Conventional Cytogenetic Analysis of Solid Tumor Abnormalities: A 25-Year Review of Proficiency Test Results from the College of American Pathologists/American College of Medical Genetics and Genomics Cytogenetics Committee.

The joint College of American Pathologists/American College of Medical Genetics and Genomics Cytogenetics Committee works to ensure the competency and proficiency of clinical cytogenetic testing laboratories through proficiency testing (PT) programs for various clinical tests offered by such laboratories, including the evaluation of cytogenetic abnormalities in solid tumors. Review and analyze 25 years (1999-2023) of solid tumor chromosome analysis PT results, utilizing G-banded karyograms. A retrospective review of results from 1999 to 2023 was performed, identifying the challenges addressing solid tumors.

Promoter Deletion Leading to Allele Specific Expression in a Genetically Unsolved Case of Primary Ciliary Dyskinesia.

Variation in the non-coding genome represents an understudied mechanism of disease and it remains challenging to predict if single nucleotide variants, small insertions and deletions, or structural variants in non-coding genomic regions will be detrimental. Our approach using complementary RNA-seq and targeted long-read DNA sequencing can prioritize identification of non-coding variants that lead to disease via alteration of gene splicing or expression. We have identified a patient with primary ciliary dyskinesia with a pathogenic coding variant on one allele of the SPAG1 gene, while the second allele appears normal by whole exome sequencing despite an autosomal recessive inheritance pattern.

Conventional Cytogenetic Analysis of Constitutional Abnormalities: A 20-Year Review of Proficiency Test Results From the College of American Pathologists/American College of Medical Genetics and Genomics Cytogenetics Committee.

Context.—: The joint College of American Pathologists/American College of Medical Genetics and Genomics Cytogenetics Committee works to ensure competency and proficiency of clinical cytogenetics testing laboratories through proficiency testing programs for various clinical tests offered by such laboratories, including the evaluation of constitutional abnormalities.

Objective.

Variant Classification for Pompe disease; ACMG/AMP specifications from the ClinGen Lysosomal Diseases Variant Curation Expert Panel.

Accurate determination of the clinical significance of genetic variants is critical to the integration of genomics in medicine. To facilitate this process, the NIH-funded Clinical Genome Resource (ClinGen) has assembled Variant Curation Expert Panels (VCEPs), groups of experts and biocurators which provide gene- and disease- specifications to the American College of Medical Genetics & Genomics and Association for Molecular Pathology's (ACMG/AMP) variation classification guidelines. With the goal of classifying the clinical significance of GAA variants in Pompe disease (Glycogen storage disease, type II), the ClinGen Lysosomal Diseases (LD) VCEP has specified the ACMG/AMP criteria for GAA.

Two years of newborn screening for Duchenne muscular dystrophy as a part of the statewide Early Check research program in North Carolina.

Purpose: Current and emerging treatments for Duchenne muscular dystrophy (DMD) position DMD as a candidate condition for newborn screening (NBS). In anticipation of the nomination of DMD for universal NBS, we conducted a prospective study under the Early Check voluntary NBS research program in North Carolina, United States.

Methods: We performed screening for creatine kinase-MM (CK-MM), a biomarker of muscle damage, on residual routine newborn dried blood spots (DBS) from participating newborns.

ETNK1 mutation occurs in a wide spectrum of myeloid neoplasms and is not specific for atypical chronic myeloid leukemia.

Background: ETNK1 mutation has been suggested as a useful tool to support the diagnosis of atypical chronic myeloid leukemia. ETNK1 mutations, however, occur in other myeloid neoplasms.

Methods: The authors assessed the clinicopathologic and molecular genetic features of 80 ETNK1-mutated myeloid neoplasms.

Development of a clinically validated functional assay to assess pathogenicity of novel variants in patients with Pompe disease identified newborn screening.

The addition of Pompe disease (Glycogen Storage Disease Type II) to the Recommended Uniform Screening Panel in the United States has led to an increase in the number of variants of uncertain significance (VUS) and novel variants identified in the gene. This presents a diagnostic challenge, especially in the setting of late-onset Pompe disease when symptoms are rarely apparent at birth. There is an unmet need for validated functional studies to aid in classification of variants.

Evaluation of the GSP Creatine Kinase-MM Assay and Assessment of CK-MM Stability in Newborn, Patient, and Contrived Dried Blood Spots for Newborn Screening for Duchenne Muscular Dystrophy.

Duchenne Muscular Dystrophy (DMD) is a fatal X-linked disorder with a birth prevalence of 19.8:100,000 males worldwide. Elevated concentration of the muscle enzyme creatine kinase-MM (CK-MM) allows for presymptomatic screening of newborns using Dried Blood Spots (DBS).

