Medical genetics and genomic medicine in the United States. Part 2: Reproductive genetics, newborn screening, genetic counseling, training, and registries

eview of genetics in the United States with emphasis on the prenatal, metabolic, genetic counseling, and training aspects of the field

Diagnosis of LCHAD/TFP deficiency in an at risk newborn using umbilical cord blood acylcarnitine analysis

Trifunctional protein deficiency/Long-chain hydroxyacyl-CoA dehydrogenase deficiency (LCHAD/TFP) deficiency is a disorder of fatty acid oxidation and ketogenesis. Severe neonatal lactic acidosis, cardiomyopathy, and hepatic dysfunction are caused by the accumulation of toxic long-chain acylcarnitines. The feasibility of umbilical cord blood use in screening for acylcarnitine analysis and free carnitine has been hypothesized but not reported in LCHAD/TFP neonates. We present a 4 week old female who was at risk of inheriting LCHAD/TFP deficiency and was diagnosed at the time of delivery using umbilical cord blood. Umbilical cord blood was collected at delivery and sent for acylcarnitine analysis. Treatment was started immediately. Acylcarnitine analysis demonstrated findings that are consistent with a biochemical diagnosis of LCHAD/TFP deficiency. Patients with LCHAD/TFP deficiency should have treatment initiated as early as possible to avoid acute decompensation and minimize the long-term complications of the disorder including cardiomyopathy. In pregnancies at risk of having a child with LCHAD/TFP deficiency, umbilical cord blood sample is an efficient method to diagnose an inborn error of metabolism such as LCHAD/TFP deficiency

A case series of familial ARID1B variants illustrating variable expression and suggestions to update the ACMG criteria

ARID1B is one of the most frequently mutated genes in intellectual disability (~1%). Most variants are readily classified, since they are de novo and are predicted to lead to loss of function, and therefore classified as pathogenic according to the American College of Medical Genetics and Genomics (ACMG) guidelines for the interpretation of sequence variants. However, familial loss-of-function variants can also occur and can be challenging to interpret. Such variants may be pathogenic with variable expression, causing only a mild phenotype in a parent. Alternatively, since some regions of the ARID1B gene seem to be lacking pathogenic variants, loss-of-function variants in those regions may not lead to ARID1B haploinsufficiency and may therefore be benign. We describe 12 families with potential loss-of-function variants, which were either familial or with unknown inheritance and were in regions where pathogenic variants have not been described or are otherwise challenging to interpret. We performed detailed clinical and DNA methylation studies, which allowed us to confidently classify most variants. In five families we observed transmission of pathogenic variants, confirming their highly variable expression. Our findings provide further evidence for an alternative translational start site and we suggest updates for the ACMG guidelines for the interpretation of sequence variants to incorporate DNA methylation studies and facial analyses

The impact of home-based call on sleep patterns and wellness in genetics and metabolism physicians compared with subspecialists

Purpose: With increases in precision medicine initiatives and genetically defined rare diseases, the genetics and metabolism workforce is necessary to provide around-the-clock care for patients. Here, we describe the impact that home-based call has on the geneticist and metabolist workforce. Methods: Physicians from 3 populations were self-identified (pediatric subspecialist, geneticist, metabolist) and completed a survey regarding the impact of home-based call service on their sleep and wellness. Results: Estimated sleep while serving on home-based call was reduced from 7.5 to 5.4 hours per night. Safety concerns were noted by geneticists and metabolists for themselves (55%) and their families (28%), similar to other subspecialists. Geneticists and metabolists were more likely than other pediatric subspecialists to be worried about their patient’s safety while on home-based call (48% vs 9%). Themes from open-ended questions regarding the impact of home-call included positive responses, decreased access to wellness activities, sleep exhaustion, impact on life responsibility, and impact on mood. Reported coping mechanisms included work-based initiatives, off-loading personal responsibility, and creating personal accommodations. Conclusion: Institutional-based supports for home-based call were endorsed by only 29% of respondents; thus, interventions at the institutional level would be expected to have a large effect on overall provider wellness

Medical genetics education in the midst of the COVID-19 pandemic: Shared resources

In the midst of the COVID-19 pandemic, it is appropriate that our focus is on patient care and preparation. However, the genetics community is well poised to fill in the educational gap created by medical students transitioning to limiting patient contact, creation of telemedicine patient care, and online learning modules. Our history of agility in learning and teaching is now only inhibited by the time constraints of current clinical demands on the genetics community. This publication is designed to offer ideas and resources for quickly transitioning our education to meet the current demands in the time of a pandemic. Not only will this allow us to continue our strong history of education, it will enhance our strong commitment to using modern educational techniques and tools to address the genetics workforce issues that have defined the recent past. We have the opportunity to aggressively educate for trainees that now have the capacity to learn, and to lead the way in showing how the genetics community rallies together no matter the challenge