Background and Aim: Type 2 diabetes (T2D) is a heterogeneous group of metabolic disorders characterized by hyperglycemia diagnosed in adulthood (generally in the middle age). Some patients however have an earlier T2D onset (i.e. <35 years) and a stronger family history of diabetes. It is of note that strong family history of diabetes and disease onset at young age are also typical features of some forms of monogenic diabetes, including MODY, thus pointing the possibility of a misclassification between early-onset T2D and diabetes monogenic forms. This is a pity because molecular diagnosis of monogenic diabetes can alter both follow-up and therapeutic approaches, representing in some cases a perfect example of precision medicine. Our aim was to investigate the proportion of individuals with monogenic diabetes forms among early-onset T2D patients. Methodology: 300 T2D patients with age at onset <35 years, selected among 9601 Italian patients with a clinical diagnosis of T2D, were investigated by a custom targeted NGS panel (Illumina) including 27 monogenic diabetes-genes. Possibly deleterious variants were retrieved after filtering by means of an established bioinformatic pipeline and likelihood of causality according to the ACMG criteria. Results: Among the investigated patients, 20 carried 21 possible deleterious variants in 13 genes, 15 of which were classified as Pathogenic/Likely Pathogenic and 6 as VUS. Nine variants were found in the 4 most common MODY genes, 10 in the rarer ones and 2 in genes in which recessive mutations are responsible for syndromic diabetes. Notably, only one of the 15 patients carrying Pathogenic/Likely Pathogenic variants fulfilled all the generally accepted MODY diagnostic criteria. Conclusions: Among patients clinically defined as having “early-onset” T2D, 5% were rather affected by monogenic diabetes. These results i) highlight the importance of genetic testing for monogenic diabetes among T2D patients with an early disease manifestation ii) support the notion that the prevalence of monogenic diabetes is underestimated because of misdiagnosis with early-onset T2D but also for the too stringent diagnostic criteria so far used to clinically frame some of forms of monogenic diabetes, including MODY.
Clinical utility for monogenic diabetes molecular testing among patients with early-onset type 2 diabetes / Pezzilli, S; Tohidirad, M; Biagini, T; Mercuri, L; Alberico, F; Garofolo, M; Mannino, Gc; Lamacchia, O; Filardi, T; Andreozzi, F; Baroni, Mg; Buzzetti, R; Cavallo, Mg; Cossu, E; D'Angelo, P; De Cosmo, S; Leonetti, F; Morano, S; Morviducci, L; Pozzilli, P; Pugliese, G; Sesti, G; Penno, G; Mazza, T; Trischitta, V; Prudente, S.. - (2020). (Intervento presentato al convegno SIGU 2020 tenutosi a Virtual Edition).
Clinical utility for monogenic diabetes molecular testing among patients with early-onset type 2 diabetes
Pezzilli S;Tohidirad M;Biagini T;Filardi T;Baroni MG;Buzzetti R;Cavallo MG;Morano S;Morviducci L;Pozzilli P;Sesti G;Mazza T;Trischitta V;Prudente S.
2020
Abstract
Background and Aim: Type 2 diabetes (T2D) is a heterogeneous group of metabolic disorders characterized by hyperglycemia diagnosed in adulthood (generally in the middle age). Some patients however have an earlier T2D onset (i.e. <35 years) and a stronger family history of diabetes. It is of note that strong family history of diabetes and disease onset at young age are also typical features of some forms of monogenic diabetes, including MODY, thus pointing the possibility of a misclassification between early-onset T2D and diabetes monogenic forms. This is a pity because molecular diagnosis of monogenic diabetes can alter both follow-up and therapeutic approaches, representing in some cases a perfect example of precision medicine. Our aim was to investigate the proportion of individuals with monogenic diabetes forms among early-onset T2D patients. Methodology: 300 T2D patients with age at onset <35 years, selected among 9601 Italian patients with a clinical diagnosis of T2D, were investigated by a custom targeted NGS panel (Illumina) including 27 monogenic diabetes-genes. Possibly deleterious variants were retrieved after filtering by means of an established bioinformatic pipeline and likelihood of causality according to the ACMG criteria. Results: Among the investigated patients, 20 carried 21 possible deleterious variants in 13 genes, 15 of which were classified as Pathogenic/Likely Pathogenic and 6 as VUS. Nine variants were found in the 4 most common MODY genes, 10 in the rarer ones and 2 in genes in which recessive mutations are responsible for syndromic diabetes. Notably, only one of the 15 patients carrying Pathogenic/Likely Pathogenic variants fulfilled all the generally accepted MODY diagnostic criteria. Conclusions: Among patients clinically defined as having “early-onset” T2D, 5% were rather affected by monogenic diabetes. These results i) highlight the importance of genetic testing for monogenic diabetes among T2D patients with an early disease manifestation ii) support the notion that the prevalence of monogenic diabetes is underestimated because of misdiagnosis with early-onset T2D but also for the too stringent diagnostic criteria so far used to clinically frame some of forms of monogenic diabetes, including MODY.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
