Phenotype driven molecular genetic test recommendation for diagnosing pediatric rare disorders.

Patients with rare diseases often experience prolonged diagnostic delays. Ordering appropriate genetic tests is crucial yet challenging, especially for general pediatricians without genetic expertise. Recent American College of Medical Genetics (ACMG) guidelines embrace early use of exome sequencing (ES) or genome sequencing (GS) for conditions like congenital anomalies or developmental delays while still recommend gene panels for patients exhibiting strong manifestations of a specific disease.

Assessing management practices for variants of uncertain significance among genetic counselors in pediatrics.

Increased utilization of genomic sequencing in pediatric medicine has increased the detection of variants of uncertain significance (VUS). Periodic VUS reinterpretation can clarify clinical significance and increase diagnostic yield, highlighting the importance of systematic VUS tracking and reinterpretation. There are currently no standardized guidelines or established best practices for VUS management, and our understanding of how genetic counselors (GCs) track and manage VUS results for pediatric patients is limited.

Exploring the evolving roles of clinical geneticists and genetic counselors in the era of genomic medicine.

The increased utilization of clinical genomic sequencing in the past decade has ushered in the era of genomic medicine, requiring genetics providers to acquire new skills and adapt their practices. The change in workplace responsibilities of clinical/medical geneticists (CMGs) and genetic counselors (GCs) in North America, due to the evolution of genetic testing, has not been studied. We surveyed CMGs (n = 80) and GCs (n = 127) with experience in general/pediatric genetics to describe their current practice of clinical tasks and the change in regularity of performing these tasks over the past 5-10 years.

Genetic counselors' utilization of ChatGPT in professional practice: A cross-sectional study.

Purpose: The precision medicine era has seen increased utilization of artificial intelligence (AI) in the field of genetics. We sought to explore the ways that genetic counselors (GCs) currently use the publicly accessible AI tool Chat Generative Pre-trained Transformer (ChatGPT) in their work.

Methods: GCs in North America were surveyed about how ChatGPT is used in different aspects of their work.

Phenotype-Driven Molecular Genetic Test Recommendation for Diagnosing Pediatric Rare Disorders.

Rare disease patients often endure prolonged diagnostic odysseys and may still remain undiagnosed for years. Selecting the appropriate genetic tests is crucial to lead to timely diagnosis. Phenotypic features offer great potential for aiding genomic diagnosis in rare disease cases.

Future Frontiers: Exploration of practices, challenges, and educational needs of genetic counselors in emerging subspecialties.

The augmented use of genomic testing across different medical subspecialties has led to increased involvement of genetic counselors (GCs) in specialized areas of medicine. However, the lack of educational infrastructure required for changing scholastic needs of GCs entering new subspecialties lends to the burden of self-directed learning and inconsistent knowledge. We conducted a cross-sectional study surveying GCs with experience in the emerging genetic subspecialties of Immunology, Dermatology, Endocrinology, and Pulmonology (abbreviated as "IDEP") on current practices, clinical challenges, and educational strategies undertaken while working in these settings.

Delineation of a KDM2B-related neurodevelopmental disorder and its associated DNA methylation signature.

Purpose: Pathogenic variants in genes involved in the epigenetic machinery are an emerging cause of neurodevelopment disorders (NDDs). Lysine-demethylase 2B (KDM2B) encodes an epigenetic regulator and mouse models suggest an important role during development. We set out to determine whether KDM2B variants are associated with NDD.

A novel biallelic loss-of-function variant in causes heterotaxy syndrome.

The majority of heterotaxy cases do not obtain a molecular diagnosis, although pathogenic variants in more than 50 genes are known to cause heterotaxy. A heterozygous missense variant in , a nodal inhibitor, which functions in early development for establishment of right-left patterning, has been implicated in heterotaxy. Recently, the first case was reported of a biallelic loss-of-function (LoF) variant in an individual with heterotaxy.

Assessment of the beliefs, needs, and expectations for genetic counseling of patients with hypermobile Ehlers-Danlos syndrome.

Ehlers-Danlos syndrome, hypermobility type (hEDS) is a heritable connective tissue disorder that currently does not have a known molecular etiology. Previous studies have explored the complex symptomology, clinical diagnosis, and psychological aspects of hEDS. Genetics providers currently aid in the diagnosis and management guidance of patients with hEDS, but there is limited data describing the needs and expectations of individuals with hEDS from a clinical genetics appointment.

Erratum: Identification and validation of candidate risk genes in endocytic vesicular trafficking associated with esophageal atresia and tracheoesophageal fistulas.

[This corrects the article DOI: 10.1016/j.xhgg.

Identification and validation of candidate risk genes in endocytic vesicular trafficking associated with esophageal atresia and tracheoesophageal fistulas.

