ESPEYB17 2. Antenatal and Neonatal Endocrinology Updates on the Genetics of Neonatal Diabetes Mellitus, Congenital Hyperinsulinism and Glucose Disorders (3 abstracts)
2.11. Update of variants identified in the pancreatic [beta]-cell KATPchannel genes KCNJ11 and ABCC8 in individuals with congenital hyperinsulinism and diabetes
De Franco E , Saint-Martin C , Brusgaard K , Knight Johnson AE , Aguilar-Bryan L , Bowman P , Arnoux JB , Larsen AR , May S , Greeley Saw , Calzada-León R , Harman B , Houghton JAL , Nishimura-Meguro , Laver TW , Ellard S , Del Gaudio D , Christesen HT , Bellanné-Chantelot C & Flanagan SE
To read the full abstract: Hum Mutat. 2020 May;41(5):884–905. doi: 10.1002/humu.23995. Epub 2020 Feb 17. PMID: 32027066
Pancreatic KATPchannels play a key role in regulating insulin secretion. These channels are composed of four subunits of SUR1 and four subunits of KIR6.2 encoded by the ABCC8 and KNCJ11 genes, respectively. Inactivating mutations in these two genes lead to unregulated insulin secretion and severe hypoglycaemia (congenital hyperinsulinism CHI) whereas activating mutations lead to decreased insulin secretion and cause either permanent or transient neonatal diabetes mellitus (NDM). Since the discovery that mutations in these two genes leads to either CHI or NDM, a significant number of variants have been reported. In this update review the authors report a total of 748 ABCC8 and 205 KCNJ11pathogenic or likely pathogenic variants identified in individuals with CHI or NDM. Founder mutations have been identified in many populations, with the best recognized example being the ABCC8 p.(Phe1388del) and c.3992–9G>A mutations present in >90% of cases from the Ashkenazi Jewish population. In addition, 368 benign/likely benign variants and variants of uncertain significance were found in both genes. Just like any genetic disease, predicting variant pathogenicity can be challenging and just finding a missense variant may not be sufficient proof of disease causality. In these cases, the authors recommend using the guidelines by the American College of Medical Genetics to help predict pathogenicity. In addition, the use of large variant databases such as GnomAD and LOVD can also aid in variant interpretation and allow for reclassification of variants. Based on the information from these databases, some variants in ABCC8/KCNJ11 that were previously reported as being pathogenic are now found to be too common to be disease causing; these are now reclassified as a variant of uncertain significance or a benign variant. The spectrum of mutations in ABCC8/KCNJ11 causing CHI and NDM continues to expand.
Volume 17
Article tools
My recent searches
My recently viewed abstracts
Authors
ESPE Yearbook of Paediatric Endocrinology
ISSN 1662-4009 (Online)
© Bioscientifica 2024 |
Privacy policy |
Cookie settings
BiosciAbstracts
Bioscientifica Abstracts is the gateway to a series of products that provide a permanent, citable record of abstracts for biomedical and life science conferences.
Find out more