Genetic counseling in diabetes mellitus: A practice resource of the National Society of Genetic Counselors.

Diabetes mellitus is a group of diseases characterized by hyperglycemia and its consequences, affecting over 34 million individuals in the United States and 422 million worldwide. While most diabetes is polygenic and is classified as type 1 (T1D), type 2 (T2D), or gestational diabetes (GDM), at least 0.4% of all diabetes is monogenic in nature. Correct diagnosis of monogenic diabetes has important implications for glycemic management and genetic counseling. We provide this Practice Resource to familiarize the genetic counseling community with (1) the existence of monogenic diabetes, (2) how it differs from more common polygenic/complex diabetes types, (3) the advantage of a correct diagnosis, and (4) guidance for identifying, counseling, and testing patients and families with suspected monogenic diabetes. This document is intended for genetic counselors and other healthcare professionals providing clinical services in any setting, with the goal of maximizing the likelihood of a correct diagnosis of monogenic diabetes and access to related care.

Elucidating the clinical and molecular spectrum of SMARCC2-associated NDD in a cohort of 65 affected individuals.

PURPOSE: Coffin-Siris and Nicolaides-Baraitser syndromes are recognizable neurodevelopmental disorders caused by germline variants in BAF complex subunits. The SMARCC2 BAFopathy was recently reported. Herein, we present clinical and molecular data on a large cohort. METHODS: Clinical symptoms for 41 novel and 24 previously published affected individuals were analyzed using the Human Phenotype Ontology. For genotype-phenotype correlations, molecular data were standardized and grouped into non-truncating and likely gene-disrupting (LGD) variants. Missense variant protein expression and BAF-subunit interactions were examined using 3D protein modeling, co-immunoprecipitation, and proximity-ligation assays. RESULTS: Neurodevelopmental delay with intellectual disability, muscular hypotonia, and behavioral disorders were the major manifestations. Clinical hallmarks of BAFopathies were rare. Clinical presentation differed significantly, with LGD variants being predominantly inherited and associated with mildly reduced or normal cognitive development, whereas non-truncating variants were mostly de novo and presented with severe developmental delay. These distinct manifestations and non-truncating variant clustering in functional domains suggest different pathomechanisms. In vitro testing showed decreased protein expression for N-terminal missense variants similar to LGD. CONCLUSION: This study improved SMARCC2 variant classification and identified discernible SMARCC2-associated phenotypes for LGD and non-truncating variants, which were distinct from other BAFopathies. The pathomechanism of most non-truncating variants has yet to be investigated.

Loss-of-function variants in TIAM1 are associated with developmental delay, intellectual disability, and seizures.

TIAM Rac1-associated GEF 1 (TIAM1) regulates RAC1 signaling pathways that affect the control of neuronal morphogenesis and neurite outgrowth by modulating the actin cytoskeletal network. To date, TIAM1 has not been associated with a Mendelian disorder. Here, we describe five individuals with bi-allelic TIAM1 missense variants who have developmental delay, intellectual disability, speech delay, and seizures. Bioinformatic analyses demonstrate that these variants are rare and likely pathogenic. We found that the Drosophila ortholog of TIAM1, still life (sif), is expressed in larval and adult central nervous system (CNS) and is mainly expressed in a subset of neurons, but not in glia. Loss of sif reduces the survival rate, and the surviving adults exhibit climbing defects, are prone to severe seizures, and have a short lifespan. The TIAM1 reference (Ref) cDNA partially rescues the sif loss-of-function (LoF) phenotypes. We also assessed the function associated with three TIAM1 variants carried by two of the probands and compared them to the TIAM1 Ref cDNA function in vivo. TIAM1 p.Arg23Cys has reduced rescue ability when compared to TIAM1 Ref, suggesting that it is a partial LoF variant. In ectopic expression studies, both wild-type sif and TIAM1 Ref are toxic, whereas the three variants (p.Leu862Phe, p.Arg23Cys, and p.Gly328Val) show reduced toxicity, suggesting that they are partial LoF variants. In summary, we provide evidence that sif is important for appropriate neural function and that TIAM1 variants observed in the probands are disruptive, thus implicating loss of TIAM1 in neurological phenotypes in humans.

Daily humidity oscillation regulates the circadian clock to influence plant physiology.

Early circadian studies in plants by de Mairan and de Candolle alluded to a regulation of circadian clocks by humidity. However, this regulation has not been described in detail, nor has its influence on physiology been demonstrated. Here we report that, under constant light, circadian humidity oscillation can entrain the plant circadian clock to a period of 24 h probably through the induction of clock genes such as CIRCADIAN CLOCK ASSOCIATED 1. Under simulated natural light and humidity cycles, humidity oscillation increases the amplitude of the circadian clock and further improves plant fitness-related traits. In addition, humidity oscillation enhances effector-triggered immunity at night possibly to counter increased pathogen virulence under high humidity. These results indicate that the humidity oscillation regulates specific circadian outputs besides those co-regulated with the light-dark cycle.

Characteristics of patients receiving long-term opioid therapy for chronic noncancer pain: a cross-sectional survey of patients attending the Pain Management Centre at Hamilton General Hospital, Hamilton, Ontario.

BACKGROUND: Characteristics of patients receiving long-term opioid therapy (≥ 6 months) for chronic noncancer pain are poorly understood. We conducted a cross-sectional survey of this patient population to explore demographic variables, pain relief, functional improvement, adverse effects and impressions of an educational pamphlet on long-term opioid therapy. METHODS: We invited 260 adult patients presenting to the Pain Management Centre at the Hamilton General Hospital, Hamilton, Ontario, with chronic noncancer pain to complete a 20-item survey. Patients who presented for procedures were not eligible for our study. We used adjusted logistic regression models to explore the association between higher morphine equivalent dose and pain relief, functional improvement, adverse events and employment. RESULTS: The survey was completed by 170 patients (a response rate of 65.4%). Most respondents (87.6%; 149 out of 170) were receiving long-term opioid therapy, and the median morphine equivalent dose was 180 mg daily (interquartile range 60-501). Most respondents reported at least modest (> 40%) opioid-specific pain relief (74.1%; 106 out of 143) and functional improvement (67.6%; 96 out of 142), and 46.5% (66 out of 142) reported troublesome adverse effects that they attributed to their opioid use. Most patients were receiving disability benefits (68.3%; 99 out of 145) and, among those respondents who were less than 65 years of age (90.3%; 131 out of 145), 10 (7.6%) were working full-time and 14 (10.7%) part-time. In our adjusted analyses, higher morphine equivalent dose was associated with greater self-reported functional improvement (odds ratio [OR] 1.45, 95% confidence interval [CI] 1.07-1.96) but not with pain relief (OR 1.38, 95% CI 1.00-1.89), troublesome adverse effects (OR 0.92, 95% CI 0.70-1.20) or employment (OR 0.80, 95% CI 0.56-1.15). INTERPRETATION: Most outpatients receiving long-term opioid therapy for chronic noncancer pain at a tertiary care chronic pain clinic reported at least moderate pain relief and functional improvement; however, adverse effects were common and few patients were engaged in competitive employment.