ESPE Abstracts

Growth failure is the gateway to a myriad of childhood and adolescent diseases. In the majority of cases, growth retardation is said to be constitutional after a detailed diagnostic evaluation. In the literature, there is a high degree of heritability of height (> 80%), underlining the predominant role of genetic factors.

Objective: To identify new causes of growth retardation in 61 patients with constitutional familial short stature by genetic exploration of a panel of 106 genes involved in growth using next-generation sequencing.

Methods: The supervised analysis of the genetic data, with classification of variants of interest according to ACMG2015, was complemented by an unsupervised analysis of the entire cohort's genetic data, which are compared with the GnomAD data (the "gene burden" approach).

Results: A diagnosis of short stature was established in 6 families (20.7%) (3 ACAN mutations, 2 NPR2 mutations and one COL1A1 mutation affecting 10.3%, 6.9% and 3.4% of families respectively). Variants of uncertain significance (class 3) were identified in 10 families (34.5%). The only factor appearing to be associated with increased performance in our cohort was the presence of radiographic abnormalities. The gene burden approach highlighted 14 genes with a significantly increased frequency of variants in our patient population compared to the GnomAD data.

Perspectives: These preliminary data provide a solid basis for future research, aimed at deepening our understanding of the genetic mechanisms influencing growth.