Navigating variants of uncertain significance in genetic dyslipidemia: how to assess and counsel patients.

Purpose Of Review: Genetic testing has become an integral component of clinical care when an inherited condition is suspected. However, the interpretation of variants identified with this testing can be nuanced. Variants of uncertain significance (VUS) are variants for which there is not enough data currently available to determine if the variant is causal for disease (i.

Performance of Dysmorphology-Based Screening for Genetic Disorders in Pediatric Congenital Heart Disease Supports Wider Genetic Testing.

Background: Dysmorphology evaluation is important for congenital heart disease (CHD) assessment, but there are no prior investigations quantifying the screening performance compared to standardized genetics evaluations. We investigated this through systematic dysmorphology assessment in CHD patients with standardized genetic testing in primarily pediatric patients with CHD.

Methods: Dysmorphology evaluations preceding genetic testing results allowed us to test for associations between dysmorphic status and genetic diagnoses while adjusting for extracardiac anomalies (ECAs).

Clinical Decision Analysis of Genetic Evaluation and Testing in 1013 Intensive Care Unit Infants with Congenital Heart Defects Supports Universal Genetic Testing.

Extracardiac anomalies (ECAs) are strong predictors of genetic disorders in infants with congenital heart disease (CHD), but there are no prior studies assessing performance of ECA status as a screen for genetic diagnoses in CHD patients. This retrospective cohort study assessed this in our comprehensive inpatient CHD genetics service focusing on neonates and infants admitted to the intensive care unit (ICU). The performance and diagnostic utility of using ECA status to screen for genetic disorders was assessed using decision curve analysis, a statistical tool to assess clinical utility, determining the threshold of phenotypic screening by ECA versus a Test-All approach.

Rapid Genome Sequencing Shows Diagnostic Utility In Infants With Congenital Heart Defects.

Congenital heart disease (CHD) is the most common birth defect and a leading cause of infant mortality. CHD often has a genetic etiology and recent studies demonstrate utility in genetic testing. In clinical practice, decisions around genetic testing choices continue to evolve, and the incorporation of rapid genome sequencing (rGS) in CHD has not been well studied.

Heterozygous loss-of-function SMC3 variants are associated with variable growth and developmental features.

Heterozygous missense variants and in-frame indels in SMC3 are a cause of Cornelia de Lange syndrome (CdLS), marked by intellectual disability, growth deficiency, and dysmorphism, via an apparent dominant-negative mechanism. However, the spectrum of manifestations associated with SMC3 loss-of-function variants has not been reported, leading to hypotheses of alternative phenotypes or even developmental lethality. We used matchmaking servers, patient registries, and other resources to identify individuals with heterozygous, predicted loss-of-function (pLoF) variants in SMC3, and analyzed population databases to characterize mutational intolerance in this gene.

Effects of hypermobile Ehlers-Danlos syndrome patients on the workflow and professional satisfaction of genetic counselors.

The Ehlers-Danlos syndromes (EDS), a group of uncommon connective tissue disorders, are, paradoxically, an increasingly common referral to genetics specialists. Of the 13 types of EDS, the most common is hypermobile EDS (hEDS), which lacks a known genetic etiology and for which diagnosis is achieved via a robust set of clinical criteria. While previous investigations have characterized many clinical aspects of EDS as a syndrome and patients' lived experiences, a gap in the literature exists regarding clinicians' experience caring for these individuals.

Genetic counselors and congenital heart disease: Clinical roles, genetic testing practices, and perceived genetic testing utility.

Genetic counseling and genetic testing are essential for individuals with congenital heart disease/defects (CHD/CHDs). However, the clinical practices of genetic counselors (GCs) and their preferences for different CHD genetic testing strategies are previously unexplored. To address these gaps, GCs (n = 112) representing diverse specialties completed an online survey regarding their counseling and testing practices for syndromic CHD and apparently isolated/non-syndromic CHDs (iCHD).

Heterozygous loss-of-function variants are associated with variable and incompletely penetrant growth and developmental features.

Heterozygous missense variants and in-frame indels in are a cause of Cornelia de Lange syndrome (CdLS), marked by intellectual disability, growth deficiency, and dysmorphism, via an apparent dominant-negative mechanism. However, the spectrum of manifestations associated with loss-of-function variants has not been reported, leading to hypotheses of alternative phenotypes or even developmental lethality. We used matchmaking servers, patient registries, and other resources to identify individuals with heterozygous, predicted loss-of-function (pLoF) variants in , and analyzed population databases to characterize mutational intolerance in this gene.

