocker, & Blumenthal, ; Park, Parisky, Celotto, Reenan, & Graveley, ). To date, there have been 16 reported cases with SNVs in PUF60 (Figure ), of which the most common phenotypes include Intellectual disability/developmental delay, short stature, cardiac defects and a recognizable facial phenotype consisting of square face, full cheeks, prominent forehead, low set eyebrows, wide nasal bridge, broad nasal tip, long philtrum, and a thin upper lip (Table ) (Dauber et al, ; Deciphering Developmental Disorders, ; El Chehadeh et al, ; Santos‐Simarro et al, ). Moreover, brain and skeletal anomalies also seems to be common among reported cases.…”

Spliceosomopathies: Diseases and mechanisms

“…35 Mutations in PUF60 are found in Verheij syndrome, a condition characterized by coloboma, ventricular septal defects, digit and hip abnormalities, developmental delay, and facial dysmorphisms. 12,13 EFTUD2 mutations occur in mandibulofacial dysostosis, Guion-Almeida type (MFDGA), which presents microcephaly, developmental delay, and craniofacial malformations. 14 SF3B4 mutations are associated with Nager syndrome (NS), in which patients exhibit midface retrusion, micrognathia, absent thumbs, and radial hypoplasia.…”

Genetic causes of optic nerve hypoplasia

“…Dauber et al 80 identified the first patient with a de novo heterozygous variant, p.H169Y in PUF60 . El Chehadeh et al 81 reported another five patients with de novo heterozygous variants in PUF60. All six patients identified to date manifest the same facial gestalt as seen in individuals with 8q24.3 microdeletion syndrome, also known as Verheij syndrome (MIM 615583).…”