Our findings suggest a potential association of these variants with growth hormone deficiency and short stature. In this study, novel pathogenic variants in RNPC3 were revealed as well as other variants in ACAN and in genes related to Vitamin-D metabolism (GC, VDR and LRP2) that some or all might be associated with growth hormone deficiency. Further large-scale studies are required to address the association of these variants with growth hormone deficiency and its subsequent short stature.

Genetic polymorphisms in genes involved in growth process and Vitamin-D metabolism form a significant etiology behind growth hormone deficiency and short stature. The aim of this study was to explore for known and unknown genes and variants related to growth hormone and short stature in a family based study using whole exome sequencing (WES). Method: This family-based study included a family with members diagnosed with growth hormone deficiency, short stature and Vitamin-D deficiency (four boys affected and four boys non-affected). The participants were recruited from King Abdulaziz University Hospital (Jeddah, Saudi Arabia) and referred to King Fahad Centre for Medical Research (Jeddah, Saudi Arabia from April 2022 to June 2022. The consanguineous parents and one of the affected boys (aged 16 years old) underwent WES.

Several variants in RNPC3, ACAN, GC, VDR and LRP2 were identified in index cases but not in controls. Novel frameshift and splice region variants in RNPC3 (c.358dupA, p.Arg120fs) were detected. Other missense variants were also observed including variants in ACAN (c.2591C>T, c.2789G>T, c.2815T>A, c.4207A>G, c.4523A>C and c.7119C>G), GC (rs4588 and rs7041) and LRP2 (rs2075252 and rs1991517). A start loss variant in VDR (rs2228570) with high impact was also observed. Conclusions: Our findings suggest a potential association of these variants with growth hormone deficiency and short stature. In this study, novel pathogenic variants in RNPC3 were revealed as well as other variants in ACAN and in genes related to Vitamin-D metabolism (GC, VDR and LRP2) that some or all might be associated with growth hormone deficiency. Further large-scale studies are required to address the association of these variants with growth hormone deficiency and its subsequent short stature.