NEW ORLEANS — Using bioinformatics and genomic testing, researchers at three children’s hospitals were able to identify genetic variants — including novel IGF1R mutations — underlying undiagnosed short stature in nearly one-third of their pediatric study participants, according to results of a proof-of-principle study presented at the Endocrine Society Annual Meeting.
“There are patients who endocrinologists are seeing in clinic with rare genetic causes of short stature who are very difficult to recognize on clinical grounds alone,” researcher Andrew Dauber, MD, a pediatric endocrinologist at Children's National Medical Center in Washington, D.C., told Endocrine Today. “However, using specific search parameters in the electronic health records, we are able to identify patients with a high likelihood of rare genetic growth disorders.”
Dauber and colleagues at Boston Children’s Hospital, Children’s Hospital of Philadelphia and Cincinnati Children’s Hospital Medical Center searched their institutions’ EHRs for pediatric patients, without known genetic conditions, chronic illness or precocious puberty, who had height below –2 standard deviation for their age and sex and an insulin-like growth factor I level greater than the 90th percentile. The researchers ultimately performed whole-exome sequencing using blood or saliva samples from 10 of these patients and their immediate family members.
The researchers identified a novel missense variant in the IGF1R gene (p.Val1013Phe) of one patient and a single amino acid deletion in the gene (p.Thr28del) inherited from the mother in another. Testing is underway to confirm the relation of these gene variants to the short stature. The genetic cause was confirmed in a third patient who was discovered to have a novel missense variant in CHD2 (p.Val540Phe).
“By collaborating across institutions, we can use genomics to understand the underlying genetic pathways involved in specific clinical subgroups of patients with short stature,” Dauber said. “The relatively high yield of genetic testing in patients with high IGFI levels will be surprising to attendees.” – by Jill Rollet
Salcedo CC, et al. OR07-6. Integrating targeted bioinformatic searches of the electronic health records and genomic testing identifies a molecular diagnosis in three patients with undiagnosed short stature. Presented at: The Endocrine Society Annual Meeting; March 23-26, 2019; New Orleans.
Disclosures: The authors report no relevant financial disclosures.