Hepatocyte nuclear factor-1α (HNF-1α) and hepatocyte nuclear factor-4α (HNF-4α) are transcription factors highly expressed in β-cells, hepatocytes, intestinal epithelial cells, and renal tubular cells. Variants in both HNF1A and HNF4A gene have been linked to maturity-onset diabetes of youth (MODY) and congenital hyperinsulinism (HI). To date, the association between HI, renal tubulopathy, and hepatopathy has been described only in patients with HNF-4α deficiency. HI due to HNF-1α deficiency has not been linked to extra-pancreatic features. Our patient presented neonatal onset of HI and hepatomegaly, cholestasis, echographic features of liver steatosis, and renal tubulopathy (glycosuria, phosphaturia, aminoaciduria, uricosuria, proteinuria) from the first month of life. The molecular analysis revealed a heterozygous maternal variant c.4432G>A (p.Gly1478Ar) in the ABCC8 gene and a heterozygous maternal variant c.1859C>T (Thr620Ile) in HNF1A gene. We describe an 8-month follow-up and discuss possible pathogenetic mechanisms linking HNF1A-HI and features of extra-pancreatic involvement. Our case describes a likely association between HI due to HNF-1α deficiency with liver and kidney involvement. Further cases are needed to validate our hypothesis and to establish if a genotype-phenotype correlation exists in case of extra-pancreatic involvement, as for the known HNF4A mutation-specific phenotype.

Integration of genomic and other data has begun to stratify type 2 diabetes in prognostically meaningful ways, but this has yet to impact on mainstream diabetes practice. The subgroup of diabetes caused by single gene defects thus provides the best example to date of the vision of 'precision diabetes'. Monogenic diabetes may be divided into primary pancreatic beta cell failure, and primary insulin resistance. In both groups, clear examples of genotype-selective responses to therapy have been advanced. The benign trajectory of diabetes due to pathogenic GCK mutations, and the sulfonylurea-hyperresponsiveness conferred by activating KCNJ11 or ABCC8 mutations, or loss-of-function HNF1A or HNF4A mutations, often decisively guide clinical management. In monogenic insulin-resistant diabetes, subcutaneous leptin therapy is beneficial in some severe lipodystrophy. Increasing evidence also supports use of 'obesity therapies' in lipodystrophic people even without obesity. In beta cell diabetes the main challenge is now implementation of the precision diabetes vision at scale. In monogenic insulin-resistant diabetes genotype-specific benefits are proven in far fewer patients to date, although further genotype-targeted therapies are being evaluated. The conceptual paradigm established by the insulin-resistant subgroup with 'adipose failure' may have a wider influence on precision therapy for common type 2 diabetes, however. For all forms of monogenic diabetes, population-wide genome sequencing is currently forcing reappraisal of the importance assigned to pathogenic mutations when gene sequencing is uncoupled from prior suspicion of monogenic diabetes.

Alpha-1 antitrypsin (AAT) encoded by SERPINA1 is an acute-phase inflammation marker, and AAT deficiency (AATD) is known as one of the common genetic disorders in European populations. However, no genetic determinants to AAT levels apart from the SERPINA gene clusters have been identified to date. Here we perform a genome-wide association study of serum AAT levels followed by a two-staged replication study recruiting a total of 9,359 Japanese community-dwelling population. Three missense variants of metabolic syndrome-related genes, namely, rs671 in ALDH2, rs1169288 in HNF1A and rs1260326 in GCKR, significantly associate with AAT levels (P≤1.5 × 10(-12)). Previous reports have shown the functional relevance of ALDH2 and HNF1A to AAT. We observe a significant interaction of rs671 and alcohol consumption on AAT levels. We confirm the association between AAT and rs2896268 in SERPINA1, which is independent of known causative variants of AATD. These findings would support various AAT functions including metabolic processes.