High prevalence of variants in skeletal dysplasia associated genes in individuals with short stature and minor skeletal anomalies.

Objective Next generation sequencing (NGS) has expanded the diagnostic paradigm turning the focus to the growth plate. The aim of the study was to determine the prevalence of variants in genes implicated in skeletal dysplasias in probands with short stature and mild skeletal anomalies. Design Clinical and radiological data were collected from 108 probands with short stature and mild skeletal anomalies. Methods A customized skeletal dysplasia NGS panel was performed. Variants were classified using ACMG recommendations and Sherloc. Anthropometric measurements and skeletal anomalies were subsequently compared in those with or without an identified genetic defect. Results Heterozygous variants were identified in 21/108 probands (19.4%). Variants were most frequently identified in ACAN (n=10) and IHH (n=7) whilst one variant was detected in COL2A1, CREBBP, EXT1 and PTPN11. Statistically significant differences (p 1 in those with an identified variant compared to those without. Conclusions A molecular defect was elucidated in a fifth of patients. Thus, the prevalence of mild forms of skeletal dysplasias is relatively high in individuals with short stature and mild skeletal anomalies, with variants in ACAN and IHH accounting for 81% of the cases. An elevated SH/H ratio appears to be associated with a greater probability in detecting a variant, but no other clinical or radiological feature has been found determinant to finding a genetic cause. Currently, we cannot perform extensive molecular studies in all short stature individuals so detailed clinical and radiological phenotyping may orientate which are the candidate patients to obtain worthwhile results. In addition, detailed phenotyping of probands and family members will often aid variant classification.