Analysis of financial barriers experienced by prospective genetic counseling students.

Purpose: High costs of applying to genetic counseling graduate programs (GCGPs) are likely a barrier to workforce diversification. We sought to determine application costs and assess differences between individuals of historically underrepresented racial and ethnic backgrounds in medicine (hURM) and non-hURM applicants.

Methods: Applicants to GCGPs between 2005 to 2020 were surveyed about application history, related expenses, volunteer hours, and financial resources; 383 responses were analyzed.

Mono- and Biallelic Protein-Truncating Variants in Alpha-Actinin 2 Cause Cardiomyopathy Through Distinct Mechanisms.

Background: ACTN2 (alpha-actinin 2) anchors actin within cardiac sarcomeres. The mechanisms linking mutations to myocardial disease phenotypes are unknown. Here, we characterize patients with novel mutations to reveal insights into the physiological function of ACTN2.

An assessment of the role of vinculin loss of function variants in inherited cardiomyopathy.

The ACMG/AMP variant classification framework was intended for highly penetrant Mendelian conditions. While it is appreciated that clinically relevant variants exhibit a wide spectrum of penetrance, accurately assessing and expressing the pathogenicity of variants with lower penetrance can be challenging. The vinculin (VCL) gene illustrates these challenges.

Summary report of the 2019 Diversity and Inclusion Task Force of the National Society of Genetic Counselors.

The size and reach of the genetic counseling profession have expanded on a global scale since the 1970s. Despite this growth, the profession of genetic counseling has remained demographically homogenous. Promoting a culture of inclusivity that supports visible and invisible diversity and leveraging that culture not only expands perspectives represented in the field, but also helps foster equity in genetic services.

Variant Interpretation for Dilated Cardiomyopathy: Refinement of the American College of Medical Genetics and Genomics/ClinGen Guidelines for the DCM Precision Medicine Study.

Background: The hypothesis of the Dilated Cardiomyopathy Precision Medicine Study is that most dilated cardiomyopathy has a genetic basis. The study returns results to probands and, when indicated, to relatives. While both the American College of Medical Genetics and Genomics/Association for Molecular Pathology and ClinGen's -cardiomyopathy specifications provide relevant guidance for variant interpretation, further gene- and disease-specific considerations were required for dilated cardiomyopathy.

A Person-Centered Approach to Cardiovascular Genetic Testing.

Cardiovascular genetic counselors provide guidance to people facing the reality or prospect of inherited cardiovascular conditions. Key activities in this role include discussing clinical cardiac screening for at-risk family members and offering genetic testing. Psychological factors often influence whether patients choose to have genetic testing and how they understand and communicate the results to at-risk relatives, so psychological counseling increases the impact of genetic education and medical recommendations.

Clinically impactful differences in variant interpretation between clinicians and testing laboratories: a single-center experience.

PurposeTo describe the frequency and nature of differences in variant classifications between clinicians and genetic testing laboratories.MethodsRetrospective review of variants identified through genetic testing ordered in routine clinical care by clinicians in the Stanford Center for Inherited Cardiovascular Disease. We compared classifications made by clinicians, the testing laboratory, and other laboratories in ClinVar.

De novo truncating variants in the AHDC1 gene encoding the AT-hook DNA-binding motif-containing protein 1 are associated with intellectual disability and developmental delay.

Whole-exome sequencing (WES) represents a significant breakthrough in clinical genetics, and identifies a genetic etiology in up to 30% of cases of intellectual disability (ID). Using WES, we identified seven unrelated patients with a similar clinical phenotype of severe intellectual disability or neurodevelopmental delay who were all heterozygous for de novo truncating variants in the AT-hook DNA-binding motif-containing protein 1 (AHDC1). The patients were all minimally verbal or nonverbal and had variable neurological problems including spastic quadriplegia, ataxia, nystagmus, seizures, autism, and self-injurious behaviors.

Impaired Health-Related Quality of Life in Children and Families Affected by Methylmalonic Acidemia.

