Genetics of Growth Hormone Deficiency: Insights from a Cohort of 203 Patients.

Context: Growth Hormone (GH) deficiency is a rare disorder characterized by severe short stature, which can result from genetic mutations affecting hypothalamic-pituitary development and function.

Objective: To determine the genetic basis of GH deficiency in a Portuguese cohort.

Design, setting, patients: Multicentre cohort of 203 GH-deficient patients (78 with Isolated GH Deficiency (IGHD) and 125 with Combined Pituitary Hormone Deficiency (CPHD)) were analysed.

Intervention: Screening of a panel of 184 GH deficiency-related genes using Sanger sequencing and Whole Exome Sequencing (WES).

Main outcome measure: Rare sequence variants (population maximum allele frequency <0.01).

Results: A genetic cause was identified in 23.2% of patients (9.0% in IGHD and 32.0% in CPHD). Mutations were found in the PROP1 (14.8% of patients), GLI2 (2.0%), KMT2D (1.0%), PROK2 (1.0%), PROKR2 (1.0%), CDON (0.5%), COL1A2 (0.5%), COL2A1 (0.5%), GHRHR (0.5%), PTPN11 (0.5%), and SOX3 (0.5%) genes. One patient (0.5%) had a digenic mutation in the BMP4 and NF1 genes. Variants of Uncertain Significance (VUS) were identified in 87.8% of patients.

Conclusions: This study revealed several novel and recurrent mutations that expand the genetic spectrum of GH deficiency and underscore the genetic heterogeneity of this disorder. A significant proportion of patients remained genetically undiagnosed, suggesting the involvement of additional unknown genetic, epigenetic, or environmental factors. These findings contribute to the understanding of the genetic architecture of GH deficiency and highlight the need for further investigations to elucidate underlying mechanisms and identify additional causative factors.