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.

The clinical and molecular spectrum of the KDM6B-related neurodevelopmental disorder.

De novo variants are a leading cause of neurodevelopmental disorders (NDDs), but because every monogenic NDD is different and usually extremely rare, it remains a major challenge to understand the complete phenotype and genotype spectrum of any morbid gene. According to OMIM, heterozygous variants in KDM6B cause "neurodevelopmental disorder with coarse facies and mild distal skeletal abnormalities." Here, by examining the molecular and clinical spectrum of 85 reported individuals with mostly de novo (likely) pathogenic KDM6B variants, we demonstrate that this description is inaccurate and potentially misleading. Cognitive deficits are seen consistently in all individuals, but the overall phenotype is highly variable. Notably, coarse facies and distal skeletal anomalies, as defined by OMIM, are rare in this expanded cohort while other features are unexpectedly common (e.g., hypotonia, psychosis, etc.). Using 3D protein structure analysis and an innovative dual Drosophila gain-of-function assay, we demonstrated a disruptive effect of 11 missense/in-frame indels located in or near the enzymatic JmJC or Zn-containing domain of KDM6B. Consistent with the role of KDM6B in human cognition, we demonstrated a role for the Drosophila KDM6B ortholog in memory and behavior. Taken together, we accurately define the broad clinical spectrum of the KDM6B-related NDD, introduce an innovative functional testing paradigm for the assessment of KDM6B variants, and demonstrate a conserved role for KDM6B in cognition and behavior. Our study demonstrates the critical importance of international collaboration, sharing of clinical data, and rigorous functional analysis of genetic variants to ensure correct disease diagnosis for rare disorders.

A clustering of heterozygous missense variants in the crucial chromatin modifier WDR5 defines a new neurodevelopmental disorder.

WDR5 is a broadly studied, highly conserved key protein involved in a wide array of biological functions. Among these functions, WDR5 is a part of several protein complexes that affect gene regulation via post-translational modification of histones. We collected data from 11 unrelated individuals with six different rare de novo germline missense variants in WDR5; one identical variant was found in five individuals and another variant in two individuals. All individuals had neurodevelopmental disorders including speech/language delays (n = 11), intellectual disability (n = 9), epilepsy (n = 7), and autism spectrum disorder (n = 4). Additional phenotypic features included abnormal growth parameters (n = 7), heart anomalies (n = 2), and hearing loss (n = 2). Three-dimensional protein structures indicate that all the residues affected by these variants are located at the surface of one side of the WDR5 protein. It is predicted that five out of the six amino acid substitutions disrupt interactions of WDR5 with RbBP5 and/or KMT2A/C, as part of the COMPASS (complex proteins associated with Set1) family complexes. Our experimental approaches in Drosophila melanogaster and human cell lines show normal protein expression, localization, and protein-protein interactions for all tested variants. These results, together with the clustering of variants in a specific region of WDR5 and the absence of truncating variants so far, suggest that dominant-negative or gain-of-function mechanisms might be at play. All in all, we define a neurodevelopmental disorder associated with missense variants in WDR5 and a broad range of features. This finding highlights the important role of genes encoding COMPASS family proteins in neurodevelopmental disorders.

Evaluating a general pediatric/adult genetic counseling clinic in a Midwest medical center.

In 2018, the Munroe-Meyer Institute for Genetics & Rehabilitation (MMI) at the University of Nebraska Medical Center (UNMC) in Omaha, NE created a genetic counseling clinic (GCC) to increase access to genetics services and decrease the time spent between a referral and being seen in a general genetics outpatient clinic. In the GCC, genetic counselors led patient encounters and geneticists served as advisors, rather than primary providers. We conducted a chart review of 109 patients seen in the GCC from November 1, 2018, to March 16, 2020, and obtained information regarding patient demographics, indications, and clinical recommendations as a result of the visit. Most patients seen in this clinic were female (65.1%) and aged 19 years of age or older (54.1%). The primary indications for patients in this clinic included review genetic test results (42.2%), coordination of genetic testing for a known familial variant (30.2%), and concerns for personal or family history suspicious of a genetic condition without dysmorphic features (24.8%). The average patient wait time between referral date and appointment date in the GCC was 49.8 days. The two most common clinical recommendations made by genetic counselors in the GCC were genetic testing (56.1%) and/or follow-up with specialist (26.5%). These specialists primarily included endocrinology (n = 5), neurology (n = 4), cardiology (n = 4), ophthalmology (n = 3), and audiology (n = 3). We found that the GCC model may be appropriate for patients with (1) genetic test results requiring interpretation, (2) a known familial variant or (3) genetic testing recommended by a specialist physician. Descriptions of the indications and recommendations for patients seen in this GCC provide a framework for potential implementation of a GCC in other regions across the nation.

Consolidation of the clinical and genetic definition of a SOX4-related neurodevelopmental syndrome.

BACKGROUND: A neurodevelopmental syndrome was recently reported in four patients with SOX4 heterozygous missense variants in the high-mobility-group (HMG) DNA-binding domain. The present study aimed to consolidate clinical and genetic knowledge of this syndrome. METHODS: We newly identified 17 patients with SOX4 variants, predicted variant pathogenicity using in silico tests and in vitro functional assays and analysed the patients' phenotypes. RESULTS: All variants were novel, distinct and heterozygous. Seven HMG-domain missense and five stop-gain variants were classified as pathogenic or likely pathogenic variant (L/PV) as they precluded SOX4 transcriptional activity in vitro. Five HMG-domain and non-HMG-domain missense variants were classified as of uncertain significance (VUS) due to negative results from functional tests. When known, inheritance was de novo or from a mosaic unaffected or non-mosaic affected parent for patients with L/PV, and from a non-mosaic asymptomatic or affected parent for patients with VUS. All patients had neurodevelopmental, neurological and dysmorphic features, and at least one cardiovascular, ophthalmological, musculoskeletal or other somatic anomaly. Patients with L/PV were overall more affected than patients with VUS. They resembled patients with other neurodevelopmental diseases, including the SOX11-related and Coffin-Siris (CSS) syndromes, but lacked the most specific features of CSS. CONCLUSION: These findings consolidate evidence of a fairly non-specific neurodevelopmental syndrome due to SOX4 haploinsufficiency in neurogenesis and multiple other developmental processes.

Research participant understanding and engagement in an institutional, self-consent biobank model.

The number of institutional and governmental biobanks and the target enrollment sizes of modern biobanks are increasing, affording more opportunities for the public to participate in biobanking efforts. In parallel with these expansions are pressures to increase the efficiency of obtaining informed consent using shorter consent forms that cover a broader scope of research and increasingly include provisions for return of research or clinical genetic test results to participants. Given these changes, how well these participants understand genetics, their level of understanding of what they are consenting to, and their wishes to engage longitudinally and receive biobank results are not well understood. We surveyed participants in a large, medical system-based biobank who had enrolled through a two-page, self-consent process about their baseline knowledge of genetics, understanding and recall of the consent process, wishes for future contact and engagement, and level of interest in receiving clinical genetic testing results. A total of 856 consented persons participated in the survey (67% women; 67% white). Participants' general reported genetics knowledge was relatively high (mean 11.60 of 15 questions answered correctly) as was recall of key elements from the two-page consent form. Overall participant enthusiasm for future contact by the biobank and for receiving clinical genetic testing results was high. The use of a two-page, self-consent process in a large, institutional biobank resulted in high levels of consent recall and enthusiasm for future ongoing engagement and receipt of genetic testing results by participants.