SLC6A1 variant pathogenicity, molecular function and phenotype: a genetic and clinical analysis.

Genetic variants in the SLC6A1 gene can cause a broad phenotypic disease spectrum by altering the protein function. Thus, systematically curated clinically relevant genotype-phenotype associations are needed to understand the disease mechanism and improve therapeutic decision-making. We aggregated genetic and clinical data from 172 individuals with likely pathogenic/pathogenic (lp/p) SLC6A1 variants and functional data for 184 variants (14.

ORCA, a values-based decision aid for selecting additional findings from genomic sequencing in adults: Efficacy results from a randomized trial.

Purpose: Individuals having genomic sequencing can choose to be notified about pathogenic variants in genes unrelated to the testing indication. A decision aid can facilitate weighing one's values before making a choice about these additional results.

Methods: We conducted a randomized trial (N = 231) comparing informed values-choice congruence among adults at risk for a hereditary cancer syndrome who viewed either the Optional Results Choice Aid (ORCA) or web-based additional findings information alone.

ClinGen's Pediatric Actionability Working Group: Clinical actionability of secondary findings from genome-scale sequencing in children and adolescents.

Purpose: Synthesis and curation of evidence regarding the clinical actionability of secondary findings (SFs) from genome-scale sequencing are needed to support decision-making on reporting of these findings. To assess actionability of SFs in children and adolescents, the Clinical Genome Resource established the Pediatric Actionability Working Group (AWG).

Methods: The Pediatric AWG modified the framework of the existing Adult AWG, which included production of summary reports of actionability for genes and associated conditions and consensus actionability scores for specific outcome-intervention pairs.

CHRNB1-associated congenital myasthenia syndrome: Expanding the clinical spectrum.

CHRNB1 encodes the β subunit of the acetylcholine receptor (AChR) at the neuromuscular junction. Inherited defects in the neuromuscular junction can lead to congenital myasthenia syndrome (CMS), a clinically and genetically heterogeneous group of disorders which includes fetal akinesia deformation sequence (FADS) on the severe end of the spectrum. Here, we report two unrelated families with biallelic CHRNB1 variants, and in each family, one child presented with lethal FADS.

A decision aid for additional findings in genomic sequencing: Development and pilot testing.

Objective: To describe the development of a web-based, patient-facing decision aid to support patients and research participants to make an informed, values-based decision about whether to receive additional results from genomic sequencing.

Methods: We developed the decision aid following the multi-step process described in the International Patient Decision Aids Standards. This utilized literature review, focus groups, and alpha testing with research participants undergoing clinical genomic sequencing.

The Impact of Rapid Exome Sequencing on Medical Management of Critically Ill Children.

Objectives: To evaluate the clinical usefulness of rapid exome sequencing (rES) in critically ill children with likely genetic disease using a standardized process at a single institution. To provide evidence that rES with should become standard of care for this patient population.

Study Design: We implemented a process to provide clinical-grade rES to eligible children at a single institution.

Rapid clinical exome sequencing in a pediatric ICU: Genetic counselor impacts and challenges.

Exome sequencing (ES) has revolutionized molecular diagnosis in children with genetic disease over the past decade. However, exome sequencing in the inpatient setting has traditionally been discouraged, in part due to an increased risk of providers failing to retrieve and act upon results, as many patients are discharged before results return. The development of rapid turn-around-times (TATs) for genomic testing has begun to shift this paradigm.

Identification of a deletion containing TBX4 in a neonate with acinar dysplasia by rapid exome sequencing.

We describe a neonate with severe respiratory failure due to acinar dysplasia found by rapid exome sequencing (rES), to have a deletion containing the TBX4 gene. rES can affect patient management in the intensive care unit and should be considered in concert with lung biopsy in neonates with undifferentiated respiratory failure.