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Updated: Jan 8, 2026
In Vivo Functional Study of Disease-associated Rare Human Variants Using Drosophila
Published on: August 20, 2019
Silver-Russell syndrome secondary to rare (epi)genotypes exhibits phenotypic heterogeneity challenging clinical
Uttara Kurup1, David B N Lim2, Avinaash V Maharaj1
1Centre for Endocrinology, William Harvey Research Institute (WHRI), John Vane Science Centre, Charterhouse Square, Barts and the London School of Medicine, London, EC1M 6BQ , UK.
Context:
Silver-Russell syndrome (SRS) is a complex multisystem condition requiring timely diagnosis for appropriate management. A clinical diagnosis is made in individuals scoring ≥ 4 Netchine-Harbison Clinical Scoring System (NH-CSS) criteria, with (epi)genetic investigations undertaken in those with NH-CSS ≥ 3 and strong clinical suspicion. Monogenic variants in imprinted (CDKN1C and IGF2) and non-imprinted (HMGA2 and PLAG1) genes are recognised as rare causes of SRS. The frequency of associated phenotypes is unclear.
Objective:
We evaluated the suitability of SRS as an umbrella term for these (epi)genotypes by identifying key clinical features and assessing the validity of NH-CSS.
Methods:
An extensive literature search identified 22 IGF2, 18 HMGA2, 11 CDKN1C and 11 PLAG1 published reports.
Main Outcome Measure:
Clinical phenotypes including the NH-CSS criteria were interrogated to assess (dis)similarity between the molecular subgroups of SRS.
Results:
Strict adherence to the NH-CSS identified clinical SRS in 91% IGF2, 82% CDKN1C, 78% HMGA2 and 45% PLAG1 affected individuals. Relative macrocephaly was observed in 82% IGF2, 82% CDKN1C, 44% HMGA2, and 27% PLAG1 affected individuals. Prominent forehead was reported in 100% CDKN1C, 91% IGF2, 72% HMGA2, and 64% PLAG1 and body asymmetry in 23% IGF2 and 11% HMGA2 affected individuals. Clinical features not typically associated with SRS included: microcephaly, challenging behaviour, cardiac abnormalities, cleft palate, and asthma.
Conclusions:
The NH-CSS missed 9-55% of monogenic SRS. The diverse phenotypes of PLAG1, CDKN1C, HMGA2 and IGF2 variants may hinder a clinical diagnosis of SRS. These rarer (epi)genotypes could be considered as distinct entities.
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