Unraveling the Genetic Heterogeneity of Isolated Growth Hormone Deficiency: Insights from the GENHYPOPIT cohort.

Abstract

Introduction: Isolated growth hormone deficiency (IGHD) involves multiple genes, yet characterization of its mutational landscape and genotype-phenotype correlations remains limited. The aim of this study is to analyze a large cohort of patients with genetic IGHD and describe associated genotypes and phenotypes.

Methods: Descriptive study of IGHD patients with an identified genetic cause referred for targeted NGS panel analysis through the GENHYPOPIT network between 2017 and 2024, and complementary targeted family analysis.

Results: Among 205 patients with IGHD, 23 (11.2%) had a pathogenic (P) or likely pathogenic (LP) variant. The average age at diagnosis was 3.9 years and 47% of patients had pituitary hypoplasia. Seventy percent of variants were in GH secretion genes, 39% in GH1, mostly with autosomal dominant transmission, 13% in GHRHR, and 18% in GHSR, with autosomal dominant or recessive inheritance and incomplete penetrance. Variants in genes involved in pituitary development were rarer (30% of variants). The most commonly affected pituitary development gene was GLI2 (13%). GLI2 variants were always associated with pituitary stalk interruption syndrome. The remaining variants were in POU1F1 (9%), HESX1 (4%) and SOX3 (4%). We report 10 new P or LP variants. Family analyses (n=30) broadened the genotype-phenotype correlation, identified de novo variants, as well as the first ever reported case of GH1 mosaicism.

Conclusion: Our study broadens the spectrum of genetic variations associated with IGHD. In most cases, the implicated gene is involved in GH secretion, but our results highlight that IGHD can also be caused by genes involved in pituitary development. These findings confirm the importance of genetic analysis in IGHD, to improve patient management and genetic counselling.