HMGA2 Variants in Silver-Russell Syndrome: Homozygous and Heterozygous Occurrence
CT Hübner, R Meyer, A Kenawy… - The Journal of …, 2020 - academic.oup.com
The Journal of Clinical Endocrinology & Metabolism, 2020•academic.oup.com
Abstract Context Silver-Russell syndrome (SRS) is a clinical and molecular heterogeneous
disorder associated with short stature, typical facial gestalt, and body asymmetry. Though
molecular causes of SRS can be identified in a significant number of patients, about one-half
of patients currently remain without a molecular diagnosis. However, determination of the
molecular cause is required for a targeted treatment and genetic counselling. Objective The
aim of this study was to corroborate the role of HMGA2 as an SRS-causing gene and …
disorder associated with short stature, typical facial gestalt, and body asymmetry. Though
molecular causes of SRS can be identified in a significant number of patients, about one-half
of patients currently remain without a molecular diagnosis. However, determination of the
molecular cause is required for a targeted treatment and genetic counselling. Objective The
aim of this study was to corroborate the role of HMGA2 as an SRS-causing gene and …
Context
Silver-Russell syndrome (SRS) is a clinical and molecular heterogeneous disorder associated with short stature, typical facial gestalt, and body asymmetry. Though molecular causes of SRS can be identified in a significant number of patients, about one-half of patients currently remain without a molecular diagnosis. However, determination of the molecular cause is required for a targeted treatment and genetic counselling.
Objective
The aim of this study was to corroborate the role of HMGA2 as an SRS-causing gene and reevaluate its mode of inheritance.
Design, Setting, Patients
Patients were part of an ongoing study aiming on SRS-causing genes. They were classified according to the Netchine-Harbison clinical scoring system, and DNA samples were investigated by whole exome sequencing. Common molecular causes of SRS were excluded before.
Results
Three novel pathogenic HMGA2 variants were identified in 5 patients from 3 SRS families, and fulfilling diagnostic criteria of SRS. For the first time, homozygosity for a variant in HMGA2 could be identified in a severely affected sibpair, whereas parents carrying heterozygous variants had a mild phenotype. Treatment with recombinant growth hormone led to a catch-up growth in 1 patient, whereas all others did not receive growth hormone and stayed small. One patient developed type 2 diabetes at age 30 years.
Conclusions
Identification of novel pathogenic variants confirms HMGA2 as an SRS-causing gene; thus, HMGA2 testing should be implemented in molecular SRS diagnostic workup. Furthermore, inheritance of HMGA2 is variable depending on the severity of the variant and its consequence for protein function.
Oxford University Press