PMID- 36585034
OWN - NLM
STAT- MEDLINE
DCOM- 20230103
LR  - 20230111
IS  - 2052-4897 (Electronic)
IS  - 2052-4897 (Linking)
VI  - 10
IP  - 6
DP  - 2022 Dec
TI  - Co-segregation analysis and functional trial in vivo of candidate genes for 
      monogenic diabetes.
LID - 10.1136/bmjdrc-2022-003038 [doi]
LID - e003038
AB  - INTRODUCTION: The aim of this study was to perform familial co-segregation 
      analysis and functional trial in vivo during mixed meal tolerance test (MMTT) of 
      novel variants in diabetes candidate genes. RESEARCH DESIGN AND METHODS: It is a 
      continuation of the project "Genetic diabetes in Lithuania" with the cohort of 
      1209 patients with diabetes. Prior screening for autoimmune markers confirmed 
      type 1 diabetes (T1D) diagnosis in 88.1% (n=1065) of patients, and targeted 
      next-generation sequencing identified 3.5% (n=42) pathogenic variants in MODY 
      genes. Subsequently, 102 patients were classified as having diabetes of unknown 
      etiology. 12/102 were found to have novel variants in potential diabetes genes 
      (RFX2, RREB1, SLC5A1 (3 patients with variants in this gene), GCKR, MC4R, CASP10, 
      TMPRSS6, HGFAC, DACH1, ZBED3). Co-segregation analysis and MMTT were carried out 
      in order to study beta-cell function in subjects with specific variants. RESULTS: 
      MMTT analysis showed that probands with variants in MC4R, CASP10, TMPRSS6, HGFAC, 
      and SLC5A1 (c.1415T>C) had sufficient residual beta-cell function with stimulated 
      C-peptide (CP) >200 pmol/L. Seven individuals with variants in RFX2, RREB1, GCKR, 
      DACH1, ZBED3 and SLC5A1 (c.1415T>C, and c.932A>T) presented with complete 
      beta-cell failure. No statistical differences were found between patients with 
      sufficient CP production and those with complete beta-cell failure when comparing 
      age at the onset and duration of diabetes. Nineteen family members were included 
      in co-segregation analysis; no diabetes cases were reported among them. Only in 
      patient with the variant c.1894G>A in RFX2 gene, none of the family members were 
      affected by proband's variant. CONCLUSIONS: Functional beta-cell study in vivo 
      allowed to select five most probable genes for monogenic diabetes. Familial 
      co-segregation analysis showed that novel variant in RFX2 gene could be a 
      possible cause of diabetes. Future functional analysis in vitro is necessary to 
      support or rule out the genetic background as a cause of diabetes.
CI  - (c) Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No 
      commercial re-use. See rights and permissions. Published by BMJ.
FAU - Stankute, Ingrida
AU  - Stankute I
AUID- ORCID: 0000-0002-0228-7143
AD  - Institute of Endocrinology, Lithuanian University of Health Sciences, Kaunas, 
      Lithuania ingridutes@gmail.com.
FAU - Kazlauskiene, Mintaute
AU  - Kazlauskiene M
AD  - Institute of Endocrinology, Lithuanian University of Health Sciences, Kaunas, 
      Lithuania.
FAU - Blouin, Jean-Louis
AU  - Blouin JL
AD  - Department of Genetic Medicine and Development, University of Geneva, Geneva, 
      Switzerland.
AD  - Department of Diagnostics, University Hospitals of Geneva, Geneva, Switzerland.
FAU - Schwitzgebel, Valerie M
AU  - Schwitzgebel VM
AD  - Pediatric Endocrine and Diabetes Unit, Department of Pediatrics, Gynecology and 
      Obstetrics, University Hospitals of Geneva, Geneva, Switzerland.
AD  - Diabetes Center of the Faculty of Medicine, University of Geneva, Geneva, 
      Switzerland.
FAU - Verkauskiene, Rasa
AU  - Verkauskiene R
AD  - Institute of Endocrinology, Lithuanian University of Health Sciences, Kaunas, 
      Lithuania.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - BMJ Open Diabetes Res Care
JT  - BMJ open diabetes research & care
JID - 101641391
RN  - 0 (C-Peptide)
SB  - IM
MH  - Humans
MH  - *Diabetes Mellitus, Type 1/genetics
MH  - High-Throughput Nucleotide Sequencing
MH  - *Insulin-Secreting Cells
MH  - C-Peptide
PMC - PMC9809257
OTO - NOTNLM
OT  - genetics
OT  - monogenic diabetes
COIS- Competing interests: None declared.
EDAT- 2022/12/31 06:00
MHDA- 2023/01/04 06:00
PMCR- 2022/12/29
CRDT- 2022/12/30 20:53
PHST- 2022/07/19 00:00 [received]
PHST- 2022/12/12 00:00 [accepted]
PHST- 2022/12/30 20:53 [entrez]
PHST- 2022/12/31 06:00 [pubmed]
PHST- 2023/01/04 06:00 [medline]
PHST- 2022/12/29 00:00 [pmc-release]
AID - 10/6/e003038 [pii]
AID - bmjdrc-2022-003038 [pii]
AID - 10.1136/bmjdrc-2022-003038 [doi]
PST - ppublish
SO  - BMJ Open Diabetes Res Care. 2022 Dec;10(6):e003038. doi: 
      10.1136/bmjdrc-2022-003038.