Context: The majority of patients presenting with short stature do not receive a definitive diagnosis. Advances in genetic sequencing allow for large-scale screening of candidate genes, potentially leading to genetic diagnoses.
Objectives: The purpose of this study was to discover genetic variants that contribute to short stature in a cohort of children with no known genetic etiology.
Design: This was a prospective cohort study of subjects with short stature.
Setting: The setting was a pediatric endocrinology and genetics clinics at an academic center.
Patients: A total of 192 children with short stature with no defined genetic etiology and 192 individuals of normal stature from the Framingham Heart Study were studied.
Intervention: Pooled targeted sequencing using next-generation DNA sequencing technology of the exons of 1077 candidate genes was performed.
Main outcome measures: The numbers of rare nonsynonymous genetic variants found in case patients but not in control subjects, known pathogenic variants in case patients, and potentially pathogenic variants in IGF1R were determined.
Results: We identified 4928 genetic variants in 1077 genes that were present in case patients but not in control subjects. Of those, 1349 variants were novel (898 nonsynonymous). False-positive rates from pooled sequencing were 4% to 5%, and the false-negative rate was 0.1% in regions covered well by sequencing. We identified 3 individuals with known pathogenic variants in PTPN11 causing undiagnosed Noonan syndrome. There were 9 rare potentially nonsynonymous variants in IGF1R, one of which is a novel, probably pathogenic, frameshift mutation. A previously reported pathogenic variant in IGF1R was present in a control subject.
Conclusions: Large-scale sequencing efforts have the potential to rapidly identify genetic etiologies of short stature, but data interpretation is complex. Noonan syndrome may be an underdiagnosed cause of short stature.