Novel variant associated with congenital heart disease and increased risk of malignant arrhythmia and sudden cardiac death.

Introduction: The NKX2.5 gene is an important cardiac developmental transcription factor, and variants in this gene are most commonly associated with CHD. However, there is an increased need to recognise associations with conduction disease and potentially dangerous ventricular arrhythmias.

Disruption of FBN1 by an Alu element insertion: A novel genetic cause of Marfan syndrome.

Alu elements are retrotransposons with ubiquitous presence in the human genome that have contributed to human genomic diversity and health. These approximately 300-bp sequences can cause or mediate disease by disrupting coding/splicing regions in the germline, by insertional mutagenesis in somatic cells, and in promoting formation of copy-number variants. Alu elements may also disrupt epigenetic regulation by affecting non-coding regulatory regions.

Genetic Testing Guidelines Impact Care in Newborns with Congenital Heart Defects.

Objective: To evaluate genetic evaluation practices in newborns with the most common birth defect, congenital heart defects (CHD), we determined the prevalence and the yield of genetic evaluation across time and across patient subtypes, before and after implementation of institutional genetic testing guidelines.

Study Design: This was a retrospective, cross-sectional study of 664 hospitalized newborns with CHD using multivariate analyses of genetic evaluation practices across time and patient subtypes.

Results: Genetic testing guidelines for hospitalized newborns with CHD were implemented in 2014, and subsequently genetic testing increased (40% in 2013 and 75% in 2018, OR 5.

Congenital heart defects caused by FOXJ1.

FOXJ1 is expressed in ciliated cells of the airways, testis, oviduct, central nervous system and the embryonic left-right organizer. Ablation or targeted mutation of Foxj1 in mice, zebrafish and frogs results in loss of ciliary motility and/or reduced length and number of motile cilia, affecting the establishment of the left-right axis. In humans, heterozygous pathogenic variants in FOXJ1 cause ciliopathy leading to situs inversus, obstructive hydrocephalus and chronic airway disease.

A multicenter cross-sectional study in infants with congenital heart defects demonstrates high diagnostic yield of genetic testing but variable evaluation practices.

Purpose: For patients with congenital heart disease (CHD), the most common birth defect, genetic evaluation is not universally accepted, and current practices are anecdotal. Here, we analyzed genetic evaluation practices across centers, determined diagnostic yield of testing, and identified phenotypic features associated with abnormal results.

Methods: This is a multicenter cross-sectional study of 5 large children's hospitals, including 2899 children ≤14 months undergoing surgical repair for CHD from 2013 to 2016, followed by multivariate logistics regression analysis.

Sleep Apnea in Children With Down Syndrome.

Objective: The authors of this study aimed to evaluate the use of polysomnography (PSG) in children with Down syndrome (DS) between ages 0 and 7 years, to assess the prevalence and severity of obstructive sleep apnea (OSA) and associated comorbidities, and to describe interventions used for OSA.

Methods: A retrospective cohort study was performed at Cincinnati Children's Hospital Medical Center for children with DS born between 2013 and 2019. Data were extracted from the electronic medical record, including demographics, age at PSG, PSG results, and interventions after an abnormal PSG.

Clinical genetic counseling and translation considerations for polygenic scores in personalized risk assessments: A Practice Resource from the National Society of Genetic Counselors.

Polygenic scores (PGS) are primed for use in personalized risk assessments for common, complex conditions and population health screening. Although there is growing evidence supporting the clinical validity of these scores in certain diseases, presently, there is no consensus on best practices for constructing PGS or demonstrated clinical utility in practice. Despite these evidence gaps, individuals can access their PGS information through commercial entities, research programs, and clinical programs.

Characterization of a novel deep-intronic variant in identified by whole-exome sequencing in a patient with a lethal form of a short-rib thoracic dysplasia type III.

Biallelic pathogenic variants in are the cause of short-rib thoracic dysplasia type III with or without polydactyly (OMIM #613091), a skeletal ciliopathy characterized by thoracic hypoplasia due to short ribs. In this report, we review the case of a patient who was admitted to the Neonatal Intensive Care Unit (NICU) of Indiana University Health (IUH) for respiratory support after experiencing respiratory distress secondary to a small, narrow chest causing restrictive lung disease. Additional phenotypic features include postaxial polydactyly, short proximal long bones, and ambiguous genitalia were noted.

