Monoallelic de novo variants in DDX17 cause a neurodevelopmental disorder.

DDX17 is an RNA helicase shown to be involved in critical processes during the early phases of neuronal differentiation. Globally, we compiled a case-series of 11 patients with neurodevelopmental phenotypes harbouring de novo monoallelic variants in DDX17. All 11 patients in our case series had a neurodevelopmental phenotype, whereby intellectual disability, delayed speech and language, and motor delay predominated.

The challenges and opportunities of offering and integrating training in clinical molecular genetics and clinical cytogenetics: A survey of LGG Fellowship Program Directors.

Purpose: The specialty of Laboratory Genetics and Genomics (LGG) was created in 2017 in an effort to reflect the increasing convergence in technologies and approaches between clinical molecular genetics and clinical cytogenetics. However, there has not yet been any formal evaluation of the merging of these disciplines and the challenges faced by Program Directors (PDs) tasked with ensuring the successful training of laboratory geneticists under the new model.

Methods: An electronic multi-question Qualtrics survey was created and was sent to the PD for each of the Accreditation Council for Graduate Medical Education-accredited LGG fellowship programs at the time.

Microarray-Based DNA Methylation Profiling: Validation Considerations for Clinical Testing.

Microarray-based methylation profiling has emerged as a valuable tool for refining diagnoses and revealing novel tumor subtypes, particularly in central nervous system tumors. Despite the increasing adoption of this technique in clinical genomic laboratories, no technical standards have been published in establishing minimum criteria for test validation. A working group with experience and expertise in DNA-based methylation profiling tests on central nervous system tumors collaborated to develop practical discussion points and focus on important considerations for validating this test in clinical laboratory settings.

Biallelic variants in HTRA2 cause 3-methylglutaconic aciduria mitochondrial disorder: case report and literature review.

Leigh syndrome is a rare, genetic, and severe mitochondrial disorder characterized by neuromuscular issues (ataxia, seizure, hypotonia, developmental delay, dystonia) and ocular abnormalities (nystagmus, atrophy, strabismus, ptosis). It is caused by pathogenic variants in either mitochondrial or nuclear DNA genes, with an estimated incidence rate of 1 per 40,000 live births. Herein, we present an infant male with nystagmus, hypotonia, and developmental delay who carried a clinical diagnosis of Leigh-like syndrome.

Exome sequencing in the pediatric neuromuscular clinic leads to more frequent diagnosis of both neuromuscular and neurodevelopmental conditions.

Introduction/aims: Exome sequencing (ES) has proven to be a valuable diagnostic tool for neuromuscular disorders, which often pose a diagnostic challenge. The aims of this study were to investigate the clinical outcomes associated with utilization of ES in the pediatric neuromuscular clinic and to determine if specific phenotypic features or abnormal neurodiagnostic tests were predictive of a diagnostic result.

Methods: This was a retrospective medical record review of 76 pediatric neuromuscular clinic patients who underwent ES.

Enhancing the didactic learning experience for Laboratory Genetics and Genomics fellows through a multi-institutional lecture series.

As a result of the pandemic, the traditional in-person didactic lecture model was adapted to a virtual learning approach. Our Laboratory Genetics and Genomics fellowship program at Nationwide Children's hospital took advantage of this opportunity to organize a multi-institutional Fellow's Conference to educate fellows from different programs on a wide range of medical genetics topics. We describe our approach of developing this lecture series utilizing subject-matter experts across institutions.

Dominant-negative variants in CBX1 cause a neurodevelopmental disorder.

Purpose: This study aimed to establish variants in CBX1, encoding heterochromatin protein 1β (HP1β), as a cause of a novel syndromic neurodevelopmental disorder.

Methods: Patients with CBX1 variants were identified, and clinician researchers were connected using GeneMatcher and physician referrals. Clinical histories were collected from each patient.

Exploring current challenges in the technologist workforce of clinical genomics laboratories.

Purpose: Workforce shortages are observed in many sectors of the economy, including clinical genomics laboratories. Although medical technologists are essential for the primary functions of laboratory operations and many institutions in the United States have reported acute staff shortages, we are unaware of any recent studies that provide concrete data detailing workforce needs. In this report, we summarize the results of a technologist-based survey sent to clinical laboratory directors across the United States.

Molecular characterization of an intronic RNASEH2B variant in a patient with Aicardi-Goutières syndrome.

Aicardi-Goutières syndrome (AGS) is a progressive multisystem disorder including encephalopathy with significant impacts on intellectual and physical abilities. An early diagnosis is becoming ever more crucial, as targeted therapies are emerging. A deep understanding of the molecular heterogeneity of AGS can help guide the early diagnosis and clinical management of patients, and inform recurrence risks.

