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

Morandi, Anita ; Fornari, Elena ; Corradi, Massimiliano ; Umano, Giuseppina Rosaria ; Olivieri, Francesca ; Piona, Claudia ; Maguolo, Alice LU orcid ; Panzeri, Carola ; Emiliani, Federica and Cirillo, Grazia , et al. (2024) In Pediatric obesity 19(12).
Abstract

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,... (More)

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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
childhood obesity, follow-up reassessment, leptin/melanocortin circuit, monogenic obesity, next-generation sequencing, variant interpretation, variant of uncertain significance
in
Pediatric obesity
volume
19
issue
12
article number
e13183
publisher
Wiley-Blackwell
external identifiers
  • scopus:85207810784
  • pmid:39462520
ISSN
2047-6302
DOI
10.1111/ijpo.13183
language
English
LU publication?
yes
id
45fb87c4-3594-40c7-927c-3f8be5c9c8d7
date added to LUP
2024-12-17 15:36:12
date last changed
2025-07-16 08:29:08
@article{45fb87c4-3594-40c7-927c-3f8be5c9c8d7,
  abstract     = {{<p>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.</p>}},
  author       = {{Morandi, Anita and Fornari, Elena and Corradi, Massimiliano and Umano, Giuseppina Rosaria and Olivieri, Francesca and Piona, Claudia and Maguolo, Alice and Panzeri, Carola and Emiliani, Federica and Cirillo, Grazia and Cavarzere, Paolo and Miraglia Del Giudice, Emanuele and Maffeis, Claudio}},
  issn         = {{2047-6302}},
  keywords     = {{childhood obesity; follow-up reassessment; leptin/melanocortin circuit; monogenic obesity; next-generation sequencing; variant interpretation; variant of uncertain significance}},
  language     = {{eng}},
  number       = {{12}},
  publisher    = {{Wiley-Blackwell}},
  series       = {{Pediatric obesity}},
  title        = {{Variant reclassification over time decreases the level of diagnostic uncertainty in monogenic obesity : Experience from two centres}},
  url          = {{http://dx.doi.org/10.1111/ijpo.13183}},
  doi          = {{10.1111/ijpo.13183}},
  volume       = {{19}},
  year         = {{2024}},
}