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Article Dans Une Revue European Journal of Human Genetics Année : 2017

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

Wilhelmina Kerstjens-Frederikse
Paul Kuentz
Candace Bensignor
  • Fonction : Auteur
Yannis Duffourd
  • Fonction : Auteur
Caroline Bonnet
Matthieu Robert
  • Fonction : Auteur
Rodica Isaiko
  • Fonction : Auteur
Morgane Straub
  • Fonction : Auteur
Catherine Creuzot-Garcher
Bart Loeys
  • Fonction : Auteur
Edwin Reyniers
  • Fonction : Auteur
Geert Vandeweyer
  • Fonction : Auteur
Frank Kooy
  • Fonction : Auteur
Miroslava Hančárová
  • Fonction : Auteur
Marketa Havlovicová
  • Fonction : Auteur
Darina Prchalová
  • Fonction : Auteur
Zdenek Sedláček
  • Fonction : Auteur
Christian Gilissen
  • Fonction : Auteur
Rolph Pfundt
  • Fonction : Auteur
Jolien Wassink-Ruiter
  • Fonction : Auteur
Laurence Faivre

Résumé

Verheij 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 microdeletion.

Dates et versions

hal-03271113 , version 1 (25-06-2021)

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Citer

Salima El Chehadeh, Wilhelmina Kerstjens-Frederikse, Julien Thevenon, Paul Kuentz, Ange-Line Bruel, et al.. Dominant variants in the splicing factor PUF60 cause a recognizable syndrome with intellectual disability, heart defects and short stature. European Journal of Human Genetics, 2017, 25 (1), pp.43-51. ⟨10.1038/ejhg.2016.133⟩. ⟨hal-03271113⟩
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