Abstract
Maternal uniparental disomy of chromosome 7 is present in 5–10% of patients with Silver-Russell syndrome (SRS), and duplication of 7p including GRB10 (Growth Factor Receptor-Bound Protein 10), an imprinted gene that affects pre-and postnatal growth retardation, has been associated with the SRS phenotype. Here, we report on a 17 year old girl referred to array-CGH analysis for short stature, psychomotor delay, and relative macrocephaly. Array-CGH analysis showed two copy number variants (CNVs): a ~12.7 Mb gain in 7p13-p11.2, involving GRB10 and an ~9 Mb loss in 7q11.21-q11.23. FISH experiments performed on the proband’s mother showed a chromosome 7 pericentric inversion that might have mediated the complex rearrangement harbored by the daughter. Indeed, we found that segmental duplications, of which chromosome 7 is highly enriched, mapped at the breakpoints of both the mother’s inversion and the daughter’s CNVs. We postulate that pairing of highly homologous sequences might have perturbed the correct meiotic chromosome segregation, leading to unbalanced outcomes and acting as the putative meiotic mechanism that was causative of the proband’s rearrangement. Comparison of the girl’s phenotype to those of patients with similar CNVs supports the presence of 7p in a locus associated with features of SRS syndrome.
Highlights
Silver-Russell syndrome (SRS, #180860) is associated with all the following six clinical criteria, of which four must be present for a diagnosis to be made: pre- and postnatal growth retardation, relative macrocephaly, prominent forehead, body asymmetry, and feeding difficulties (Netchine-Harbison clinical scoring system, Netchine Harbison clinical scoring systems (NH-CSS)) [1]
We reviewed the clinical reports of all patients on the basis of the Netchine Harbison clinical scoring systems (NH-CSS) [1]
Based on the FISH results, we propose that the inversion breakpoints were localized at the distal breakpoint of the daughter’s gain (7p13) and at the distal breakpoint of the daughter’s deletion (7q11.23)
Summary
Silver-Russell syndrome (SRS, #180860) is associated with all the following six clinical criteria, of which four must be present for a diagnosis to be made: pre- and postnatal growth retardation, relative macrocephaly, prominent forehead, body asymmetry, and feeding difficulties (Netchine-Harbison clinical scoring system, NH-CSS) [1]. Duplications involving GRB10 on the maternal allele are described in patients with growth delay and SRS features [2,3,4], whereas those on the paternal allele are associated with overgrowth [5]. Only five patients with maternal 7p duplication including GRB10 have been described in the literature and some of them are related [2,3,4]. Array-CGH (Array based Comparative Genomic Hybridization) analysis detected a complex rearrangement composed of an ~12.7 Mb gain at 7p13-p11.2 and an ~9 Mb loss at 7q11.21-q11.23. By FISH (Fluorescence In Situ Hybridization) analysis, the proband’s mother was found to carry an apparently balanced, pericentric inversion that could have triggered the complex rearrangement
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