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.
Highlights
Silver–Russell syndrome (SRS) is an imprinting disorder primarily caused by genetic and epigenetic aberrations on chromosomes 11 and 7
This study aimed to evaluate, through high-resolution aCGH, a cohort of 34 patients with clinical signs resembling SRS but negative togenetic tests
Five individuals, accounting for 15% of the starting cohort, were found to harbor pathogenic copy number variants (CNVs) (P-CNVs), attesting a frequency higher than that shown by similar studies, ranging from 6% (Inoue et al, 2017) or 7% (Azzi et al, 2015) to 12% (Sachwitz et al, 2017)
Summary
Silver–Russell syndrome (SRS) is an imprinting disorder primarily caused by genetic and epigenetic aberrations on chromosomes 11 and 7. In accordance with the statement, patients meeting NH-CSS criteria including both protruding forehead and relative macrocephaly, but normal at all molecular tests, receive a diagnosis of clinical SRS. In addition chromosome 14q32.2 imprinting defects, underpinning Temple syndrome (TS; OMIM#616222), represent an alternative molecular diagnosis to SRS, as numerous molecularly confirmed TS patients (70–72.7%) were found to fulfill the NH-CSS criteria (Kagami et al, 2017; Geoffron et al, 2018). That is, point mutations in imprinted genes at 11p15 or in other disease-causing genes, and non-recurrent copy number variants (CNVs) affecting different chromosome regions have been detected in a small number of SRS patients (Bruce et al, 2010; Lin et al, 2010; Spengler et al, 2012; Fuke et al, 2013; Inoue et al, 2017; Meyer et al, 2017; Sachwitz et al, 2017; Wakeling et al, 2017; Tumer et al, 2018)
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