ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Endocrine Abstracts (2019) 66 OC4.5 | DOI: 10.1530/endoabs.66.OC4.5

Novel genetic defects in a cohort of Silver-Russell Syndrome (SRS) and SRS-like patients

Emily Cottrell1, Miho Ishida2, Gudrun Moore2 & Helen L Storr1

1Centre for Endocrinology, William Harvey Research Institute, Queen Mary University London, London, UK; 2Great Ormond Street Institute of Child Health, University College London, London, UK

Background: Silver-Russell Syndrome (SRS) is a clinically and genetically heterogenous condition. 40% patients with ‘clinical’ SRS remain without a genetic diagnosis despite fulfilling the Netchine-Harbison Clinical Scoring System (NH-CSS) criteria. There is increasing recognition of the wide range of clinical phenotypes within the SRS spectrum and overlap with other short stature syndromes.

Methods: We analysed 26 undiagnosed patients with features of SRS by whole exome sequencing (WES). There were 2 patient cohorts: (1) Twelve SRS (n=9) and SRS-like (n=3) patients negative for 11p15 LOM +/− upd(7)mat, (2) Fourteen patients referred to our centre with undiagnosed short stature (SS) who fulfilled at least 2/6 NH-CSS with additional SRS features (8M, mean age 5.6 years, range 1.2–17 years, mean BW SDS −1.98, range +0.95 to −4.58, mean height SDS −3.73, range −2.21 to −7.07). Genetic variants were filtered using our ‘virtual’ gene panel with curated list of 85 candidate SRS genes. This included genes with important roles in growth, methylation and histone modification. 16 SRS and SRS-like patients were also assessed for copy number variation (CNV) by Array CGH with median resolution of 120 Kb for 15 patients and 1 Mb for 1 patient due to reduced DNA quality.

Results: WES identified rare, putative genetic variants in 5/26 (19%) individuals. In 1 patient we identified a homozygous frameshift ANKRD11 mutation, recognised to cause KBG syndrome, a rare genetic disorder with a SS phenotype and triangular face. Additionally, 4 rare variants in 3 SRS candidate genes were validated by Sanger sequencing. 2 were predicted damaging by ≥ 2/3 of SIFT, PolyPhen-2 and CADD pathogenicity scores. 1 variant was predicted to cause aberrant splicing and another is in a highly conserved region in the C-terminal catalytic domain. Functional investigation is planned to determine pathogenicity. CNVs were detected in 2/16 (13%) patients. 16q23 and 17q21 deletions in a male patient and 9q34 deletion in a female patient with learning difficulty, clinodactyly and hypoglycaemic episodes.

Conclusion: We identified 2 CNVs and 5 rare variants (30% with putative diagnosis) in 7 undiagnosed SRS and SRS-like patients. This work expands our knowledge of SRS genetic aetiology and SRS subtypes.

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