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

European Journal of Human Genetics (2024)Cite this article

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Abstract

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 ERF and 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 ERF haploinsufficiency. These findings provide evidence that heterozygous loss-of-function variants in ERF cause 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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Fig. 1: Facial features of the subjects carrying heterozygous truncating variants in ERF.

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Data availability

The sequencing data that support the findings of this work are available on request from the corresponding author (MT). The data are not publicly available due to privacy/ethical restrictions. The pathogenic variants identified in this work and their clinical association have been submitted to ClinVar (SCV004229149 to SCV004229155, SCV004807477).

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Acknowledgements

We are grateful to the families who participated in this study. This work has been carried out in the frame of the “European Reference Network for Rare Malformation Syndromes, Intellectual and Other Neurodevelopmental Disorders” (ERN-ITHACA) activity.

Funding

This work was supported by the Italian Ministry of Health (5 per 1000_2024, Current Research Funds and PNRR-MR1-2022-12376811 to MT, and 5×1000_2023 to AC), Fondazione AIRC (IG28768, to MT), and European Joint Programme on Rare Diseases (NSEuroNet to MT, HC, and MZ).

Author information

Author notes

  1. These authors contributed equally: Maria Lisa Dentici, Marcello Niceta.

Authors and Affiliations

  1. Rare Diseases and Medical Genetics, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146, Rome, Italy

    Maria Lisa Dentici, Vito Luigi Colona, Lorenzo Sinibaldi & Maria Cristina Digilio

  2. Molecular Genetics and Functional Genomics, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146, Rome, Italy

    Marcello Niceta, Cecilia Mancini, Camilla Cappelletti, Andrea Ciolfi, Simone Pizzi, Marco Ferilli, Bruno Dallapiccola & Marco Tartaglia

  3. Translational Cytogenomics, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146, Rome, Italy

    Francesca Romana Lepri, Mafalda Mucciolo & Antonio Novelli

  4. Medical and Molecular Genetics, Ospedale Cardarelli, 80131, Naples, Italy

    Manuela Priolo

  5. Service de de Génétique Moléculaire Hôpital Robert Debré, GHU AP-HP Nord - Université Paris Cité, INSERM UMR_S1131, Institut Universitaire d’Hématologie, Université Paris Cité, Paris-Cité, 75019, Paris, France

    Adeline Alice Bonnard & Helene Cavé

  6. Department of Biomedicine and Prevention, Università di Roma “Tor Vergata”, 00133, Rome, Italy

    Camilla Cappelletti

  7. Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168, Rome, Italy

    Chiara Leoni & Giuseppe Zampino

  8. Department of Life Sciences and Public Health, Università Cattolica del Sacro Cuore, 00168, Rome, Italy

    Chiara Leoni & Giuseppe Zampino

  9. Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, 00161, Rome, Italy

    Viviana Cordeddu

  10. Medical Genetics, IRCSS Azienda Ospedaliero-Universitaria di Bologna, 40138, Bologna, Italy

    Cesare Rossi

  11. Institute for Human Genetics, Medical University Innsbruck, 6020, Innsbruck, Austria

    Christine Fauth

  12. Pediatrics and Neonatology, Gugliemo da Saliceto Hospital, 29121, Piacenza, Italy

    Melissa Bellini & Giacomo Biasucci

  13. Genetics and Pharmacogenetics, Ospedale Universitario “Gaetano Martino”, 98125, Messina, Italy

    Silvana Briuglia

  14. Pediatric Clinical Genetics, Ospedale Pediatrico “Regina Margherita”, 10126, Torino, Italy

    Andrea Gazzin

  15. Department of Medical Sciences, Università of Torino, 10126, Torino, Italy

    Diana Carli, Maria Luca & Alessandro Mussa

  16. Medical Genetics, Institute for Maternal and Child Health-IRCCS, Burlo Garofolo, 34127, Trieste, Italy

    Luigi Memo

  17. Department of Women’s and Children’s Health, Università di Padova, 35128, Padova, Italy

    Eva Trevisson

  18. Department of Pediatrics, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138, Bologna, Italy

    Concetta Schiavariello & Emanuela Scarano

  19. Center for Skeletal Dysplasia, Necker-Enfants Malades Hospital, Paris Cité University, INSERM UMR 1163, Imagine Institute, 75015, Paris, France

    Caroline Michot

  20. Service de Pédiatrie, Centre hospitalier de Saint-Quentin, 02321, Saint-Quentin, France

    Anne Sweertvaegher

  21. Département de Génétique, CEA Paris-Saclay, NeuroSpin, Gif-sur-Yvette, France

    David Germanaud

  22. Service de Génétique Clinique, AP-HP, Hôpital Robert-Debré, 75019, Paris, France

    David Germanaud

  23. Medical Genetics Division, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013, San Giovanni, Rotondo, Italy

    Alessandro De Luca

  24. Institute of Human Genetics, University Hospital Magdeburg, 39120, Magdeburg, Germany

    Martin Zenker

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  1. Maria Lisa Dentici
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Contributions

MT conceived the work. MLD, MN and MT took the lead in writing the manuscript. MN, FRL, CM, AAB, CC, AC, SP, VC, CR, MF, MM, ET, AN, ADL, and HC performed the genomic analyses and analyzed and validated the genomic data. MN, CL, VLC, CF, MB, GB, LS, SB, AG, DC, LM, CS, ML, CM, AS, DG, ES, GZ, MZ, AM, BD, and MCD collected the clinical data. MLD and MP performed the clinical data analyses. All coauthors provided critical feedback on the manuscript.

Corresponding author

Correspondence to Marco Tartaglia.

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Competing interests

The authors declare no competing interests.

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Dentici, M.L., Niceta, M., Lepri, F.R. et al. Loss-of-function variants in ERF are associated with a Noonan syndrome-like phenotype with or without craniosynostosis. Eur J Hum Genet (2024). https://doi.org/10.1038/s41431-024-01642-7

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