Esophageal atresias/tracheoesophageal fistulas (EA/TEF) are rare congenital anomalies caused by aberrant development of the foregut. Previous studies indicate that rare or genetic variants significantly contribute to EA/TEF risk, and most individuals with EA/TEF do not have pathogenic genetic variants in established risk genes. To identify the genetic contributions to EA/TEF, we performed whole genome sequencing of 185 trios (probands and parents) with EA/TEF, including 59 isolated and 126 complex cases with additional congenital anomalies and/or neurodevelopmental disorders.

Clinical genetic counselor experience in the adoption of telehealth in the United States and Canada during the COVID-19 pandemic.

The COVID-19 pandemic has significantly impacted the service delivery model (SDM) of clinical genetic counseling across the United States and Canada. A cross-sectional survey was distributed to 4,956 genetic counselors (GCs) from the American Board of Genetic Counselors and Canadian Association of Genetic Counselors mailing lists in August 2020 to assess the change in utilization of telehealth for clinical genetic counseling during the COVID-19 pandemic compared with prior to the pandemic. Data from 411 eligible clinical genetic counselors on GC attitudes and their experiences prior to and during the pandemic were collected and analyzed to explore the change in SDM, change in appointment characteristics, change in billing practices, GC perceived benefits and limitations of telehealth, and prediction of future trends in SDM in the post-pandemic era.

PPA2-associated sudden cardiac death: extending the clinical and allelic spectrum in 20 new families.

Purpose: Biallelic hypomorphic variants in PPA2, encoding the mitochondrial inorganic pyrophosphatase 2 protein, have been recently identified in individuals presenting with sudden cardiac death, occasionally triggered by alcohol intake or a viral infection. Here we report 20 new families harboring PPA2 variants.

Methods: Synthesis of clinical and molecular data concerning 34 individuals harboring five previously reported PPA2 variants and 12 novel variants, 11 of which were functionally characterized.

COVID contingencies: Early epicenter experiences of different genetics clinics at a New York City institution inform emergency adaptation strategies.

The unique situational challenges of the COVID-19 pandemic have demanded creative modifications to the delivery of genetic services. Institutions across the country have adapted workflows to continue to provide quality care while minimizing the need for physical visits. As the first epicenter of the pandemic in the country, New York City healthcare workers and residents had to make rapid, unprecedented changes to their way of life.

A novel homozygous variant in results in a neurodevelopmental disorder and disrupts TRAPP complex function.

Background: Next-generation sequencing has facilitated the diagnosis of neurodevelopmental disorders with variable and non-specific clinical findings. Recently, a homozygous missense p.(Asp37Tyr) variant in a core subunit of TRAPP complexes which function as tethering factors during membrane trafficking, was reported in two unrelated individuals with neurodevelopmental delay, post-infectious encephalopathy-associated developmental arrest, tetraplegia and accompanying rhabdomyolysis.

Novel candidate genes in esophageal atresia/tracheoesophageal fistula identified by exome sequencing.

The various malformations of the aerodigestive tract collectively known as esophageal atresia/tracheoesophageal fistula (EA/TEF) constitute a rare group of birth defects of largely unknown etiology. Previous studies have identified a small number of rare genetic variants causing syndromes associated with EA/TEF. We performed a pilot exome sequencing study of 45 unrelated simplex trios (probands and parents) with EA/TEF.

Bi-allelic missense disease-causing variants in RPL3L associate neonatal dilated cardiomyopathy with muscle-specific ribosome biogenesis.

Dilated cardiomyopathy (DCM) belongs to the most frequent forms of cardiomyopathy mainly characterized by cardiac dilatation and reduced systolic function. Although most cases of DCM are classified as sporadic, 20-30% of cases show a heritable pattern. Familial forms of DCM are genetically heterogeneous, and mutations in several genes have been identified that most commonly play a role in cytoskeleton and sarcomere-associated processes.

Impact of patient education videos on genetic counseling outcomes after exome sequencing.

Objective: Growing use of clinical exome sequencing (CES) has led to an increased burden of genomic education. Self-guided educational tools can minimize the educational burden for genetic counselors (GCs). The effectiveness of these tools must be evaluated.

Examining the Psychosocial Impact of Genetic Testing for Cardiomyopathies.

Inherited cardiomyopathies, including hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM), are the most common monogenic cause of cardiac disease and can rarely lead to sudden cardiac death (SCD). They are characterized by incomplete and age-dependent penetrance and are usually initially symptomatic in adulthood yet can present in childhood as well. Over 20 genes have been identified to cause HCM, and more than 40 genes are known to cause DCM.

De novo mutations in PURA are associated with hypotonia and developmental delay.

PURA is the leading candidate gene responsible for the developmental phenotype in the 5q31.3 microdeletion syndrome. De novo mutations in PURA were recently reported in 15 individuals with developmental features similar to the 5q31.