Maturity onset diabetes of the young and beyond: the changing face of single-gene diabetes.

Maturity onset diabetes of the young (MODY) is the most common form of monogenic diabetes. A genetic diagnosis can help tailor treatment. However, it is vital to test the right genes.

Rare Variants in NEUROD1 and PDX1 Are Low-Penetrance Causes of MODY, Whereas Those in APPL1 and WFS1 Are Not Associated With MODY.

Unlabelled: An accurate genetic diagnosis of maturity-onset diabetes of the young (MODY) is critical for personalized treatment. To avoid misdiagnosis, only genes with strong evidence of causality must be tested. Heterozygous variants in NEUROD1, PDX1, APPL1, and WFS1 have been implicated in MODY, but strong genetic evidence supporting causality is lacking.

Children with diabetes and at least one non-autoimmune feature should be considered for monogenic diabetes testing.

Aims: Monogenic diabetes testing in children currently targets Maturity Onset Diabetes in the Young (MODY) or recognised genetic syndromes. We aim to determine whether genetic testing for monogenic diabetes should be performed for all children with diabetes and at least one non-autoimmune extra-pancreatic feature (syndromic diabetes).

Methods: We recruited 183 children with diabetes and at least one non-autoimmune extra-pancreatic feature (50% (n=91) with self-reported consanguinity).

Identification of a moxidectin dose for 4- to 11-year-old children to support registration and potential use for onchocerciasis elimination: results of an open-label pharmacokinetic and safety study.

Background: The WHO and onchocerciasis-endemic countries target elimination of the transmission of Onchocerca volvulus, the parasite causing onchocerciasis, primarily through ivermectin mass drug administration (MDA). In Africa, alternative treatment strategies are required to achieve or accelerate elimination. One of these is the MDA of moxidectin, an anthelmintic drug for which an 8 mg dose to individuals aged 12 years and older has received regulatory approval.

Non-autoimmune, insulin-deficient diabetes in children and young adults in Africa: evidence from the Young-Onset Diabetes in sub-Saharan Africa (YODA) cross-sectional study.

Background: Studies of type 1 diabetes in sub-Saharan Africa have suggested that the clinical phenotype might differ from phenotypes reported elsewhere. We aimed to establish whether type 1 diabetes diagnosed in children and young adults in three countries across sub-Saharan Africa is of autoimmune origin.

Methods: In this observational, cross-sectional study, we identified participants without obesity from outpatient clinics in government and private hospitals in Cameroon, Uganda, and South Africa who were of self-reported Black African ethnicity with young-onset (age <30 years), insulin-treated, clinically diagnosed type 1 diabetes.

Medullary Thyroid Cancer Risk and Mortality in Carriers of Incidentally Identified MEN2A RET Variants.

Importance: RET germline pathogenic variants cause multiple endocrine neoplasia type 2 (MEN2), which is associated with medullary thyroid cancer. With increasing incidental identification of these variants in asymptomatic individuals outside family screening, these individuals' risk of medullary thyroid cancer and all-cause mortality without intervention remain unknown in this context.

Objective: To evaluate the risk of medullary thyroid cancer and all-cause mortality in clinically unselected individuals with incidentally identified RET variants and assess whether the risk of medullary thyroid cancer differs from those with clinically ascertained RET variants.

Medically Integrated Dispensing Pharmacy: ASCO-Network for Collaborative Oncology Development & Advancement Standards Update.

Purpose: To update standards for dispensing oral anticancer medications and supportive care medications using a medically integrated dispensing pharmacy (MIP).

Methods: A multidisciplinary expert panel of oncology professionals integral to MIP and a patient representative participated in updating the guidelines. The revised standards address patient-centered and operational interventions of MIP that improve the access, quality, safety, and outcomes of prescribed oral anticancer medications or other supportive care medications.

Reassessing the role of the p.(Arg304Gln) missense AIP variant in pituitary tumorigenesis.

Objective: Heterozygous germline loss-of-function variants in AIP are associated with young-onset growth hormone and/or prolactin-secreting pituitary tumours. However, the pathogenic role of the c.911G > A; p.

Validation of the Sudbury Vertigo Risk Score to risk stratify for a serious cause of vertigo.

Introduction: In 2022, nearly 0.5 million Canadians visited an emergency department (ED) for dizziness, accounting for over 3.5% of all ED visits.

Whole-genome sequencing analysis identifies rare, large-effect noncoding variants and regulatory regions associated with circulating protein levels.

The contribution of rare noncoding genetic variation to common phenotypes is largely unknown, as a result of a historical lack of population-scale whole-genome sequencing data and the difficulty of categorizing noncoding variants into functionally similar groups. To begin addressing these challenges, we performed a cis association analysis using whole-genome sequencing data, consisting of 1.1 billion variants, 123 million noncoding aggregate-based tests and 2,907 circulating protein levels in ~50,000 UK Biobank participants.

The influence of fetal sex on maternal blood pressure in pregnancy.

Background: Pregnancy with a male fetus carries a higher risk of term pre-eclampsia than pregnancy with a female fetus. Based on evidence that maternal blood pressure (BP) may be raised in pregnancies with Beckwith-Wiedemann syndrome (fetal overgrowth), a possible contributing factor to the association between male sex and term pre-eclampsia is that males grow faster, reaching ~130 g higher birth weight, on average, than females. The association between fetal sex and maternal BP in healthy pregnancies is not known.

