Three Newly Recognized Likely Pathogenic Gene Variants Associated with Hereditary Transthyretin Amyloidosis.

Introduction: Hereditary transthyretin amyloidosis (ATTRv [variant]) is a clinically heterogeneous, progressively debilitating, fatal disease resulting from the deposition of insoluble amyloid fibrils in various organs and tissues. Early diagnosis of ATTRv can be facilitated with genetic testing; however, such testing of the TTR gene identifies variants of uncertain significance (VUS) in a minority of cases, a small percentage of which have the potential to be pathogenic. The Akcea/Ambry VUS Initiative is dedicated to gathering molecular, clinical, and inheritance data for each TTR VUS identified by genetic testing programs to reclassify TTR variants to a clinically actionable status (e.

Harmonizing the Collection of Clinical Data on Genetic Testing Requisition Forms to Enhance Variant Interpretation in Hypertrophic Cardiomyopathy (HCM): A Study from the ClinGen Cardiomyopathy Variant Curation Expert Panel.

Diagnostic laboratories gather phenotypic data through requisition forms, but there is no consensus as to which data are essential for variant interpretation. The ClinGen Cardiomyopathy Variant Curation Expert Panel defined a phenotypic data set for hypertrophic cardiomyopathy (HCM) variant interpretation, with the goal of standardizing requisition forms. Phenotypic data elements listed on requisition forms from nine leading cardiomyopathy testing laboratories were compiled to assess divergence in data collection.

Clinical validity assessment of genes for inclusion in multi-gene panel testing: A systematic approach.

Background: Advances in sequencing technology have led to expanded use of multi-gene panel tests (MGPTs) for clinical diagnostics. Well-designed MGPTs must balance increased detection of clinically significant findings while mitigating the increase in variants of uncertain significance (VUS). To maximize clinical utililty, design of such panels should include comprehensive gene vetting using a standardized clinical validity (CV) scoring system.

Next Generation Sequencing of Prenatal Structural Chromosomal Rearrangements Using Large-Insert Libraries.

Precise tests for genomic structural variation (SV) are essential for accurate diagnosis of prenatal genome abnormalities. The two most ubiquitous traditional methods for prenatal SV assessment, karyotyping and chromosomal microarrays, do not provide sufficient resolution for some clinically actionable SVs. Standard whole-genome sequencing (WGS) overcomes shortcomings of traditional techniques by providing base-pair resolution of the entire accessible genome.

MYLK pathogenic variants aortic disease presentation, pregnancy risk, and characterization of pathogenic missense variants.

Purpose: Heritable thoracic aortic disease can result from null variants in MYLK, which encodes myosin light-chain kinase (MLCK). Data on which MYLK missense variants are pathogenic and information to guide aortic disease management are limited.

Methods: Clinical data from 60 cases with MYLK pathogenic variants were analyzed (five null and two missense variants), and the effect of missense variants on kinase activity was assessed.