(75) Genetic Diagnostic Yield of Exome Sequencing for Short Stature at a Pediatric Tertiary Care Center

Background: Short stature refers to a height 2 standard deviations below the mean for age, sex, and population. Genetic testing has been increasingly used to identify the underlying cause of short stature. The 2021 American College of Medical Genetics and Genomics (ACMG) practice resource advised exome sequencing to be considered for patients with short stature and features suggestive of a monogenic cause, such as facial dysmorphism, skeletal abnormalities, and intellectual disability. However, studies on exome diagnostic yields for short stature have been limited.

Objectives: To assess the diagnostic yield of exome sequencing in patients with short stature analyzed at Cincinnati Children's and investigate the association between Human Phenotype Ontology (HPO) terms and diagnostic outcomes to inform clinical utility and testing guidelines.

Design/Methods: In this study, we summarized the diagnostic results of 107 exome sequencing cases evaluated from September 2018 to August 2023, with short stature as one of the HPO terms during exome analysis. We also compared the distribution of the HPO terms between the diagnostic and nondiagnostic groups.

Results: The overall diagnostic yield was 29.0% (31/107). Genetic findings included heterozygous pathogenic or likely pathogenic (P/LP) variants in genes associated with autosomal dominant conditions, including but not limited to ANKRD11, BPTF, IGFR1, NSD2, and TAOK1, in 23 cases. Compound heterozygous or homozygous P/LP variants in genes related to autosomal recessive conditions (e.g., CKAP2L and SLC12A3) were found in another 6 cases. In 2 cases, variants in X-linked genes, namely CDKL5 and MECP2, were identified. HPO term analysis revealed that developmental delay and failure to thrive were the most common among all 107 cases. Dysmorphic facial features, including downslanted palpebral fissures and low-set ears, were more prevalent in the diagnostic group, as was macrocephaly. In contrast, microcephaly was more present in the nondiagnostic group. However, none of these differences were statistically significant.

Conclusions: The diagnostic yield of this study aligns with previously reported ranges (16.5-46.0%). However, the identified disease genes showed little overlap with those reported earlier, highlighting the rarity and heterogeneity of short stature-related syndromes, thus reaffirming the utility of exome sequencing. Larger cohort analyses are required to further investigate if the enrichment of HPO terms in the diagnostic group is significant.