Loss-of-function variants in ERFare associated with a Noonan syndrome-like phenotype with or without craniosynostosis

Autor: Dentici, Maria Lisa, Niceta, Marcello, Lepri, Francesca Romana, Mancini, Cecilia, Priolo, Manuela, Bonnard, Adeline Alice, Cappelletti, Camilla, Leoni, Chiara, Ciolfi, Andrea, Pizzi, Simone, Cordeddu, Viviana, Rossi, Cesare, Ferilli, Marco, Mucciolo, Mafalda, Colona, Vito Luigi, Fauth, Christine, Bellini, Melissa, Biasucci, Giacomo, Sinibaldi, Lorenzo, Briuglia, Silvana, Gazzin, Andrea, Carli, Diana, Memo, Luigi, Trevisson, Eva, Schiavariello, Concetta, Luca, Maria, Novelli, Antonio, Michot, Caroline, Sweertvaegher, Anne, Germanaud, David, Scarano, Emanuela, De Luca, Alessandro, Zampino, Giuseppe, Zenker, Martin, Mussa, Alessandro, Dallapiccola, Bruno, Cavé, Helene, Digilio, Maria Cristina, Tartaglia, Marco
Zdroj: European Journal of Human Genetics: EJHG; 20240101, Issue: Preprints p1-10, 10p
Abstrakt: Pathogenic, largely truncating variants in the ETS2 repressor factor (ERF) gene, encoding a transcriptional regulator negatively controlling RAS-MAPK signaling, have been associated with syndromic craniosynostosis involving various cranial sutures and Chitayat syndrome, an ultrarare condition with respiratory distress, skeletal anomalies, and facial dysmorphism. Recently, a single patient with craniosynostosis and a phenotype resembling Noonan syndrome (NS), the most common disorder among the RASopathies, was reported to carry a de novo loss-of-function variant in ERF. Here, we clinically profile 26 individuals from 15 unrelated families carrying different germline heterozygous variants in ERFand showing a phenotype reminiscent of NS. The majority of subjects presented with a variable degree of global developmental and/or language delay. Their shared facial features included absolute/relative macrocephaly, high forehead, hypertelorism, palpebral ptosis, wide nasal bridge, and low-set/posteriorly angulated ears. Stature was below the 3rd centile in two-third of the individuals, while no subject showed typical NS cardiac involvement. Notably, craniosynostosis was documented only in three unrelated individuals, while a dolichocephalic aspect of the skull in absence of any other evidence supporting a premature closing of sutures was observed in other 10 subjects. Unilateral Wilms tumor was diagnosed in one individual. Most cases were familial, indicating an overall low impact on fitness. Variants were nonsense and frameshift changes, supporting ERFhaploinsufficiency. These findings provide evidence that heterozygous loss-of-function variants in ERFcause a “RASopathy” resembling NS with or without craniosynostosis, and allow a first dissection of the molecular circuits contributing to MAPK signaling pleiotropy.
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