A descriptive investigation of clinical practice models used by cardiovascular genetic counselors in North America.

Cardiovascular genetic counseling has expanded as an established genetic counseling specialty over the last 20 years. Despite guidelines recommending genetic counseling for heritable cardiac diseases, there have been limited descriptions of the practice model types used for different clinical indications seen in this genetic counseling subspecialty. We aimed to describe current clinical practice models used by cardiovascular genetic counselors and to document practice model strengths, challenges, and areas for improvement.

Learning to Crawl: Determining the Role of Genetic Abnormalities on Postoperative Outcomes in Congenital Heart Disease.

Background Our cardiac center established a systematic approach for inpatient cardiovascular genetics evaluations of infants with congenital heart disease, including routine chromosomal microarray (CMA) testing. This provides a new opportunity to investigate correlation between genetic abnormalities and postoperative course. Methods and Results Infants who underwent congenital heart disease surgery as neonates (aged ≤28 days) from 2015 to 2020 were identified.

Missense variants in ANKRD11 cause KBG syndrome by impairment of stability or transcriptional activity of the encoded protein.

Purpose: Although haploinsufficiency of ANKRD11 is among the most common genetic causes of neurodevelopmental disorders, the role of rare ANKRD11 missense variation remains unclear. We characterized clinical, molecular, and functional spectra of ANKRD11 missense variants.

Methods: We collected clinical information of individuals with ANKRD11 missense variants and evaluated phenotypic fit to KBG syndrome.

Comparison of willingness and preference for genetic counseling via telemedicine: before vs. during the COVID-19 pandemic.

The COVID-19 pandemic required genetic counseling services, like most outpatient healthcare, to rapidly adopt a telemedicine model. Understanding the trends in patients' preferences for telemedicine relative to in-person service delivery both before and after the advent of the COVID-19 pandemic may aid in navigating how best to integrate telemedicine in a post-COVID-19 era. Our study explored how respondents' willingness to use, and preference for, telemedicine differed from before to after the onset of the COVID-19 pandemic.

Reanalysis of a novel variant in the gene in a family with variable prenatal and postnatal growth retardation and dysmorphic features: benefits and feasibility of IUSM-URDC (Undiagnosed Rare Disease Clinic) program.

-related disorders are associated with intrauterine growth restriction (IUGR), postnatal growth failure, short stature, microcephaly, developmental delay, and dysmorphic facial features. We report a patient who presented to medical genetics at 7 mo of age with a history of IUGR, poor feeding, mild developmental delays, microcephaly, and dysmorphic facial features. Whole-exome sequencing revealed a novel c.

Assessing genetic counselors' graduate school education and training in congenital heart defects.

Genetic counselors are one of the many providers involved in caring for patients with congenital heart defects (CHDs); however, little is known about the cardiovascular genetics training they receive by their graduate programs. To explore the recalled education experiences regarding CHDs by practicing genetic counselors, we surveyed graduates of programs primarily accredited by the American Council on Genetic Counseling (ACGC) about their graduate training in this area, the depth of CHD-specific education they received, and whether CHDs are a substantial referral indication in their current practice. Genetic counselors were recruited from the National Society of Genetic Counselors and Twitter (n = 112), and participants reflecting multiple specialties and 35 graduate programs completed an online survey which included questions about fieldwork placements and lectures in cardiovascular genetics, exposure to classification schemes regarding cardiac embryology, and education in counseling strategies for CHDs and CHD-related topics during their graduate training.

Management of amended variant classification laboratory reports by genetic counselors in the United States and Canada: An exploratory study.

For the past two decades, the guidelines put forth by the American College of Medical Genetics and Genomics (ACMG) detailing providers' clinical responsibility to recontact patients have remained mostly unchanged, despite evolving variant interpretation practices which have yielded substantial rates of reclassification and amended reports. In fact, there is little information regarding genetic counselors' roles in informing patients of reclassified variants, or the process by which these amended reports are currently being handled. In this study, we developed a survey to measure current experiences with amended variant reports and preferences for ideal management, which was completed by 96 genetic counselors from the United States and Canada.