Human inherited PD-L1 deficiency is clinically and immunologically less severe than PD-1 deficiency.

We previously reported two siblings with inherited PD-1 deficiency who died from autoimmune pneumonitis at 3 and 11 years of age after developing other autoimmune manifestations, including type 1 diabetes (T1D). We report here two siblings, aged 10 and 11 years, with neonatal-onset T1D (diagnosed at the ages of 1 day and 7 wk), who are homozygous for a splice-site variant of CD274 (encoding PD-L1). This variant results in the exclusive expression of an alternative, loss-of-function PD-L1 protein isoform in overexpression experiments and in the patients' primary leukocytes. Surprisingly, cytometric immunophenotyping and single-cell RNA sequencing analysis on blood leukocytes showed largely normal development and transcriptional profiles across lymphoid and myeloid subsets in the PD-L1-deficient siblings, contrasting with the extensive dysregulation of both lymphoid and myeloid leukocyte compartments in PD-1 deficiency. Our findings suggest that PD-1 and PD-L1 are essential for preventing early-onset T1D but that, unlike PD-1 deficiency, PD-L1 deficiency does not lead to fatal autoimmunity with extensive leukocytic dysregulation.

The Role of ONECUT1 Variants in Monogenic and Type 2 Diabetes Mellitus.

ONECUT1 (also known as HNF6) is a transcription factor involved in pancreatic development and ß-cell function. Recently, biallelic variants in ONECUT1 were reported as a cause of neonatal diabetes mellitus (NDM) in two subjects, and missense monoallelic variants were associated with type 2 diabetes and possibly maturity-onset diabetes of the young (MODY). Here we examine the role of ONECUT1 variants in NDM, MODY, and type 2 diabetes in large international cohorts of subjects with monogenic diabetes and >400,000 subjects from UK Biobank. We identified a biallelic frameshift ONECUT1 variant as the cause of NDM in one individual. However, we found no enrichment of missense or null ONECUT1 variants among 484 individuals clinically suspected of MODY, in whom all known genes had been excluded. Finally, using a rare variant burden test in the UK Biobank European cohort, we identified a significant association between heterozygous ONECUT1 null variants and type 2 diabetes (P = 0.006) but did not find an association between missense variants and type 2 diabetes. Our results confirm biallelic ONECUT1 variants as a cause of NDM and highlight monoallelic null variants as a risk factor for type 2 diabetes. These findings confirm the critical role of ONECUT1 in human ß-cell function.

A biallelic loss-of-function PDIA6 variant in a second patient with polycystic kidney disease, infancy-onset diabetes, and microcephaly.

We report a second patient with intrauterine growth retardation, congenital polycystic kidney disease, infancy-onset diabetes, microcephaly, and liver fibrosis caused by a homozygous PDIA6 loss-of-function variant. Our study further defines the genetic and clinical features of this rare syndromic form of infancy-onset diabetes.