Exome sequencing may aid short stature investigation where genetic syndrome is suspected

medwireNews: Exome sequencing (ES) and chromosomal microarray analysis (CMA) are useful tools for the identification of genetic causes underlying short stature, indicate the results of a systematic review and meta-analysis.

“The findings serve as a solid reference for clinicians when making informed decisions about recommending these genetic tests”, say Nan Wu (Peking Union Medical College Hospital, Beijing, China) and co-investigators.

As reported in JAMA Pediatrics, the team identified six ES studies, 10 CMA studies and four reports on the use of both techniques that were published between 2014 and 2022.

Finding significant heterogeneity between the 10 ES studies, the team used a random-effects model to adjust for the steps involved in ES testing and this gave a diagnostic yield of 27.1%. That is, 362 of 1350 assessed patients were diagnosed with a pathological or likely pathological mutation in one of 250 genes, most commonly FGFR3, PTPN11, NF1, ANKRD11, COL2A1, IDS and ACAN.

Further analysis showed that patients who were assessed with ES as a first-tier investigation were more likely to have a positive diagnosis than those who were assessed with it as a last resort (27.8 vs 25.6%), but the difference was not statistically significant. The team also identified a trend towards an increase in first-tier diagnostic yield by ES over time albeit this too was not statistically significant.

CMA diagnostic yield across 14 studies also showed high heterogeneity and the random-effects model gave a diagnostic yield of 13.6%, with 402 of the 1070 individuals tested having a positive diagnosis.

Wu et al explain that as CMA is used for identifying copy number variants and is complementary to ES, subgroup analysis was not performed to compare first-tier and last-resort testing yields. The authors note there was a small but nonsignificant decrease in diagnostic yield over time but suggest that “further optimization of CMA techniques and data interpretation may enhance its diagnostic yield in the future.”

Discussing the findings, the authors say that gene sequencing may be the most cost-effective diagnostic approach for short stature among patients with “distinct phenotypes”, whereas ES may be superior for those with “overlapping phenotypes or attenuated presentations”.

They continue: “The choice between gene panel and ES depends on various factors, including diagnostic yield, examination cost, turnaround time, gene panel design, patients’ phenotype, potential need for discovering novel genes, and insurance policies.”

Wu and co-workers conclude that “[i]ntegrating these genetic tests into a comprehensive diagnostic framework, along with advancements in sequencing technologies and data interpretation, can lead to timely and precise treatment, ultimately improving the quality of life for affected individuals.”

Monica Wojcik and Anne Chen Wu, both from Harvard Medical School in Boston, Massachusetts, USA, observe in a separate editorial that the diagnostic yield with ES in the study was around 10–20% when testing children with isolated short stature versus almost 50% when patients also had neurodevelopmental or other types of anomalies.

“Thus, the results of this study are more supportive of the use of ES as a first-line diagnostic tool for any suspicion of mendelian disease, rather than short stature itself”, they remark.

“Although the authors suggest that targeted testing should instead be undertaken if a specific genetic syndrome is suspected, their results clearly indicate the difficulty in isolating a specific feature or syndrome and associating it with a diagnostic yield.”

Wojcik and Wu conclude: “[T]hese data provide further support of genome-wide testing as a first-tier test for anyone suspected to have a rare genetic condition.”

By Lynda Williams

medwireNews is an independent medical news service provided by Springer Healthcare Ltd. © 2023 Springer Healthcare Ltd, part of the Springer Nature Group

JAMA Pediatr 2023; doi:10.1001/jamapediatrics.2023.3566
JAMA Pediatr 2023; doi:10.1001/jamapediatrics.2023.3566
Martin Savage
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