Journal Article

Characterization of HMGA2 variants expands the spectrum of Silver-Russell syndrome

Aguirre, Gabriel Amador, van der Kaay, Danielle, Castilla de Cortázar Larrea, María Inmaculada, De Bruin, Christiaan, Storr, Helen L., Hwa, Vivian, van Duyvenvoorde, Hermine A., Cottrell, Emily, Fujimoto, Masanobu, Martín del Estal, Irene, Hombach-Klonisch, Sabine, Massoud, Ahmed, Maharaj, Avinaash V., Thanasupawat, Thatchawan, Triggs-Raine, Barbara, Clement-de Boers, Agnes, Kant, Sarina G., Joustra, Sjoerd D., Brooks, Alice S., Klonisch, Thomas

2024

Overview

Silver-Russell syndrome (SRS) is a heterogeneous disorder characterized by intrauterine and postnatal growth retardation. HMGA2 variants are a rare cause of SRS and its functional role in human linear growth is unclear. Patients with suspected SRS negative for 11p15LOM/mUPD7 underwent whole-exome and/or targeted-genome sequencing. Mutant HMGA2 protein expression and nuclear localization were assessed. Two Hmga2-knockin mouse models were generated. Five clinical SRS patients harbored HMGA2 variants with differing functional impacts: 2 stop-gain nonsense variants (c.49G>T, c.52C>T), c.166A>G missense variant, and 2 frameshift variants (c.144delC, c.145delA) leading to an identical, extended-length protein. Phenotypic features were highly variable. Nuclear localization was reduced/absent for all variants except c.166A>G. Homozygous knockin mice recapitulating the c.166A>G variant (Hmga2K56E) exhibited a growth-restricted phenotype. An Hmga2Ter76-knockin mouse model lacked detectable full-length Hmga2 protein, similarly to patient 3 and 5 variants. These mice were infertile, with a pygmy phenotype. We report a heterogeneous group of individuals with SRS harboring variants in HMGA2 and describe the first Hmga2 missense knockin mouse model (Hmga2K56E) to our knowledge causing a growth-restricted phenotype. In patients with clinical features of SRS but negative genetic screening, HMGA2 should be included in next-generation sequencing testing approaches.

• Publisher: American Society for Clinical Investigation,American Society for Clinical investigation
• Subject: Age / Amino acids / Animal models / Animals / Apoptosis / Base Sequence / Bats / Birth weight / Cell growth / Child development / Chromosomes / Endocrinology / Failure to thrive / Females / Genetic screening / Genetic testing / Genetics / Genomes / Genotype & phenotype / Growth Disorders - genetics / Growth rate / HMGA2 Protein - genetics / Humans / Localization / Mice / Next-generation sequencing / Patients / Phenotype / Phenotypes / Postpartum period / Proteins / Silver-Russell Syndrome - diagnosis / Silver-Russell Syndrome - genetics