Update of variants identified in the pancreatic β‐cell KATP channel genes KCNJ11 and ABCC8 in individuals with congenital hyperinsulinism and diabetes

The most common genetic cause of neonatal diabetes and hyperinsulinism is pathogenic variants in ABCC8 and KCNJ11. These genes encode the subunits of the β‐cell ATP‐sensitive potassium channel, a key component of the glucose‐stimulated insulin secretion pathway. Mutations in the two genes cause dysregulated insulin secretion; inactivating mutations cause an oversecretion of insulin, leading to congenital hyperinsulinism, whereas activating mutations cause the opposing phenotype, diabetes. This review focuses on variants identified in ABCC8 and KCNJ11, the phenotypic spectrum and the treatment implications for individuals with pathogenic variants.     

Isoniazid-related hepatotoxicity: a study of the effect of rifampicin administration on the metabolism of acetylisoniazid in man

It has been proposed that isoniazid-induced hepatotoxicity may be increased by concomitant rifampicin treatment and that this could be mediated by inducing the metabolism of the isoniazid metabolite monoacetylhydrazine to potent acylating agents capable of causing liver necrosis. To investigate this postulated mechanism we studied the kinetics of the metabolism of acetylisoniazid in a slow and a rapid acetylator prior to and after rifampicin administration. Pretreatment with rifampicin did not modify the metabolism of acetylisoniazid to any noteworthy extent nor did it increase the metabolism by non-acetylation routes of the monoacetylhydrazine liberated in vivo from acetylisoniazid.     

Evaluation of Evidence for Pathogenicity Demonstrates That BLK,KLF11, and PAX4 Should Not Be Included in Diagnostic Testing for MODY

Maturity-onset diabetes of the young (MODY) is an autosomal dominant form of monogenic diabetes, reported to be caused by variants in 16 genes. Concern has been raised about whether variants in BLK (MODY11), KLF11 (MODY7), and PAX4 (MODY9) cause MODY. We examined variant-level genetic evidence (cosegregation with diabetes and frequency in population) for published putative pathogenic variants in these genes and used burden testing to test gene-level evidence in a MODY cohort (n = 1,227) compared with a control population (UK Biobank [n = 185,898]). For comparison we analyzed well-established causes of MODY, HNF1A, and HNF4A. The published variants in BLK, KLF11, and PAX4 showed poor cosegregation with diabetes (combined logarithm of the odds [LOD] scores ≤1.2), compared with HNF1A and HNF4A (LOD scores >9), and are all too common to cause MODY (minor allele frequency >4.95 × 10⁻⁵). Ultra-rare missense and protein-truncating variants (PTV) were not enriched in a MODY cohort compared with the UK Biobank population (PTV P > 0.05, missense P > 0.1 for all three genes) while HNF1A and HNF4A were enriched (P < 10⁻⁶). Findings of sensitivity analyses with different population cohorts supported our results. Variant and gene-level genetic evidence does not support BLK, KLF11, or PAX4 as a cause of MODY. They should not be included in MODY diagnostic genetic testing.