IMPACT webinars: Improving Patient Access to genetic Counselling and Testing using webinars-the Alberta experience with hypertrophic cardiomyopathy.

Growing demand for genetic counselling and testing has created a need for innovative service delivery models to provide quality care in an efficient manner. The goal of this study was to develop and evaluate a patient-facing webinar providing pre-test genetic counselling to individuals with hypertrophic cardiomyopathy. A patient-facing webinar was developed and implemented between April 2019 and January 2021. It was evaluated using the Alberta Quality Matrix for Health framework, which considers the patient experience across the domains of effectiveness, appropriateness, acceptability, accessibility, and efficiency. The webinar group showed comparable scores to controls with regard to self-perceived knowledge and decisional conflict. The majority of patients reported that the webinar met their expectations and was an acceptable replacement for a 1:1 genetic counselling appointment. Finally, the webinar reduced genetic counsellor time to an average of 24 min per patient. Providing pre-test genetic counselling to index hypertrophic cardiomyopathy patients via a group webinar has achieved a high quality of care, and optimized use of provider and space resources.

Early Death of 2 Siblings Related to Mutations in LMOD2, a Recently Discovered Cause of Neonatal Dilated Cardiomyopathy.

We report a family with 2 neonatal deaths related to dilated cardiomyopathy (DCM) and compound heterozygous loss-of-function variants (c.1243_1244del, p.Leu415Valfs*108 and c.1537C > T, p.Arg513*) in Leiomodin 2 (LMOD2), a recently documented cause of early DCM. The phenotype in mice and humans consists of early, severe cardiac dilation and dysfunction related to decreased functional LMOD2, which results in abnormal actin filaments and abnormal myocardial contractility. Our cases confirm mutations in LMOD2 as a cause of DCM in humans and highlight the rapid changes occurring in cardiac genetics and the importance of reviewing previously negative genetic test results in the context of emerging literature.

Notre compte rendu concerne une famille dont deux nouveau-nés sont décédés des suites d'une cardiomyopathie dilatée (CMD) et qui présentaient une perte hétérozygote composite de variants fonctionnels (c.1243_1244del, p.Leu415Valfs*108 et c.1537C > T, p.Arg513*) du gène Leiomodin 2 (LMOD2), une cause récemment avérée de CMD précoce. Chez la souris et l'humain, le phénotype de cette anomalie consiste en une dilatation et une dysfonction cardiaques sévères précoces liées à une diminution de la fonction du gène LMOD2 entraînant des anomalies dans les filaments d'actine et la contractilité du myocarde. Nos cas permettent de confirmer que les mutations du gène LMOD2 sont une cause de CMD chez l'humain. Ils mettent en évidence les modifications rapides se produisant dans la génétique cardiaque et l'importance de revoir les résultats négatifs d'anciens tests génétiques à la lumière des nouvelles données publiées.

Mutations in ILK, encoding integrin-linked kinase, are associated with arrhythmogenic cardiomyopathy.

Arrhythmogenic cardiomyopathy is a genetic heart muscle disorder characterized by fibro-fatty replacement of cardiomyocytes leading to life-threatening ventricular arrhythmias, heart failure, and sudden cardiac death. Mutations in genes encoding cardiac junctional proteins are known to cause about half of cases, while remaining genetic causes are unknown. Using exome sequencing, we identified 2 missense variants (p.H33N and p.H77Y) that were predicted to be damaging in the integrin-linked kinase (ILK) gene in 2 unrelated families. The p.H33N variant was found to be de novo. ILK links integrins and the actin cytoskeleton, and is essential for the maintenance of normal cardiac function. Both of the new variants are located in the ILK ankyrin repeat domain, which binds to the first LIM domain of the adaptor proteins PINCH1 and PINCH2. In silico binding studies proposed that the human variants disrupt the ILK-PINCH complex. Recombinant mutant ILK expressed in H9c2 rat myoblast cells shows aberrant prominent cytoplasmic localization compared to the wild-type. Expression of human wild-type and mutant ILK under the control of the cardiac-specific cmlc2 promotor in zebrafish shows that p.H77Y and p.P70L, a variant previously reported in a dilated cardiomyopathy family, cause cardiac dysfunction and death by about 2-3 weeks of age. Our findings provide genetic and functional evidence that ILK is a cardiomyopathy disease gene and highlight its relevance for diagnosis and genetic counseling of inherited cardiomyopathies.

