Genetic evaluation of pediatric pituitary adenomas and USP8-related genotype-phenotype correlations in Cushing's disease.

Purpose: Pituitary adenomas (PAs) constitute a rare pediatric diagnosis and their pathogenetic mechanisms are not clearly understood. The aim of this study was to evaluate the prevalence of genetic defects in pediatric PAs through germline and tumor testing, and to describe genotype-phenotype correlations.

Methods: Fifty-four pediatric patients with PAs and available germline and/or tumor samples were studied.

Further Personalizing Medicine in Immune Disorders: Genomic Findings and Hematopoietic Cell Transplantation Survival.

Background: Hematopoietic cell transplantation (HCT) provides effective long-term management for some inborn errors of immunity. Genetic findings can inform donor selection, considerations in conditioning intensity and agents, and graft-versus-host disease prophylaxis. Exome/genome sequencing is increasingly accessible but of uncertain clinical utility.

Genome Sequencing Uncovers Additional Findings in Phelan-McDermid Syndrome.

Phelan-McDermid syndrome (PMS) is a genetic condition caused by deletions of chromosome 22q13.3 or pathogenic variants in the SHANK3 gene. Neurologic features typically include intellectual disability, autism spectrum disorder, hypotonia, and absent speech, though there is considerable variability even among individuals with the same molecular cause.

Reconstitution of Norovirus-Specific T-Cell Responses Following Hematopoietic Stem Cell Transplantation in Patients With Inborn Errors of Immunity and Chronic Norovirus Infection.

Background: Chronic norovirus infection (CNI) causes significant morbidity in immunocompromised patients. No effective prevention or treatment currently exists.

Methods: Two patients with inborn errors of immunity, X-linked severe combined immunodeficiency (X-SCID) and DOCK8 deficiency, were followed longitudinally for clinical course, immune reconstitution, norovirus-specific T-cell (NST) response, B-cell reconstitution, and norovirus-specific antibody production.

Myotonic dystrophy type 1 testing, 2024 revision: A technical standard of the American College of Medical Genetics and Genomics (ACMG).

Myotonic dystrophy type 1 (DM1) is a form of muscular dystrophy causing progressive muscle loss and weakness. Although clinical features can manifest at any age, it is the most common form of muscular dystrophy with onset in adulthood. DM1 is an autosomal dominant condition, resulting from an unstable CTG expansion in the 3'-untranslated region of the myotonic dystrophy protein kinase (DMPK) gene.

Genetic Risk Factors for Early-Onset Merkel Cell Carcinoma.

Importance: Merkel cell carcinoma (MCC) is a rare, aggressive neuroendocrine skin cancer. Of the patients who develop MCC annually, only 4% are younger than 50 years.

Objective: To identify genetic risk factors for early-onset MCC via genomic sequencing.

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.

The global prevalence and ethnic heterogeneity of primary ciliary dyskinesia gene variants: a genetic database analysis.

Background: Primary ciliary dyskinesia (PCD) is a motile ciliopathy characterised by otosinopulmonary infections. Inheritance is commonly autosomal recessive, with extensive locus and allelic heterogeneity. The prevalence is uncertain.

Chromosomal microarray analysis, including constitutional and neoplastic disease applications, 2021 revision: a technical standard of the American College of Medical Genetics and Genomics (ACMG).

Chromosomal microarray technologies, including array comparative genomic hybridization and single-nucleotide polymorphism array, are widely applied in the diagnostic evaluation for both constitutional and neoplastic disorders. In a constitutional setting, this technology is accepted as the first-tier test for the evaluation of chromosomal imbalances associated with intellectual disability, autism, and/or multiple congenital anomalies. Furthermore, chromosomal microarray analysis is recommended for patients undergoing invasive prenatal diagnosis with one or more major fetal structural abnormalities identified by ultrasonographic examination, and in the evaluation of intrauterine fetal demise or stillbirth when further cytogenetic analysis is desired.

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.

Specifications of the ACMG/AMP variant interpretation guidelines for germline TP53 variants.

Germline pathogenic variants in TP53 are associated with Li-Fraumeni syndrome, a cancer predisposition disorder inherited in an autosomal dominant pattern associated with a high risk of malignancy, including early-onset breast cancers, sarcomas, adrenocortical carcinomas, and brain tumors. Intense cancer surveillance for individuals with TP53 germline pathogenic variants is associated with reduced cancer-related mortality. Accurate and consistent classification of germline variants across clinical and research laboratories is important to ensure appropriate cancer surveillance recommendations.

Evaluating the Clinical Validity of Hypertrophic Cardiomyopathy Genes.

Background: Genetic testing for families with hypertrophic cardiomyopathy (HCM) provides a significant opportunity to improve care. Recent trends to increase gene panel sizes often mean variants in genes with questionable association are reported to patients. Classification of HCM genes and variants is critical, as misclassification can lead to genetic misdiagnosis.

Determining the clinical validity of hereditary colorectal cancer and polyposis susceptibility genes using the Clinical Genome Resource Clinical Validity Framework.

Purpose: Gene-disease associations implicated in hereditary colorectal cancer and polyposis susceptibility were evaluated using the ClinGen Clinical Validity framework.

Methods: Forty-two gene-disease pairs were assessed for strength of evidence supporting an association with hereditary colorectal cancer and/or polyposis. Genetic and experimental evidence supporting each gene-disease relationship was curated independently by two trained biocurators.

Clinical validity assessment of genes frequently tested on hereditary breast and ovarian cancer susceptibility sequencing panels.

Purpose: Several genes on hereditary breast and ovarian cancer susceptibility test panels have not been systematically examined for strength of association with disease. We employed the Clinical Genome Resource (ClinGen) clinical validity framework to assess the strength of evidence between selected genes and breast or ovarian cancer.

Methods: Thirty-one genes offered on cancer panel testing were selected for evaluation.

Whole Exome Sequencing Identifies Truncating Variants in Nuclear Envelope Genes in Patients With Cardiovascular Disease.

Background: The genetic variation underlying many heritable forms of cardiovascular disease is incompletely understood, even in patients with strong family history or early age at onset.

Methods And Results: We used whole exome sequencing to detect pathogenic variants in 55 patients with suspected monogenic forms of cardiovascular disease. Diagnostic analysis of established disease genes identified pathogenic variants in 21.

Evaluating the Clinical Validity of Gene-Disease Associations: An Evidence-Based Framework Developed by the Clinical Genome Resource.

With advances in genomic sequencing technology, the number of reported gene-disease relationships has rapidly expanded. However, the evidence supporting these claims varies widely, confounding accurate evaluation of genomic variation in a clinical setting. Despite the critical need to differentiate clinically valid relationships from less well-substantiated relationships, standard guidelines for such evaluation do not currently exist.