ESPE Abstracts

Context: Data and studies based on exome sequencing for the genetic evaluation of short stature are limited, and more large-scale studies are warranted. Some factors increase the likelihood of a monogenic cause of short stature, including severe short stature (<–3 standard deviation scores) and small for gestational age (SGA) without catch-up growth. However, whether these factors can serve as predictors of molecular diagnosis remains unknown.

Objectives: We aimed to define the diagnostic efficiency of associated risk factors and their exome sequences for screening.

Design, Settings, and Patients: We defined and applied factors that increased the likelihood of monogenic causes of short stature in diagnostic genetic tests based on next-generation sequencing (NGS) in 814 patients with short stature and at least one other factor.

Results: The overall diagnostic yield was 44.72%, and 34.64% and 8.85% of the patients harbored pathogenic (P)/likely pathogenic (LP) variants in genes or P/LP copy number variations (CNVs). We found P/LP variants among 114 genes, and RASopathies comprised the most important etiology. The diagnostic yield of NGS for short stature combined with intellectual disability or developmental delay was 70.71%, and 70.97% when patients had facial dysmorphisms. CNVs should be considered for screening SGA with intellectual disability or developmental delay.

Conclusions: NGS combined with risk factor screening significantly improved the diagnostic yield for short stature. Our findings provide novel insights into the current understanding of the etiology of short stature in patients with different phenotypes and indicate the importance of NGS.