Phenotype-genotype correlations of GH1 gene variants in patients with isolated growth hormone deficiency (IGHD) or multiple pituitary hormone deficiency (MPHD)

Background and objective: Genetic forms of growth hormone deficiency (GHD) may occur as isolated (IGHD) or as a component of multiple pituitary hormone deficiency (MPHD). This study aimed to present patients' clinical and molecular characteristics with IGHD/MPHD due to the GH1 gene variants.Material and Methods: A gene panel accommodating 25 genes associated with MPHD and short stature was used to search for small sequence variants. Multiplex Ligation-dependent Probe Amplification (MLPA) was performed in patients with normal panel results to investigate gross deletion/duplications. Segregation in the family was performed by Sanger sequencing. Results: The GH1 gene variants were detected in five patients from four unrelated families. One patient had IGHD IA due to homozygous whole GH1 gene deletion and one had IGHD IB due to novel homozygous c.162C>G/p.(Tyr54*) variant. Two patients from a family had previously reported heterozygous c.291+1G>A/p.(?) variant in which clinical and genetic characteristics were compatible with IGHD II accompanying MPHD. One patient had clinical and laboratory characteristics of IGHD II with MPHD but the heterozygous c.468 C>T/p.(R160W) variant had conflicting results about the relationship with the phenotype.Conclusion: Expanding our knowledge of the spectrum of GH1 gene variants by apprehending clinical and molecular data of more cases, helps to identify the genotype-phenotype correlation of IGHD/MPHD and the GH1 gene variants. These patients must be regularly followed up for the occurrence of additional pituitary hormone deficiencies.