A Decade's Experience in Pediatric Chromosomal Microarray Reveals Distinct Characteristics Across Ordering Specialties.

Chromosomal microarray (CMA) is a testing modality frequently used in pediatric patients; however, published data on its utilization are limited to the genetic setting. We performed a database search for all CMA testing performed from 2010 to 2020, and delineated the diagnostic yield based on patient characteristics, including sex, age, clinical specialty of providers, indication of testing, and pathogenic finding. The indications for testing were further categorized into Human Phenotype Ontology categories for analysis.

Exome sequencing identifies PD-L2 as a potential predisposition gene for lymphoma.

To investigate germline predisposition in lymphoma, we performed whole-exome sequencing and discovered a novel variant (c.817-1G>T) in programmed cell death 1 ligand 2 (PD-L2) in a family with early-onset lymphomas and other cancers. The variant was present in the proband with follicular lymphoma and his son with Hodgkin's lymphoma.

Systematic evidence-based review: The application of noninvasive prenatal screening using cell-free DNA in general-risk pregnancies.

Purpose: Noninvasive prenatal screening (NIPS) using cell-free DNA has been assimilated into prenatal care. Prior studies examined clinical validity and technical performance in high-risk populations. This systematic evidence review evaluates NIPS performance in a general-risk population.

A Framework of Critical Considerations in Clinical Exome Reanalyses by Clinical and Laboratory Standards Institute.

Exome reanalysis is useful for providing molecular diagnoses for previously uninformative samples. However, challenges exist in implementing a practical solution for clinicians and laboratories. This study complements the current literature by providing practical considerations for patient-level and cohort-level reanalyses.

Clinical Exome Reanalysis: Current Practice and Beyond.

Novel gene-disease discoveries, rapid advancements in technology, and improved bioinformatics tools all have the potential to yield additional molecular diagnoses through the reanalysis of exome sequencing data. Collaborations between clinical laboratories, ordering physicians, and researchers are also driving factors that can contribute to these new insights. Automation in ongoing natural history collection, evolving phenotype updates, advancements in processing next-generation sequencing data, and up-to-date variant-gene-disease databases are increasingly needed for systematic exome reanalysis.

A Transparent Approach to Calculate Detection Rate and Residual Risk for Carrier Screening.

Carrier screening involves detection of carrier status for genes associated with recessive conditions. A negative carrier screening test result bears a nonzero residual risk (RR) for the individual to have an affected child. The RR depends on the prevalence of specific conditions and the detection rate (DR) of the test itself.

Transient commensal clonal interactions can drive tumor metastasis.

The extent and importance of functional heterogeneity and crosstalk between tumor cells is poorly understood. Here, we describe the generation of clonal populations from a patient-derived ovarian clear cell carcinoma model which forms malignant ascites and solid peritoneal tumors upon intraperitoneal transplantation in mice. The clonal populations are engineered with secreted Gaussia luciferase to monitor tumor growth dynamics and tagged with a unique DNA barcode to track their fate in multiclonal mixtures during tumor progression.

Evaluating sequence data quality from the Swift Accel-Amplicon CFTR Panel.

Cystic fibrosis (CF) is one of the most common genetic diseases worldwide with high carrier frequencies across different ethnicities. Next generation sequencing of the cystic fibrosis transmembrane conductance regulator (CFTR) gene has proven to be an effective screening tool to determine carrier status with high detection rates. Here, we evaluate the performance of the Swift Biosciences Accel-Amplicon CFTR Capture Panel using CFTR-positive DNA samples.

Looking beyond the exome: a phenotype-first approach to molecular diagnostic resolution in rare and undiagnosed diseases.

PurposeTo describe examples of missed pathogenic variants on whole-exome sequencing (WES) and the importance of deep phenotyping for further diagnostic testing.MethodsGuided by phenotypic information, three children with negative WES underwent targeted single-gene testing.ResultsIndividual 1 had a clinical diagnosis consistent with infantile systemic hyalinosis, although WES and a next-generation sequencing (NGS)-based ANTXR2 test were negative.

Single-cell DNA sequencing reveals a late-dissemination model in metastatic colorectal cancer.

Metastasis is a complex biological process that has been difficult to delineate in human colorectal cancer (CRC) patients. A major obstacle in understanding metastatic lineages is the extensive intra-tumor heterogeneity at the primary and metastatic tumor sites. To address this problem, we developed a highly multiplexed single-cell DNA sequencing approach to trace the metastatic lineages of two CRC patients with matched liver metastases.