Canadian College of Medical Geneticists: clinical practice advisory document - responsibility to recontact for reinterpretation of clinical genetic testing.

Background: Advances in technology and knowledge have facilitated both an increase in the number of patient variants reported and variants reclassified. While there is currently no duty to recontact for reclassified genetic variants, there may be a responsibility. The purpose of this clinical practice advisory document is to provide healthcare practitioners guidance for recontact of previously identified and classified variants, suggest methods for recontact, and principles to consider, taking account patient safety, feasibility, ethical considerations, health service capacity and resource constraints.

A Study on the Incidence and Prevalence of 5q Spinal Muscular Atrophy in Canada Using Multiple Data Sources.

Objectives: Spinal muscular atrophy (SMA) is a leading genetic cause of infant death and represents a significant burden of care. An improved understanding of the epidemiology of SMA in Canada may help inform strategies to improve the standard of care for individuals living with SMA.

Methods: We employed a multisource approach to estimate the minimal incidence and prevalence of 5q SMA and to gain greater insight into recent clinical practices and treatment trends for the Canadian SMA population.

Next generation of free? Points to consider when navigating sponsored genetic testing.

Genetics has been integrated into patient care across many subspecialties. However, genetic and genomic testing (GT) remain expensive with disparities in access both within Canada and internationally. It is, therefore, not surprising that sponsored GT has emerged as one alternative.

Genetic and metabolic investigations for neurodevelopmental disorders: position statement of the Canadian College of Medical Geneticists (CCMG).

Purpose And Scope: The aim of this position statement is to provide recommendations for clinicians regarding the use of genetic and metabolic investigations for patients with neurodevelopmental disorders (NDDs), specifically, patients with global developmental delay (GDD), intellectual disability (ID) and/or autism spectrum disorder (ASD). This document also provides guidance for primary care and non-genetics specialists caring for these patients while awaiting consultation with a clinical geneticist or metabolic specialist.

Methods Of Statement Development: A multidisciplinary group reviewed existing literature and guidelines on the use of genetic and metabolic investigations for the diagnosis of NDDs and synthesised the evidence to make recommendations relevant to the Canadian context.

Clinical application of fetal genome-wide sequencing during pregnancy: position statement of the Canadian College of Medical Geneticists.

Purpose And Scope: The aim of this position statement is to provide recommendations for Canadian healthcare professionals regarding the use of genome-wide sequencing (GWS) in the context of diagnostic testing of the fetus during pregnancy. This statement was developed to facilitate clinical translation of GWS as a prenatal diagnostic test and the development of best practices in Canada, but the applicability of this document is broader and aims to help professionals in other healthcare systems.

Methods Of Statement Development: A multidisciplinary group was assembled to review existing literature on fetal GWS for genetic diagnosis in the context of suspected monogenic diseases and to make recommendations relevant to the Canadian context.

Is the diagnostic rate for the common subtypes of A1AT deficiency consistent across two Canadian Provinces?

Background: The diagnosis of alpha-1-antitrypsin (A1AT) deficiency has been hindered by obscurity concerning the testing process and treatment implications. In this study, we aimed to identify regional differences in the diagnostic rates for A1AT deficiency in the western Canadian provinces of British Columbia (BC) and Alberta (AB).

Methods: The number of A1AT deficiency variant genotype (ZZ, SZ, MZ, SS, and MS) diagnoses were reviewed for BC and AB.

Performance of a Three-Tier (IRT-DNA-IRT) Cystic Fibrosis Screening Algorithm in British Columbia.

Newborn screening for Cystic Fibrosis has been implemented in most programs worldwide, but the approach used varies, including combinations of immunoreactive trypsinogen (IRT) and CFTR mutation analysis on one or more specimens. The British Columbia (BC) newborn screening program tests ~45,000 infants per year in BC and the Yukon Territory, covering almost 1.5 million km in western Canada.

Integration of genetic counsellors in genomic testing triage: Outcomes of a genomic consultation service in British Columbia, Canada.

Purpose: Clinical diagnostic genome-wide (exome or genome) sequencing (GWS) in British Columbia requires funding approval by a provincial agency on a case-by-case basis. The CAUSES Clinic was a pediatric translational trio-based GWS study at BC Children's and Women's Hospitals. Referrals to the CAUSES Clinic were made through a Genomic Consultation Service (GCS), a multidisciplinary team led by genetic counsellors that provided advice regarding genomic testing for physicians considering GWS for their patients.

The expanding clinical phenotype of germline ABL1-associated congenital heart defects and skeletal malformations syndrome.

Congenital heart defects and skeletal malformations syndrome (CHDSKM) is a rare autosomal dominant disorder characterized by congenital heart disease, skeletal abnormalities, and failure to thrive. CHDSKM is caused by germline mutations in ABL1. To date, three variants have been in association with CHDSKM.

Null: A novel α-antitrypsin allele with in cis variants Glu366Lys and Ile100Asn.

Background: α-Antitrypsin (A1AT) deficiency predisposes patients to pulmonary disease due to inadequate protection against human neutrophil elastase released during inflammatory responses. A1AT deficiency is caused by homozygosity or compound heterozygosity for A1AT variants; individuals with A1AT deficiency most commonly have at least one Z variant allele (c.1096G > A (Glu366Lys)).

Renpenning syndrome in a female.

Renpenning syndrome (OMIM: 309500) is a rare X-linked disorder that causes intellectual disability, microcephaly, short stature, a variety of eye anomalies, and characteristic craniofacial features. This condition results from pathogenic variation of PQBP1, a polyglutamine-binding protein involved in transcription and pre-mRNA splicing. Renpenning syndrome has only been reported in affected males.