Impact of using time-averaged exposure metrics on binary endpoints in exposure-response analyses.

Exposure-response (ER) analyses are routinely performed as part of model-informed drug development to evaluate the risk-to-benefit ratio for dose selection, justification, and confirmation. For logistic regression analyses with binary endpoints, several exposure metrics are investigated, based on pharmacological plausibility, including time-averaged concentration to event (C). C is informative because it accounts for dose interruptions, modifications, and reductions and is therefore often compared against ER relationships identified using steady-state exposures.

Rare variant associations with birth weight identify genes involved in adipose tissue regulation, placental function and insulin-like growth factor signalling.

Investigating the genetic factors influencing human birth weight may lead to biological insights into fetal growth and long-term health. We report analyses of rare variants that impact birth weight when carried by either fetus or mother, using whole exome sequencing data in up to 234,675 participants. Rare protein-truncating and deleterious missense variants are collapsed to perform gene burden tests.

Type 1 diabetes genetic risk score variation across ancestries using whole genome sequencing and array-based approaches.

A Type 1 Diabetes Genetic Risk Score (T1DGRS) aids diagnosis and prediction of Type 1 Diabetes (T1D). While traditionally derived from imputed array genotypes, Whole Genome Sequencing (WGS) provides a more direct approach and is now increasingly used in clinical and research studies. We investigated the concordance between WGS-based and array-based T1DGRS across genetic ancestries in 149,265 UK Biobank participants using WGS, TOPMed-imputed, and 1000 Genomes-imputed array genotypes.

The Impact of Age and Sex on Fasting Plasma Glucose and Glycated Haemoglobin (HbA1c) in the Non-diabetes Population.

Introduction: We previously reported sex differences in the distribution of glycated haemoglobin (HbA1c) for men/women aged < 50 years vs older individuals, with implications for delayed diabetes diagnosis. Here, we explored whether this pattern was also seen in matched fasting plasma glucose (FPG) levels.

Methods: We extracted data on same-day, paired HbA1c and FPG levels from clinical biochemistry laboratory databases from Mersey and West Lancashire Teaching Hospitals NHS Trust (n = 10,153) and Cambridge University Hospitals NHS Foundation Trust (n = 10,022) between Jan 2019 and Dec 2023.

Real-world impact of luspatercept on red blood cell transfusions among patients with myelodysplastic syndromes: A United States healthcare claims database study.

Myelodysplastic syndromes (MDS) are associated with anemia and the need for blood transfusions. In clinical trials, luspatercept reduced transfusion dependency among patients with lower-risk MDS. This United States (US) study describes real-world clinical outcomes pre- and post-luspatercept initiation among patients with MDS.

Widening the phenotypic spectrum caused by pathogenic variants in individuals with neonatal diabetes.

Introduction: Biallelic variants are a rare cause of isolated pancreatic agenesis and neonatal diabetes (NDM) without exocrine pancreatic insufficiency, with 17 cases reported in the literature.

Research Design And Methods: To determine the phenotypic variability caused by this rare genetic aetiology, we investigated 19 individuals with NDM resulting from biallelic disease-causing variants.

Results: Of the 19 individuals, 8 (42%) were confirmed to have exocrine insufficiency requiring replacement therapy.

A homozygous TARS2 variant is a novel cause of syndromic neonatal diabetes.

Aims: Neonatal diabetes is a monogenic condition which can be the presenting feature of complex syndromes. The aim of this study was to identify novel genetic causes of neonatal diabetes with neurological features including developmental delay and epilepsy.

Methods: We performed genome sequencing in 27 individuals with neonatal diabetes plus epilepsy and/or developmental delay of unknown genetic cause.

Guidance for estimating penetrance of monogenic disease-causing variants in population cohorts.

Penetrance is the probability that an individual with a pathogenic genetic variant develops a specific disease. Knowing the penetrance of variants for monogenic disorders is important for counseling of individuals. Until recently, estimates of penetrance have largely relied on affected individuals and their at-risk family members being clinically referred for genetic testing, a 'phenotype-first' approach.

Precision treatment of beta-cell monogenic diabetes: a systematic review.

Background: Beta-cell monogenic forms of diabetes have strong support for precision medicine. We systematically analyzed evidence for precision treatments for GCK-related hyperglycemia, HNF1A-, HNF4A- and HNF1B-diabetes, and mitochondrial diabetes (MD) due to m.3243 A > G variant, 6q24-transient neonatal diabetes mellitus (TND) and SLC19A2-diabetes.

Comparison of Bayesian approaches for developing prediction models in rare disease: application to the identification of patients with Maturity-Onset Diabetes of the Young.

Background: Clinical prediction models can help identify high-risk patients and facilitate timely interventions. However, developing such models for rare diseases presents challenges due to the scarcity of affected patients for developing and calibrating models. Methods that pool information from multiple sources can help with these challenges.

Development of a clinical calculator to aid the identification of MODY in pediatric patients at the time of diabetes diagnosis.

Maturity Onset Diabetes of the Young (MODY) is a young-onset, monogenic form of diabetes without needing insulin treatment. Diagnostic testing is expensive. To aid decisions on who to test, we aimed to develop a MODY probability calculator for paediatric cases at the time of diabetes diagnosis, when the existing "MODY calculator" cannot be used.