ESPE Abstracts

Background: Most children with short stature (SS) remain without a clear diagnosis despite extensive workup and are thus classified as idiopathic short stature (ISS). Whole exome sequencing (WES) in particular, has become a revolutionary approach in identifying monogenic causes of growth disorders. Therefore, this study aims to determine the diagnostic yield of WES in identifying the genetic etiology in children with ISS.

Methods: In this retrospective study, a total of 794 patients with the problem of SS were extracted from our hospital’s database and reviewed to recruit patients who fit the definition of ISS with a height of <-2.25 standard deviation score (SDS) for age, sex, and population with no identified etiology after extensive examinations. Ethical approval was taken for this study (reference: 2241172).

Results: A total of 173 of 794 (21%) patients were found to have ISS. A total of 120 of 173 (69%) patients with ISS underwent WES; with a median height SDS of -3.4 (IQR: -4.9, -2.9). A molecular diagnosis was made in 50 of 120 (41%) children who were molecularly investigated (25 autosomal recessive conditions, 20 autosomal dominant conditions; 4 of which are confirmed de novo. 4 are linked to X-linked conditions and 1 chromosomal aberration). Of the 50 patients, 47 (94%) were found to have genes that are associated with SS. However, 3/50 (6%) patients yielded positive findings with genes that are not SS linked. 12/120 (10%) children demonstrated VUS variants that were neither upgraded nor downgraded. A negative WES result was reported in 58/120 (48%) patients, calling for additional investigations.

Conclusion: Next generation sequencing, WES in particular, significantly enhances the molecular diagnosis with a diagnostic yield of approximately 41% in patients with ISS. However, there's still a gap between the phenotype and associated genotype that must be further studied through functional analysis.

Keywords: Idiopathic Short Stature, children, diagnostic yield, Saudi Arabia