An understanding of health related quality of life (HRQoL) in children and families affected by methylmalonic acidemia (MMA) is important in planning counseling and therapeutic intervention. Liver transplantation (LT) is used as a treatment for MMA; however, its risks and benefits continue to be investigated. The purpose of this study was twofold: (1) to measure HRQoL in children and families affected by MMA using the Pediatric Quality of Life Inventory (PedsQL™) parent version, and (2) to assess the impact of LT on HRQoL by comparing LT and non-LT patient scores and free responses.

Mutations in NGLY1 cause an inherited disorder of the endoplasmic reticulum-associated degradation pathway.

Purpose: The endoplasmic reticulum-associated degradation pathway is responsible for the translocation of misfolded proteins across the endoplasmic reticulum membrane into the cytosol for subsequent degradation by the proteasome. To define the phenotype associated with a novel inherited disorder of cytosolic endoplasmic reticulum-associated degradation pathway dysfunction, we studied a series of eight patients with deficiency of N-glycanase 1.

Methods: Whole-genome, whole-exome, or standard Sanger sequencing techniques were employed.

Clinical whole-exome sequencing: are we there yet?

Background: Clinical laboratories began offering whole-exome sequencing in 2011 at a cost between $4,500 and $9,000. Reported detection rates for deleterious mutations range from 25 to 50%. Based on the experience of our clinical genetics service, actual success rates may be lower than estimated rates.

Points to consider in the clinical use of NGS panels for mitochondrial disease: an analysis of gene inclusion and consent forms.

Mitochondrial next generation sequencing (NGS) panels offer single-step analysis of the numerous nuclear genes involved in the structure, function, and maintenance of mitochondria. However, the complexities of mitochondrial biology and genetics raise points for consideration in clinical use of these tests. To understand the current status of mitochondrial genetic testing, we assessed the gene offerings and consent forms of mitochondrial NGS panels available from seven US-based clinical laboratories.

Severity of cardiomyopathy associated with adenine nucleotide translocator-1 deficiency correlates with mtDNA haplogroup.

Mutations of both nuclear and mitochondrial DNA (mtDNA)-encoded mitochondrial proteins can cause cardiomyopathy associated with mitochondrial dysfunction. Hence, the cardiac phenotype of nuclear DNA mitochondrial mutations might be modulated by mtDNA variation. We studied a 13-generation Mennonite pedigree with autosomal recessive myopathy and cardiomyopathy due to an SLC25A4 frameshift null mutation (c.

Intrafamilial variability for novel TAZ gene mutation: Barth syndrome with dilated cardiomyopathy and heart failure in an infant and left ventricular noncompaction in his great-uncle.

Background: The tafazzin gene (TAZ) is located at Xq28 and encodes a protein involved in the transacylation of cardiolipin, an essential mitochondrial phospholipid. Mutations in TAZ are associated with Barth syndrome (BTHS), the X-linked recessive condition with dilated cardiomyopathy, skeletal myopathy, growth retardation, neutropenia and organic aciduria. TAZ mutations also contribute to left ventricular noncompaction (LVNC), a cardiomyopathy characterized by loose, trabeculated myocardium.

Mitochondrial DNA variant associated with Leber hereditary optic neuropathy and high-altitude Tibetans.

The distinction between mild pathogenic mtDNA mutations and population polymorphisms can be ambiguous because both are homoplasmic, alter conserved functions, and correlate with disease. One possible explanation for this ambiguity is that the same variant may have different consequences in different contexts. The NADH dehydrogenase subunit 1 (ND1) nucleotide 3394 T > C (Y30H) variant is such a case.

Leigh syndrome caused by a novel m.4296G>A mutation in mitochondrial tRNA isoleucine.

Leigh syndrome is a severe neurodegenerative disease with heterogeneous genetic etiology. We report a novel m.4296G>A variant in the mitochondrial tRNA isoleucine gene in a child with Leigh syndrome, mitochondrial proliferation, lactic acidosis, and abnormal respiratory chain enzymology.