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 skeletal dysplasia, severe short stature, and small for gestational age (SGA) without catch-up growth. However, whether these factors can serve as predictors of molecular diagnosis remains unknown.
Objective: We aimed to explore the diagnostic efficiency of the associated risk factors and their exome sequences for screening.
Methods: 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 1 other factor.
Results: Pathogenic/likely pathogenic (P/LP) variants in genes, copy number variations, and chromosomal abnormalities were identified in 361 patients. We found P/LP variants among 111 genes, and RASopathies comprised the most important etiology. Short stature combined with other phenotypes significantly increased the likelihood of a monogenic cause, including skeletal dysplasia, facial dysmorphism, and intellectual disability, compared with simple severe short stature (<-3 SD scores). We report novel candidate pathogenic genes, KMT2C for unequivocal growth hormone insensitivity and GATA6 for SGA.
Conclusion: Our study identified the diagnostic characteristics of NGS in short stature with different risk factors. Our study provides novel insights into the current understanding of the etiology of short stature in patients with different phenotypes.
Keywords: next generation sequencing; short stature; whole exome sequencing.
© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.