CCMG practice guideline: laboratory guidelines for next-generation sequencing.

PurposeThe purpose of this document is to provide guidance for the use of next-generation sequencing (NGS, also known as massively parallel sequencing or MPS) in Canadian clinical genetic laboratories for detection of genetic variants in genomic DNA and mitochondrial DNA for inherited disorders, as well as somatic variants in tumour DNA for acquired cancers. They are intended for Canadian clinical laboratories engaged in developing, validating and using NGS methods. METHODS OF STATEMENT DEVELOPMENT: The document was drafted by the Canadian College of Medical Geneticists (CCMG) Ad Hoc Working Group on NGS Guidelines to make recommendations relevant to NGS.

Diagnostic Yield and Treatment Impact of Targeted Exome Sequencing in Early-Onset Epilepsy.

Targeted whole-exome sequencing (WES) is a powerful diagnostic tool for a broad spectrum of heterogeneous neurological disorders. Here, we aim to examine the impact on diagnosis, treatment and cost with early use of targeted WES in early-onset epilepsy. WES was performed on 180 patients with early-onset epilepsy (≤5 years) of unknown cause.

The Responsibility to Recontact Research Participants after Reinterpretation of Genetic and Genomic Research Results.

The evidence base supporting genetic and genomic sequence-variant interpretations is continuously evolving. An inherent consequence is that a variant's clinical significance might be reinterpreted over time as new evidence emerges regarding its pathogenicity or lack thereof. This raises ethical, legal, and financial issues as to whether there is a responsibility to recontact research participants to provide updates on reinterpretations of variants after the initial analysis.

Severe hemolytic disease of the fetus and newborn due to allo-anti-D in a patient with a partial DEL phenotype arising from the variant allele described as RHD*148+1T (RHD*01EL.31).

Background: RhD DEL variants may show complete or partial expression of RhD epitopes. There have been only rare reports of anti-D causing hemolytic disease of the fetus and newborn (HDFN) in this context. We report a case of severe HDFN associated with a recently described DEL variant.

The Genomic Consultation Service: A clinical service designed to improve patient selection for genome-wide sequencing in British Columbia.

Background: Access to clinical diagnostic genome-wide sequencing (GWS; exome or whole genome sequencing) is limited in British Columbia. The establishment of a translational research initiative (CAUSES) to provide diagnostic genome-wide sequencing for 500 children necessitated the development of a genomic consultation service, a clinical service established to provide consultation for physicians considering GWS for their pediatric patients throughout British Columbia. The Genomic Consultation Service provides patient-specific genomic advice that may include: GWS, multi-gene panel, single gene test, referral to medical genetics for clinical evaluation, or no genetic testing.

Patient engagement in type 2 diabetes mellitus research: what patients want.

Background: As patients are the ultimate stakeholder in their health, their perspectives should be included along with researchers, providers, and funders of research design, execution, and interpretation. Despite the high prevalence of type 2 diabetes mellitus (T2DM), patients are rarely directly included in these decisions.

Purpose: We sought to determine areas of research most important to patients with T2DM, identify ways through which patients with T2DM want to engage in research, and evaluate online patient research networks as a source for obtaining patient perspectives on research engagement.

Practice guideline: joint CCMG-SOGC recommendations for the use of chromosomal microarray analysis for prenatal diagnosis and assessment of fetal loss in Canada.

Background: The aim of this guideline is to provide updated recommendations for Canadian genetic counsellors, medical geneticists, maternal fetal medicine specialists, clinical laboratory geneticists and other practitioners regarding the use of chromosomal microarray analysis (CMA) for prenatal diagnosis. This guideline replaces the 2011 Society of Obstetricians and Gynaecologists of Canada (SOGC)-Canadian College of Medical Geneticists (CCMG) Joint Technical Update.

Methods: A multidisciplinary group consisting of medical geneticists, genetic counsellors, maternal fetal medicine specialists and clinical laboratory geneticists was assembled to review existing literature and guidelines for use of CMA in prenatal care and to make recommendations relevant to the Canadian context.

An Infant With Epilepsy and Recurrent Hemiplegia due to Compound Heterozygous Variants in ATP1A2.

Background: Pathogenic heterozygous variants in the ATP1A2 gene have most commonly been associated with familial hemiplegic migraine. However, a wide spectrum of phenotypes that include alternating hemiplegia of childhood and epilepsy have been described.

Patient Description: We describe a boy who presented at age three months with a complex phenotype that included epilepsy, nonepileptic paroxysmal events, and recurrent hemiplegia.

De Novo Mutations in EBF3 Cause a Neurodevelopmental Syndrome.

Early B cell factor 3 (EBF3) is an atypical transcription factor that is thought to influence the laminar formation of the cerebral cortex. Here, we report that de novo mutations in EBF3 cause a complex neurodevelopmental syndrome. The mutations were identified in two large-scale sequencing projects: the UK Deciphering Developmental Disorders (DDD) study and the Canadian Clinical Assessment of the Utility of Sequencing and Evaluation as a Service (CAUSES) study.

De novo mutation in 2 patients with neonatal-onset epilepsy.

Objective: We describe 2 additional patients with early-onset epilepsy with a de novo mutation.

Methods: Whole-exome sequencing was performed in 2 unrelated patients with early-onset epilepsy and their unaffected parents. Genetic variants were assessed by comparative trio analysis.