ESPE Abstracts (2023) 97 P1-507

1Centre for Endocrinology, William Harvey Research Institute, London, United Kingdom. 2Department of Human Anatomy and Cell Science, University of Manitoba, Winnipeg, Canada. 3Division of Paediatric Endocrinology, Department of Paediatrics, Willem-Alexander Children's Hospital, Leiden University Medical Centre, Leiden, Netherlands. 4Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Canada. 5Cincinnati Center for Growth Disorders, Division of Endocrinology, Cincinnati Children’s Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, USA. 6Division of Paediatric Endocrinology, Department of Paediatrics, Erasmus University Medical Centre, Sophia Children's Hospital, Rotterdam, Netherlands. 7Department of Paediatrics, Juliana Children's Hospital/Haga Teaching Hospital, The Hague, Netherlands. 8Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, Netherlands. 9CITES - Escuela Nacional de Medicina, TEC de Monterrey, Ave. Morones Prieto No. 3000 Pte. Col. Los Doctores 64710, Monterrey, Mexico. 10Department of Paediatrics and Child Health, HCA Healthcare UK, London, United Kingdom. 11Laboratory for Diagnostic Genome analysis (LDGA), Department of Clinical Genetics, Leiden University Medical Centre, Leiden, Netherlands. 12Department of Pathology, University of Manitoba, Winnipeg, Canada. 13Department of Surgery, University of Manitoba, Winnipeg, Canada. 14Department of Medical Microbiology and Infectious Diseases, University of Manitoba, Winnipeg, Canada

Background: Silver Russell syndrome (SRS) is a heterogeneous disorder characterised by intrauterine and post-natal growth retardation, relative macrocephaly, protruding forehead, feeding difficulties and body asymmetry. Variants in HMGA2 are a rare cause of SRS and despite strong evidence for the crucial role of HMGA2 in growth regulation, its functional role in human linear growth is unclear.

Methods: Patients with variants in the HMGA2 gene were phenotyped. Single nucleotide substitutions were created by mutagenesis of an N-terminal FLAG tagged-HMGA2 cDNA whilst a frameshift construct was customized to recapitulate reading frame extension. HMGA2 protein expression and nuclear localisation were assessed by immunoblotting and confocal microscopy. Two Hmga2 knock-in mouse models were generated by CRISPR/Cas9 technology.

Results: We report five novel variants in five unrelated individuals (height SDS ranging from -3.2 to -3.9) occurring in different critical regions of the HMGA2 gene. These include two stop-gain nonsense variants (c.49G>T, c.52C>T), two frameshift variants (c.144delC, c.145delA) leading to an identical prolonged protein and a missense variant, c.166A>G (p.K56E), located in the linker 2 region of HMGA2. Phenotypic features were highly variable. However, microcephaly appeared to be a highly penetrant and consistent feature in these patients. Nuclear localisation was markedly reduced or absent for all variants except c.166A>G. Transgenic mice homozygous for Hmga2K56E present with significant growth impairment and demonstrate for the first time, that a single amino acid change located outside of AT-hook domains, can modulate growth in mice. A further Hmga2Ter76 knock-in mouse model for a Hmga2 protein lacking a functional third AT-hook and the C-terminus, results in a pygmy phenotype and infertility.

Conclusions: We report a heterogeneous group of individuals with SRS harbouring variants in HMGA2 and describe the first Hmga2 missense knock-in mouse model (Hmga2K56E) causing a growth restricted phenotype. In undiagnosed patients with clinical features of SRS but negative molecular/genetic analysis, HMGA2 testing should be considered, particularly in those presenting with microcephaly.

Volume 97

61st Annual ESPE (ESPE 2023)

The Hague, Netherlands
21 Sep 2023 - 23 Sep 2023

European Society for Paediatric Endocrinology 

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