Congenital diaphragmatic hernia and early lethality in PIGL-related disorder.

We report on three male siblings who presented prenatally with a nearly identical combination of congenital anomalies and who died shortly after preterm birth. The first baby was a singleton pregnancy, and the other two babies were dichorionic diamniotic twins. Key features included: left-sided congenital diaphragmatic hernia, inferior vermian dysgenesis/hypoplasia, prenasal edema, cleft palate, micropenis/ambiguous genitalia (in 2 of 3 babies), bilateral renal pelvic dilatation (in twins, first baby showed slightly enlarged kidneys) and polyhydramnios (in 2 of 3). Whole genome sequencing performed on DNA from all three babies revealed homozygous missense PIGL gene variants: c.438C>A, p.(Phe146Leu). Both parents were heterozygous carriers of the variant. The reporting clinical laboratory classified the change as a variant of uncertain significance (VUS), and concluded "A genetic diagnosis of autosomal recessive CHIME syndrome is possible". The PIGL gene has been reported to cause two different autosomal recessive conditions: CHIME syndrome and Mabry syndrome. CHIME (Zunich neuroectodermal syndrome) is characterized by ocular Colobomas, Heart defects, Ichthyosiform dermatosis, Mental retardation (intellectual disability), and Ear anomalies, including conductive hearing loss. Mabry [aka hyperphosphatasia mental retardation syndrome (HPMRS)] is characterized by severe developmental delay, moderate to severe intellectual disability, distinctive facial features, brachytelephalangy, increased serum levels of alkaline phosphatase (ALP), and recurrent seizures. Neonatal demise and lack of postmortem examination precluded assessment of some key features (including seizures, developmental delay, ALP levels, colobomas and deafness), but overlapping features observed included cleft palate, brain anomalies, genitourinary abnormalities and prenasal edema. Notably, diaphragmatic hernia is not a common feature of either condition, but is a cardinal feature of Fryns syndrome. The genetic etiology of Fryns syndrome has not been definitively established, although, much like CHIME and Mabry syndrome, can be caused by variants in glycosylphosphatidylinositol (GPI) anchor pathway genes. Our findings suggest further overlap between inherited GPI deficiencies, and possible expansion of the clinical phenotype of PIGL-related disorders to include prenatal presentations with congenital diaphragmatic hernia. Although reported as a VUS, we present phenotypic and familial segregation evidence that supports likely pathogenicity of the c.438C>A variant.

Development of patient "profiles" to tailor counseling for incidental genomic sequencing results.

Guidelines recommend that providers engage patients in shared decision-making about receiving incidental results (IR) prior to genomic sequencing (GS), but this can be time-consuming, given the myriad of IR and variation in patients' preferences. We aimed to develop patient profiles to inform pre-test counseling for IR. We conducted semi-structured interviews with participants as a part of a randomized trial of the GenomicsADvISER.com, a decision aid for selecting IR. Interviews explored factors participants considered when deliberating over learning IR. Interviews were analyzed by thematic analysis and constant comparison. Participants were mostly female (28/31) and about half of them were over the age of 50 (16/31). We identified five patient profiles that reflect common contextual factors, attitudes, concerns, and perceived utility of IR. Information Enthusiasts self-identified as "planners" and valued learning most or all IR to enable planning and disease prevention because "knowledge is power". Concerned Individuals defined themselves as "anxious," and were reluctant to learn IR, anticipating negative psychological impacts from IR. Contemplators were discerning about the value and limitations of IR, weighing health benefits with the impacts of not being able to "un-know" information. Individuals of Advanced Life Stage did not consider IR relevant for themselves and primarily considered their implications for family members. Reassurance Seekers were reassured by previous negative genetic test results which shaped their expectations for receiving no IR: "hopefully [GS will] be negative, too. And then I can rest easy". These profiles could inform targeted counseling for IR by providing a framework to address common values, concerns. and misconceptions.

Evaluation of a decision aid for incidental genomic results, the Genomics ADvISER: protocol for a mixed methods randomised controlled trial.

INTRODUCTION: Genome sequencing, a novel genetic diagnostic technology that analyses the billions of base pairs of DNA, promises to optimise healthcare through personalised diagnosis and treatment. However, implementation of genome sequencing faces challenges including the lack of consensus on disclosure of incidental results, gene changes unrelated to the disease under investigation, but of potential clinical significance to the patient and their provider. Current recommendations encourage clinicians to return medically actionable incidental results and stress the importance of education and informed consent. Given the shortage of genetics professionals and genomics expertise among healthcare providers, decision aids (DAs) can help fill a critical gap in the clinical delivery of genome sequencing. We aim to assess the effectiveness of an interactive DA developed for selection of incidental results. METHODS AND ANALYSIS: We will compare the DA in combination with a brief Q&A session with a genetic counsellor to genetic counselling alone in a mixed-methods randomised controlled trial. Patients who received negative standard cancer genetic results for their personal and family history of cancer and are thus eligible for sequencing will be recruited from cancer genetics clinics in Toronto. Our primary outcome is decisional conflict. Secondary outcomes are knowledge, satisfaction, preparation for decision-making, anxiety and length of session with the genetic counsellor. A subset of participants will complete a qualitative interview about preferences for incidental results. ETHICS AND DISSEMINATION: This study has been approved by research ethics boards of St. Michael's Hospital, Mount Sinai Hospital and Sunnybrook Health Sciences Centre. This research poses no significant risk to participants. This study evaluates the effectiveness of a novel patient-centred tool to support clinical delivery of incidental results. Results will be shared through national and international conferences, and at a stakeholder workshop to develop a consensus statement to optimise implementation of the DA in practice. TRIAL REGISTRATION NUMBER: NCT03244202; Pre-results.