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

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.

Need for a precise molecular diagnosis in Beckwith-Wiedemann and Silver-Russell syndrome: what has to be considered and why it is important

“…It should be noted that in all cases, the region 7q32 with the imprinted MEST locus is affected; therefore, this region represents a conclusive candidate gene region. However, as single SRS description with structural variants of 7p13 (including GRB10 [20]) show, this region should also be analysed.…”

Role of Imprinting Disorders in Short Children Born SGA and Silver-Russell Syndrome Spectrum

“…Major genetic causes of SRS are loss of methylation of the H19 / IGF2 :intergenic (IG)-DMR ( H19 LOM) and maternal uniparental disomy chromosome 7 (UPD(7)mat) ( 7 , 13 ); however, some patients with H19 LOM and UPD(7)mat did not satisfy NH-CSS criteria, and were diagnosed as SGA-SS ( 12 ). Moreover, some patients with etiologies other than H19 LOM and UPD(7)mat met NH-CSS criteria and were diagnosed as SRS ( 12 , 14 ).…”

A familial t(4;8) translocation segregates with epilepsy and migraine with aura

“…Specific primers pairs were used to verify the expression of STIM2 , CSMD1 , and RGS7 on control blood RNA. RNA collection and quantitative real‐time RT‐PCR based on the TaqMan methodology, were performed as previously described 8 . All assays were provided by Thermo Fisher Scientific (TaqMan Gene Expression Assays: ID# Hs00372705_m1 STIM2; Hs99999905_m1 GAPDH; Hs99999910_m1 TBP).…”