Clinical, Genetic, and Biochemical Characteristics of Early-Onset Diabetes in the Finnish Population

Huopio, Hanna; Miettinen, Päivi J.; Ilonen, Jorma; Nykänen, Päivi; Veijola, Riitta; Keskinen, Päivi; Näntö‐Salonen, Kirsti; Vangipurapu, Jagadish; Raivo, Joose; Stančáková, Alena; Männistö, Jonna M E; Kuulasmaa, Teemu; Knip, Mikael; Otonkoski, Timo; Laakso, Markku

doi:10.1210/jc.2015-4296

Cited by 29 publications

(27 citation statements)

References 40 publications

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“…Finally, these variants are likely to have a functional effect due to nonsense-mediated decay causing haploinsufficiency 12, 22 . This is further supported by the studies that showed that the homozygous RFX6 PTVs cause neonatal diabetes 15, 23, 24 . Among unknown MODY cases, RFX6 PTVs were responsible for 7.5% Finnish cases compared to only ~1% of non-Finnish European cases.…”

Section: Discussionmentioning

confidence: 52%

“…29/47 were part of the discovery and replication cohorts. 18/47 were identified separately or had been previously reported 18, 23 (Supplementary Fig. 2 – Families 3–5, Supplementary Fig.…”

Section: Methodsmentioning

confidence: 99%

“…Family co-segregation analysis was performed in available family members using a Sanger sequencing assay for the specific RFX6 variant identified in that family. DNA analysis of the METSIM study has been described before 23 .…”

Section: Methodsmentioning

confidence: 99%

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Heterozygous RFX6 protein truncating variants are associated with MODY with reduced penetrance

et al. 2017

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Finding new causes of monogenic diabetes helps understand glycaemic regulation in humans. To find novel genetic causes of maturity-onset diabetes of the young (MODY), we sequenced MODY cases with unknown aetiology and compared variant frequencies to large public databases. From 36 European patients, we identify two probands with novel RFX6 heterozygous nonsense variants. RFX6 protein truncating variants are enriched in the MODY discovery cohort compared to the European control population within ExAC (odds ratio = 131, P = 1 × 10−4). We find similar results in non-Finnish European (n = 348, odds ratio = 43, P = 5 × 10−5) and Finnish (n = 80, odds ratio = 22, P = 1 × 10−6) replication cohorts. RFX6 heterozygotes have reduced penetrance of diabetes compared to common HNF1A and HNF4A-MODY mutations (27, 70 and 55% at 25 years of age, respectively). The hyperglycaemia results from beta-cell dysfunction and is associated with lower fasting and stimulated gastric inhibitory polypeptide (GIP) levels. Our study demonstrates that heterozygous RFX6 protein truncating variants are associated with MODY with reduced penetrance.

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Section: Discussionmentioning

confidence: 52%

Section: Methodsmentioning

confidence: 99%

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Heterozygous RFX6 protein truncating variants are associated with MODY with reduced penetrance

et al. 2017

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“…RFX6 PTVs were highly enriched in both discovery and replication cohorts compared to control cohorts, supporting their pathogenicity. The ExAC database has been very useful in identifying benign variants because of an unusually high frequency in the population compared to frequency of the disease in question 15,23,24 . However, caution is required for reduced penetrance variants as their frequency can be higher than estimated disease frequency in the general population.…”

Section: Discussionmentioning

confidence: 99%

“…29/47 were part of the discovery and replication cohorts. 18/47 were identified separately or had been previously reported 18,23 (Supplementary Fig. 2–Family 3–5, Supplementary Fig.…”

Section: Methodsmentioning

confidence: 99%

HeterozygousRFX6protein truncating variants are associated with Maturity-Onset Diabetes of the Young (MODY) with reduced penetrance

Patel

Kettunen

Laakso

et al. 2017

Preprint

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Finding new genetic causes of monogenic diabetes can help to understand development and function of the human pancreas. We aimed to find novel protein–truncating variants causing Maturity–Onset Diabetes of the Young (MODY), a subtype of monogenic diabetes. We used a combination of next–generation sequencing of MODY cases with unknown aetiology along with comparisons to the ExAC database to identify new MODY genes. In the discovery cohort of 36 European patients, we identified two probands with novel RFX6 heterozygous nonsense variants. RFX6 protein truncating variants were enriched in the MODY discovery cohort compared to the European control population within ExAC (odds ratio, OR=131, P=l×l0‐4). We found similar results in non–Finnish European (n=348, OR=43, P=5×l0‐5) and Finnish (n=80, OR=22, P=1×l0‐6) replication cohorts. The overall meta–analysis OR was 34 (P=l×l0‐16). RFX6 heterozygotes had reduced penetrance of diabetes compared to common HNF1A and HNF4A–MODY mutations (27%, 70% and 55% at 25 years of age, respectively). The hyperglycaemia resulted from beta–cell dysfunction and was associated with lower fasting and stimulated gastric inhibitory polypeptide (GIP) levels. Our study demonstrates that heterozygous RFX6 protein truncating variants are associated with MODY with reduced penetrance.

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ABCC8 variants in MODY12: Review of the literature and report of a case with severe complications

Timmers

Dirinck

Lauwers

et al. 2021

Diabetes Metabolism Res

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More than 1000 variants of the ATP-binding cassette transporter subfamily C member 8 (ABCC8) gene have been reported in neonatal diabetes mellitus. Up to now only 55 ABCC8 variants were associated with Maturity-Onset Diabetes of the Young 12 (MODY12). We present a c.3544C>T p.(Arg1182Trp) ABCC8 variant in a 35-year-old women who had pronounced microvascular diabetic complications and a charcot arthropathy necessitating a lower limb amputation. The unusual severity of the disease course prompted us to perform a systematic review of all genetic variants in MODY12. The present mutation has mostly been associated with neonatal diabetes and in only three papers reporting a MODY12. The 55 MODY12 variants show a large clinical heterogeneity, even in relatives with the same mutation, ranging from mild impaired glucose tolerance to severe insulin-dependent diabetes mellitus. HbA1c at diagnosis ranged from 5% to 14% and age at diagnosis ranged from 2 to 53 years. However, several case reports lack documentation of diabetic complications. Hence, more detailed reports remain necessary to improve insight in MODY12 pathophysiology and outcome. In this article current data regarding therapeutic management are provided, and key points to consider for the individual patient affected by MODY12 are presented.

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Clinical, Genetic, and Biochemical Characteristics of Early-Onset Diabetes in the Finnish Population

Abstract: Mutations in the K-ATP channel and INS genes were the most common cause of early diagnosed monogenic diabetes. After 6 months of age, patients with diabetes had high HLA risk genotypes and islet autoantibodies, reflecting the autoimmune character of diabetes in that age group.

Cited by 29 publications

References 40 publications

Heterozygous RFX6 protein truncating variants are associated with MODY with reduced penetrance

Heterozygous RFX6 protein truncating variants are associated with MODY with reduced penetrance

HeterozygousRFX6protein truncating variants are associated with Maturity-Onset Diabetes of the Young (MODY) with reduced penetrance

ABCC8 variants in MODY12: Review of the literature and report of a case with severe complications

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