Molecular Etiology Disclosed by Array CGH in Patients With Silver-Russell Syndrome or Similar Phenotypes

Milena Crippa; Maria Teresa Bonati; Luciano Calzari; Chiara Picinelli; Cristina Gervasini; Alessandra Sironi; Ilaria Bestetti; Sara Guzzetti; Simonetta Bellone; Angelo Selicorni; Alessandro Mussa; Andrea Riccio; Giovanni Battista Ferrero; Silvia Russo; Lidia Larizza; Palma Finelli

doi:10.3389/fgene.2019.00955

Molecular Etiology Disclosed by Array CGH in Patients With Silver-Russell Syndrome or Similar Phenotypes

Front Genet. 2019 Oct 15:10:955. doi: 10.3389/fgene.2019.00955. eCollection 2019.

Authors

Milena Crippa^{1

2}, Maria Teresa Bonati³, Luciano Calzari¹, Chiara Picinelli¹, Cristina Gervasini⁴, Alessandra Sironi^{1

2}, Ilaria Bestetti^{1

2}, Sara Guzzetti¹, Simonetta Bellone⁵, Angelo Selicorni⁶, Alessandro Mussa⁷, Andrea Riccio^{8

9}, Giovanni Battista Ferrero⁷, Silvia Russo¹, Lidia Larizza¹, Palma Finelli^{1

2}

Affiliations

¹ Research Laboratory of Medical Cytogenetics and Molecular Genetics, IRCCS Istituto Auxologico Italiano, Milan, Italy.
² Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy.
³ Clinic of Medical Genetics, IRCCS Istituto Auxologico Italiano, Milan, Italy.
⁴ Medical Genetics, Department of Health Sciences, University of Milan, Milan, Italy.
⁵ Division of Pediatrics, Department of Health Sciences, University of Piemonte Orientale, Novara, Italy.
⁶ Department of Pediatrics, ASST-Lariana, Como, Italy.
⁷ Department of Pediatric and Public Health Sciences, University of Turin, Turin, Italy.
⁸ Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania "Luigi Vanvitelli," Caserta, Italy.
⁹ Institute of Genetics and Biophysics "Adriano Buzzati-Traverso," Consiglio Nazionale delle Ricerche (CNR), Naples, Italy.

Abstract

Introduction: Silver-Russell syndrome (SRS) is an imprinting disorder primarily caused by genetic and epigenetic aberrations on chromosomes 11 and 7. SRS is a rare growth retardation disorder often misdiagnosed due to its heterogeneous and non-specific clinical features. The Netchine-Harbison clinical scoring system (NH-CSS) is the recommended tool for differentiating patients into clinical SRS or unlikely SRS. However, the clinical diagnosis is molecularly confirmed only in about 60% of patients, leaving the remaining substantial proportion of SRS patients with unknown genetic etiology. Materials and Methods: A cohort of 34 Italian patients with SRS or SRS-like features scored according to the NH-CSS and without any SRS-associated (epi)genetic alterations was analyzed by high-resolution array-based comparative genomic hybridization (CGH) in order to identify potentially pathogenic copy number variants (CNVs). Results and Discussion: In seven patients, making up 21% of the initial cohort, five pathogenic and two potentially pathogenic CNVs were found involving distinct genomic regions either previously associated with growth delay conditions (1q24.3-q25.3, 17p13.3, 17q22, and 22q11.2-q11.22) and with SRS spectrum (7p12.1 and 7p15.3-p14.3) or outlined for the first time (19q13.42), providing a better definition of reported and as yet unreported SRS overlapping syndromes. All the variants involve genes with a defined role in growth pathways, and for two genes mapping at 7p, IGF2BP3 and GRB10, the association with SRS turns out to be reinforced. The deleterious effect of the two potentially pathogenic variants, comprising GRB10 and ZNF331 genes, was explored by targeted approaches, though further studies are needed to validate their pathogenic role in the SRS etiology. In conclusion, we reconfirm the utility of performing a genome-wide scan to achieve a differential diagnosis in patients with SRS or similar features and to highlight novel chromosome alterations associated with SRS and growth retardation disorders.

Keywords: Netchine–Harbison clinical scoring system; Silver–Russell syndrome; array CGH; differential diagnosis; pathogenic CNVs.