%0 Journal Article
%T Characterization of HMGA2 variants expands the spectrum of Silver-Russell syndrome.
%A Maharaj AV
%A Cottrell E
%A Thanasupawat T
%A Joustra SD
%A Triggs-Raine B
%A Fujimoto M
%A Kant SG
%A van der Kaay D
%A Clement-de Boers A
%A Brooks AS
%A Aguirre GA
%A Martín Del Estal I
%A Castilla de Cortázar Larrea MI
%A Massoud A
%A van Duyvenvoorde HA
%A De Bruin C
%A Hwa V
%A Klonisch T
%A Hombach-Klonisch S
%A Storr HL
%J JCI Insight
%V 9
%N 6
%D 2024 Feb 20
%M 38516887
%F 9.484
%R 10.1172/jci.insight.169425
%X 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.