Monogenic diabetes clinic (MDC): 3-year experience

Rapini, Novella; Patera, Patrizia Ippolita; Schiaffini, Riccardo; Ciampalini, Paolo; Pampanini, Valentina; Cristina, Matteoli M; Deodati, Annalisa; Bracaglia, Giorgia; Porzio, Ottavia; Ruta, Rosario; Novelli, Antonio; Mucciolo, Mafalda; Cianfarani, Stefano; Barbetti, Fabrizio

doi:10.1007/s00592-022-01972-2

Cited by 2 publications

(1 citation statement)

References 27 publications

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“…The overall spectrum of monogenic diabetes genes found in our study population was different from what is found in non-consanguineous populations [ 10 , 25 ]. We observed homozygous, causal variants in genes such as PTF1A , GLIS3 , INSR and SLC29A3 , which are uncommon in non-consanguineous populations.…”

Section: Discussioncontrasting

confidence: 97%

Paediatric diabetes subtypes in a consanguineous population: a single-centre cohort study from Kurdistan, Iraq

Amaratunga,

Hussein Tayeb,

Muhamad Sediq

et al. 2023

Diabetologia

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Aims/hypothesis Monogenic diabetes is estimated to account for 1–6% of paediatric diabetes cases in primarily non-consanguineous populations, while the incidence and genetic spectrum in consanguineous regions are insufficiently defined. In this single-centre study we aimed to evaluate diabetes subtypes, obtain the consanguinity rate and study the genetic background of individuals with syndromic and neonatal diabetes in a population with a high rate of consanguinity. Methods Data collection was carried out cross-sectionally in November 2021 at the paediatric diabetic clinic, Dr Jamal Ahmad Rashed Hospital, in Sulaimani, Kurdistan, Iraq. At the time of data collection, 754 individuals with diabetes (381 boys) aged up to 16 years were registered. Relevant participant data was obtained from patient files. Consanguinity status was known in 735 (97.5%) participants. Furthermore, 12 families of children with neonatal diabetes and seven families of children with syndromic diabetes consented to genetic testing by next-generation sequencing. Prioritised variants were evaluated using the American College of Medical Genetics and Genomics guidelines and confirmed by Sanger sequencing. Results A total of 269 of 735 participants (36.5%) with known consanguinity status were offspring of consanguineous families. An overwhelming majority of participants (714/754, 94.7%) had clinically defined type 1 diabetes (35% of them were born to consanguineous parents), whereas only eight (1.1%) had type 2 diabetes (38% consanguineous). Fourteen (1.9%) had neonatal diabetes (50% consanguineous), seven (0.9%) had syndromic diabetes (100% consanguineous) and 11 (1.5%) had clinically defined MODY (18% consanguineous). We found that consanguinity was significantly associated with syndromic diabetes (p=0.0023) but not with any other diabetes subtype. The genetic cause was elucidated in ten of 12 participants with neonatal diabetes who consented to genetic testing (homozygous variants in GLIS3 [sibling pair], PTF1A and ZNF808 and heterozygous variants in ABCC8 and INS) and four of seven participants with syndromic diabetes (homozygous variants in INSR, SLC29A3 and WFS1 [sibling pair]). In addition, a participant referred as syndromic diabetes was diagnosed with mucolipidosis gamma and probably has type 2 diabetes. Conclusions/interpretation This unique single-centre study confirms that, even in a highly consanguineous population, clinically defined type 1 diabetes is the prevailing paediatric diabetes subtype. Furthermore, a pathogenic cause of monogenic diabetes was identified in 83% of tested participants with neonatal diabetes and 57% of participants with syndromic diabetes, with most variants being homozygous. Causative genes in our consanguineous participants were markedly different from genes reported from non-consanguineous populations and also from those reported in other consanguineous populations. To correctly diagnose syndromic diabetes in consanguineous populations, it may be necessary to re-evaluate diagnostic criteria and include additional phenotypic features such as short stature and hepatosplenomegaly. Graphical Abstract

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Section: Discussioncontrasting

confidence: 97%

Paediatric diabetes subtypes in a consanguineous population: a single-centre cohort study from Kurdistan, Iraq

Amaratunga,

Hussein Tayeb,

Muhamad Sediq

et al. 2023

Diabetologia

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The Changing Landscape of Neonatal Diabetes Mellitus in Italy Between 2003 and 2022

Rapini,

Delvecchio,

Mucciolo

et al. 2024

The Journal of Clinical Endocrinology &Amp; Metabolism

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Context In the last decade Sanger method of DNA sequencing has been replaced by next generation sequencing (NGS). NGS is valuable in conditions characterized by high genetic heterogeneity such as neonatal diabetes mellitus (NDM). Objective To compare results of genetic analysis of patients with NDM and congenital severe insulin resistance (c.SIR) identified in Italy in 2003-2012 (Sanger) versus 2013-2022 (NGS). Methods We reviewed clinical and genetic records of 104 cases with diabetes onset before 6 months of age (NDM+c.SIR) of the Italian dataset. Results Fiftyfive patients (50 NDM + 5 c.SIR) were identified during 2003-2012 and 49 (46 NDM + 3 c.SIR) in 2013-2022. Twenty-year incidence was 1:103,340 (NDM) and 1:1,240,082 (c.SIR) live births. Frequent NDM/c.SIR genetic defects (KCNJ11, INS, ABCC8, 6q24, INSR) were detected in 41 and 34 probands during 2003-2012 and 2013-2022, respectively. We identified a pathogenic variant in rare genes in a single proband (GATA4) (1/42 or 2.4%) during 2003-2012 and in 8 infants (RFX6, PDX1, GATA6, HNF1B, FOXP3, IL2RA, LRBA, BSCL2) during 2013-2022 (8/42 or 19%, p= 0.034 vs 2003-2012). Notably, five among rare genes were recessive. Swift and accurate genetic diagnosis led to appropriate treatment: patients with autoimmune NDM (FOXP3, IL2RA, LRBA), were subjected to bone marrow transplant; patients with pancreas agenesis/hypoplasia (RFX6, PDX1) were supplemented with pancreatic enzymes and the individual with lipodystrophy caused by BSCL2 was started on metreleptin. Conclusions NGS substantially improved diagnosis and precision therapy of monogenic forms of neonatal diabetes and congenital SIR in Italy.

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Monogenic diabetes clinic (MDC): 3-year experience

Cited by 2 publications

References 27 publications

Paediatric diabetes subtypes in a consanguineous population: a single-centre cohort study from Kurdistan, Iraq

Paediatric diabetes subtypes in a consanguineous population: a single-centre cohort study from Kurdistan, Iraq

The Changing Landscape of Neonatal Diabetes Mellitus in Italy Between 2003 and 2022

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