A leading genetic cause of short stature in an Arab population

Abstract Human height is highly heritable and polygenic, yet much of its genetic architecture remains unexplained, especially in underrepresented populations. Here, we analyzed genomic data from 4,862 Middle Eastern patients, including 851 pediatric patients with short stature, and identified a single rare GHSR missense variant, p.Arg141Leu, enriched 19-fold in Arab Emirati short stature cases (N=771) vs healthy controls (N=5,151, P = 1.1 × 10⁻⁵⁶), explaining 10.2% of Emirati short stature referrals. GHSR encodes the ghrelin receptor, and its variants, mostly heterozygous, have previously been linked to short stature. Structural modelling, in vitro assays and Caenorhabditis elegans studies confirmed loss of function of GHSR p.Arg141Leu. Frequent homozygosity and large extended families enabled clinical and biochemical phenotyping of 99 patients across 71 families, revealing semidominant inheritance: homozygotes are more severely affected, and penetrance in heterozygotes is modulated by a polygenic score for height. Both homozygous and heterozygous patients responded to growth hormone therapy. The variant arose through a founder event in the northern United Arab Emirates about 1,700 years ago and is absent from other populations examined. Given its frequency and available treatment, our findings support targeted testing as standard of care in short stature in this population and reveal a hidden contributor to the missing heritability of height.