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Variant reclassification over time decreases the level of diagnostic uncertainty in monogenic obesity: Experience from two centres.

Authors :
Morandi, Anita
Fornari, Elena
Corradi, Massimiliano
Umano, Giuseppina Rosaria
Olivieri, Francesca
Piona, Claudia
Maguolo, Alice
Panzeri, Carola
Emiliani, Federica
Cirillo, Grazia
Cavarzere, Paolo
Miraglia Del Giudice, Emanuele
Maffeis, Claudio
Source :
Pediatric Obesity; Dec2024, Vol. 19 Issue 12, p1-9, 9p
Publication Year :
2024

Abstract

Summary: Background: The diagnosis of monogenic obesity is burdened by frequent variants of uncertain significance (VUS). We describe our real‐life approach of variant reassessment over time and we assess whether inconclusive variants are decreasing in monogenic obesity. Methods: We tested for monogenic obesity (genes: LEPR, POMC, ADCY3, PCSK1, CARTPT, SIM1, MRAP2, LEP, NTRK2, BDNF, KSR2, MAGEL2, SH2B1, MC4R, MC3R) in 101 children/adolescents (11.7 [7.3–13.7] years, 3.6 [3.3–4.0] z‐BMI) in Verona and 183 (11.3 [8.4–12.2] years, 3.2 [2.7–3.9] z‐BMI) in Naples from January 2020 to February 2023. In March–July 2024 we reassessed the baseline variants by updated software interpretation and literature renavigation. Results: We initially found 20 VUS, 4 Likely Pathogenic (LP), 5 Likely Benign (LB) and 1 benign variant in 33 individuals. At follow‐up, 6 VUS were reclassified as benign/LB, one LP as pathogenic and 3 LB as benign. Overall, 10/30 variants (6/18 in Verona, 3/11 in Naples and a variant found in both centres) were reclassified, leading to a less uncertain report for 13 of 33 variant‐carrying patients. Monogenic obesity was diagnosed in 3 probands in Verona and 4 in Naples, carrying variants at MC4R or NTRK2. Conclusion: Our variant reassessment was effective to improve classification certainty for the 39% of patients and suggested that the molecular diagnosis of monogenic obesity is becoming more accurate over time. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
20476302
Volume :
19
Issue :
12
Database :
Complementary Index
Journal :
Pediatric Obesity
Publication Type :
Academic Journal
Accession number :
180737615
Full Text :
https://doi.org/10.1111/ijpo.13183