Genes (Nov 2022)
Genome-Wide DNA Methylation Profiling Solves Uncertainty in Classifying <i>NSD1</i> Variants
- Marco Ferilli,
- Andrea Ciolfi,
- Lucia Pedace,
- Marcello Niceta,
- Francesca Clementina Radio,
- Simone Pizzi,
- Evelina Miele,
- Camilla Cappelletti,
- Cecilia Mancini,
- Tiziana Galluccio,
- Marco Andreani,
- Maria Iascone,
- Luigi Chiriatti,
- Antonio Novelli,
- Alessia Micalizzi,
- Marta Matraxia,
- Lucia Menale,
- Flavio Faletra,
- Paolo Prontera,
- Alba Pilotta,
- Maria Francesca Bedeschi,
- Rossella Capolino,
- Anwar Baban,
- Marco Seri,
- Corrado Mammì,
- Giuseppe Zampino,
- Maria Cristina Digilio,
- Bruno Dallapiccola,
- Manuela Priolo,
- Marco Tartaglia
Affiliations
- Marco Ferilli
- Area di Ricerca Genetica e Malattie Rare, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146 Rome, Italy
- Andrea Ciolfi
- Area di Ricerca Genetica e Malattie Rare, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146 Rome, Italy
- Lucia Pedace
- Department of Pediatric Onco-Haematology and Cell and Gene Therapy, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146 Rome, Italy
- Marcello Niceta
- Area di Ricerca Genetica e Malattie Rare, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146 Rome, Italy
- Francesca Clementina Radio
- Area di Ricerca Genetica e Malattie Rare, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146 Rome, Italy
- Simone Pizzi
- Area di Ricerca Genetica e Malattie Rare, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146 Rome, Italy
- Evelina Miele
- Department of Pediatric Onco-Haematology and Cell and Gene Therapy, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146 Rome, Italy
- Camilla Cappelletti
- Area di Ricerca Genetica e Malattie Rare, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146 Rome, Italy
- Cecilia Mancini
- Area di Ricerca Genetica e Malattie Rare, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146 Rome, Italy
- Tiziana Galluccio
- Department of Pediatric Onco-Haematology and Cell and Gene Therapy, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146 Rome, Italy
- Marco Andreani
- Department of Pediatric Onco-Haematology and Cell and Gene Therapy, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146 Rome, Italy
- Maria Iascone
- Medical Genetics Laboratory, ASST Papa Giovanni XXIII, 24127 Bergamo, Italy
- Luigi Chiriatti
- Unità di Genetica Medica, Grande Ospedale Metropolitano “Bianchi-Melacrino-Morelli”, 89124 Reggio Calabria, Italy
- Antonio Novelli
- Translational Cytogenomics Research Unit, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146 Rome, Italy
- Alessia Micalizzi
- Translational Cytogenomics Research Unit, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146 Rome, Italy
- Marta Matraxia
- Translational Cytogenomics Research Unit, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146 Rome, Italy
- Lucia Menale
- Translational Cytogenomics Research Unit, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146 Rome, Italy
- Flavio Faletra
- Medical Genetics Unit, IRCCS Burlo Garofolo, 34137 Trieste, Italy
- Paolo Prontera
- Maternal-Infantile Department, University Hospital of Perugia, 06156 Perugia, Italy
- Alba Pilotta
- Auxo-Endocrinology, Diabetology and Medical Genetic Unit, Department of Paediatrics, ASST Spedali Civili, 25123 Brescia, Italy
- Maria Francesca Bedeschi
- Medical Genetic Unit, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico Clinica Mangiagalli, 20122 Milan, Italy
- Rossella Capolino
- Area di Ricerca Genetica e Malattie Rare, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146 Rome, Italy
- Anwar Baban
- Medical and Surgical Department of Pediatric Cardiology, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146 Rome, Italy
- Marco Seri
- U.O. Genetica Medica, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
- Corrado Mammì
- Unità di Genetica Medica, Grande Ospedale Metropolitano “Bianchi-Melacrino-Morelli”, 89124 Reggio Calabria, Italy
- Giuseppe Zampino
- Dipartimento Scienze della Vita, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
- Maria Cristina Digilio
- Area di Ricerca Genetica e Malattie Rare, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146 Rome, Italy
- Bruno Dallapiccola
- Area di Ricerca Genetica e Malattie Rare, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146 Rome, Italy
- Manuela Priolo
- Unità di Genetica Medica, Grande Ospedale Metropolitano “Bianchi-Melacrino-Morelli”, 89124 Reggio Calabria, Italy
- Marco Tartaglia
- Area di Ricerca Genetica e Malattie Rare, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146 Rome, Italy
- DOI
- https://doi.org/10.3390/genes13112163
- Journal volume & issue
-
Vol. 13,
no. 11
p. 2163
Abstract
Background: Inactivating NSD1 mutations causing Sotos syndrome have been previously associated with a specific genome-wide DNA methylation (DNAm) pattern. Sotos syndrome is characterized by phenotypic overlap with other overgrowth syndromes, and a definite diagnosis might not be easily reached due to the high prevalence of variants of unknown significance (VoUS) that are identified in patients with a suggestive phenotype. Objective: we performed microarray DNAm profiling in a set of 11 individuals with a clinical suspicion of Sotos syndrome and carrying an NSD1 VoUS or previously unreported variants to solve uncertainty in defining pathogenicity of the observed variants. The impact of the training cohort size on sensitivity and prediction confidence of the classifier was assessed. Results: The Sotos syndrome-specific DNAm signature was validated in six individuals with a clinical diagnosis of Sotos syndrome and carrying bona fide pathogenic NSD1 variants. Applying this approach to the remaining 11 individuals with NSD1 variants, we succeeded in confirming pathogenicity in eight subjects and excluding the diagnosis of Sotos syndrome in three. The sensitivity and prediction confidence of the classifier based on the different sizes of the training sets did not show substantial differences, though the overall performance was improved by using a data balancing strategy. Conclusions: The present approach solved uncertainty in cases with NDS1 VoUS, further demonstrating the clinical utility of DNAm profiling.
Keywords
- DNA methylation
- overgrowth
- <i>NSD1</i>
- Sotos syndrome
- genomic variant classification
- VoUS validation