Interpretation and reporting of large regions of homozygosity and suspected consanguinity/uniparental disomy, 2021 revision: A technical standard of the American College of Medical Genetics and Genomics (ACMG).

Genomic testing, including single-nucleotide variation (formerly single-nucleotide polymorphism)-based chromosomal microarray and exome and genome sequencing, can detect long regions of homozygosity (ROH) within the genome. Genomic testing can also detect possible uniparental disomy (UPD). Platforms that can detect ROH and possible UPD have matured since the initial American College of Medical Genetics and Genomics (ACMG) standard was published in 2013, and the detection of ROH and UPD by these platforms has shown utility in diagnosis of patients with genetic/genomic disorders.

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma With Secondary Acquisition of t(11;14)(q13;q32)/CCND1-IGH: A Rare Variant Of Richter Transformation to Mantle Cell Lymphoma.

Introduction: Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) occasionally undergoes Richter transformation, mostly to diffuse large B-cell lymphoma, but its evolution to other types of B-cell lymphoma is rare. We report a CLL evolved to mantle cell lymphoma by acquiring t(11;14)(q13;q32); CCND1-IGH.

Method: A Retrospective review of clinical and laboratory data.

Interpretation of Incidental Genetic Findings Localizing to Genes Associated With Cardiac Channelopathies and Cardiomyopathies.

Recent advances in next-genetic sequencing technology have facilitated an expansion in the use of exome and genome sequencing in the research and clinical settings. While this has aided in the genetic diagnosis of individuals with atypical clinical presentations, there has been a marked increase in the number of incidentally identified variants of uncertain diagnostic significance in genes identified as clinically actionable by the American College of Medical Genetics guidelines. Approximately 20 of these genes are associated with cardiac diseases, which carry a significant risk of sudden cardiac death.

Detection of a mosaic CDKL5 deletion and inversion by optical genome mapping ends an exhaustive diagnostic odyssey.

Background: Currently available structural variant (SV) detection methods do not span the complete spectrum of disease-causing SVs. Optical genome mapping (OGM), an emerging technology with the potential to resolve diagnostic dilemmas, was performed to investigate clinically-relevant SVs in a 4-year-old male with an epileptic encephalopathy of undiagnosed molecular origin.

Methods: OGM was utilized to image long, megabase-size DNA molecules, fluorescently labeled at specific sequence motifs throughout the genome with high sensitivity for detection of SVs greater than 500 bp in size.

Next-generation sequencing for constitutional variants in the clinical laboratory, 2021 revision: a technical standard of the American College of Medical Genetics and Genomics (ACMG).

Next-generation sequencing (NGS) technologies are now established in clinical laboratories as a primary testing modality in genomic medicine. These technologies have reduced the cost of large-scale sequencing by several orders of magnitude. It is now cost-effective to analyze an individual with disease-targeted gene panels, exome sequencing, or genome sequencing to assist in the diagnosis of a wide array of clinical scenarios.

Infantile leukemia-What factors determine its distinct biological nature? Clinicopathological study of 78 cases.

Introduction: Infantile leukemia encompasses a heterogeneous group which needs stratifying for treatment selection.

Methods: We collected 78 cases of infantile leukemia and retrospectively analyzed their clinicopathological data.

Results: Infantile leukemia featured a ratio of acute myeloid leukemia (AML) to B-lymphoblastic leukemia (B-ALL) of 1:2, with a better survival for AML than B-ALL (median survival 36 vs 24 months).

A Voluntary Statewide Newborn Screening Pilot for Spinal Muscular Atrophy: Results from Early Check.

Prior to statewide newborn screening (NBS) for spinal muscular atrophy (SMA) in North Carolina, U.S.A.

Variable Genotype-Phenotype Correlation of Pompe's Disease Caused by a c.2015 G > A (p.Arg672Gln) Mutation in the GAA Gene.

Pompe's disease occurs due to an autosomal recessive trait resulting from numerous distinctive mutations in the gene. It manifests as a broad spectrum of clinical phenotypes with progressive weakness that impairs motor and respiratory functions being common for all its forms. Cardiac hypertrophy is a prominent feature of its classic infantile form.

An Unusual Association: Total Anomalous Pulmonary Venous Return and Aortic Arch Obstruction in Patients with Cat Eye Syndrome.

Cat eye syndrome (CES) is a rare genetic defect, characterized by iris colobomas, preauricular skin tags, and anal malformations. Affecting 1 in 150,000 people, this defect is caused by duplication or triplication of the proximal long (q) arm of chromosome 22. Congenital heart disease is associated with CES.

Assessment of an Online Tool to Simulate the Effect of Pooled Testing for SARS-CoV-2 Detection in Asymptomatic and Symptomatic Populations.

This diagnostic study describes an online tool created with actual severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus copy number data to help policy makers understand how pooled testing compares with single-sample testing in different populations.