Original Research ARTICLE
MOLECULAR ETIOLOGY DISCLOSED BY ARRAY CGH IN PATIENTS WITH SILVER RUSSELL SYNDROME OR SIMILAR PHENOTYPES
- 1Departement of Medical Biotechnology and Translational Medicine, University of Milan, Italy
- 2Research Lab of Medical Cytogenetics and Molecular Genetics, Italian Auxological Institute (IRCCS), Italy
- 3Clinic of Medical Genetics, Italian Auxological Institute (IRCCS), Italy
- 4Research Lab of Medical Cytogenetics and Molecular Genetics, Istituto Auxologico Italiano (IRCCS), Italy
- 5Medical Genetics, Department of Health Sciences, University of Milan, Italy
- 6Division of Pediatrics, Department of Health Sciences, University of Eastern Piedmont, Italy
- 7Department of Pediatrics, Ospedale Sant Anna, ASST Lariana, Italy
- 8Department of Pediatric and Public Health Sciences, University of Turin, Italy
- 9Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania Luigi Vanvitelli, Italy
- 10Institute of Genetics and Biophysics "Adriano Buzzati-Traverso", Italian National Research Council (CNR), Italy
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.
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 CGH in order to identify potentially pathogenic copy number variants (CNVs).
In 7 patients, making up 21% of the initial cohort, 5 pathogenic and 2 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, 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: Silver-Russell Syndrome, Netchine–Harbison clinical scoring system, Array CGH, pathogenic CNVs, differential diagnosis
Received: 11 Mar 2019;
Accepted: 06 Sep 2019.
Copyright: © 2019 Crippa, Bonati, Calzari, Picinelli, Gervasini, Sironi, Bestetti, Guzzetti, Bellone, Selicorni, Mussa, Riccio, Ferrero, Russo, Larizza and Finelli. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Prof. Palma Finelli, University of Milan, Departement of Medical Biotechnology and Translational Medicine, Milan, 20122, Lombardy, Italy, email@example.com