Reversible Dilated Cardiomyopathy Caused by a High Burden of Ventricular Arrhythmias in Andersen-Tawil Syndrome.

Andersen-Tawil syndrome (ATS) is caused by mutations in KCNJ2 (Kir2.1). It remains unclear whether dilated cardiomyopathy (DCM) is a primary feature of ATS. We studied a proband with typical physical features of ATS plus DCM and moderate to severe left ventricular dysfunction (left ventricular ejection fraction = 30.5%). Genetic screening revealed a novel mutation in Kir2.1 (c.665T>C, p.L222S). Functional studies showed that this mutation reduced ionic currents in a dominant-negative manner. Suppression of ventricular arrhythmias with bisoprolol led to normalization of left ventricular size and function. We conclude that DCM is likely a secondary phenotype in ATS and is caused by high ventricular arrhythmia burden.

Mutations in FLNC are Associated with Familial Restrictive Cardiomyopathy.

Individuals affected by restrictive cardiomyopathy (RCM) often develop heart failure at young ages resulting in early heart transplantation. Familial forms are mainly caused by mutations in sarcomere proteins and demonstrate a common genetic etiology with other inherited cardiomyopathies. Using next-generation sequencing, we identified two novel missense variants (p.S1624L; p.I2160F) in filamin-C (FLNC), an actin-cross-linking protein mainly expressed in heart and skeletal muscle, segregating in two families with autosomal-dominant RCM. Affected individuals presented with heart failure due to severe diastolic dysfunction requiring heart transplantation in some cases. Histopathology of heart tissue from patients of both families showed cytoplasmic inclusions suggesting protein aggregates, which were filamin-C specific for the p.S1624L by immunohistochemistry. Cytoplasmic aggregates were also observed in transfected myoblast cell lines expressing this mutant filamin-C indicating further evidence for its pathogenicity. Thus, FLNC is a disease gene for autosomal-dominant RCM and broadens the phenotype spectrum of filaminopathies.

The establishment of core competencies for canadian genetic counsellors: validation of practice based competencies.

Numerous groups of health professionals have undertaken the task of defining core competencies for their profession. The goal of establishing core competencies is to have a defined standard for such professional needs as practice guidelines, training curricula, certification, continuing competency and re-entry to practice. In 2006, the Canadian Association of Genetic Counsellors (CAGC) recognized the need for uniform practice standards for the profession in Canada, given the rapid progress of genetic knowledge and technologies, the expanding practice of genetic counsellors and the increasing demand for services. We report here the process by which the CAGC Practice Based Competencies were developed and then validated via two survey cycles, the first within the CAGC membership, and the second with feedback from external stakeholders. These competencies were formally approved in 2012 and describe the integrated skills, attitudes and judgment that genetic counsellors in Canada require in order to perform the services and duties that fall within the practice of the profession responsibly, safely, effectively and ethically.

Gaucher disease with prenatal onset and perinatal death due to compound heterozygosity for the missense R131C and null Rec Nci I GBA mutations.

Gaucher disease is an autosomal recessive disorder resulting from deficient activity of the lysosomal enzyme glucocerebrosidase (GBA, E.C.3.2.1.45). Three clinical forms of Gaucher disease have been described: type 1, nonneuronopathic; type 2, acute neuronopathic; and type 3, subacute neuronopathic (OMIM 230800, 230900, 231000). Over the past decade, recognition of a distinct, perinatal lethal form of Gaucher disease (PLGD) has led researchers and clinicians to evaluate Gaucher disease in the differential diagnosis of congenital ichthyosis and nonimmune hydrops fetalis. To date, more than 30 cases of PLGD have been genotyped and reported. It has been observed that homozygosity for recombinant GBA alleles, which are fundamentally null alleles, leads to early lethality, usually in utero or during the 1st few days of life, whereas genotypes involving a recombinant allele and a missense mutation may be less detrimental. Here, we report a case of Gaucher disease with prenatal onset and death within hours of birth, likely due to compound heterozygosity for the GBA Rec Nci I null allele and a R131C missense mutation. In view of the patient's severe clinical course, and based on reviews of other PLGD cases, we postulate that a missense mutation that abruptly disrupts the structure/function of GBA, in combination with a null allele, may result in early lethality in patients with PLGD. We also speculate that R131C is an extremely severe mutation that has occurred more than once in different populations and, in either the homozygous form or heterozygous with another severe mutation, will result in a poor prognosis.