Kathleen Hodgkinson

Recommendations for the use of genetic testing in the clinical evaluation of inherited cardiac arrhythmias associated with sudden cardiac death: Canadian Cardiovascular Society/Canadian Heart Rhythm Society joint position paper.

The era of gene discovery and molecular medicine has had a significant impact on clinical practice. Knowledge of specific genetic findings causative for or associated with human disease may enhance diagnostic accuracy and influence treatment decisions. In cardiovascular disease, gene discovery for inherited arrhythmia syndromes has advanced most rapidly. The arrhythmia specialist is often confronted with the challenge of diagnosing and managing genetic arrhythmia syndromes. There is now a clear need for guidelines on the appropriate use of genetic testing for the most common genetic conditions associated with a risk of sudden cardiac death. This document represents the first ever published recommendations outlining the role of genetic testing in various clinical scenarios, the specific genes to be considered for testing, and the utility of test results in the management of patients and their families.

Premature death in adults with 22q11.2 Deletion Syndrome

Background: 22q11.2 deletion syndrome (22q11.2DS) is a multisystem disease with a prevalence of 1/4000. Variable expression of congenital and later onset features contributes to its under-recognition. Longevity in those surviving childhood is believed to be normal but data are limited. Methods: We prospectively followed 264 subjects; 102 adults (>17 years) with 22q11.2DS (44 male (M), 58 female (F); mean (SD) age 33.6 (10.9) years) and their 162 unaffected siblings (77 M, 85 F; mean age 36.1 (12.2) years). We compared survival between groups using Kaplan–Meier estimates. Results: Twelve (11.8%; 4 M, 8 F) individuals with 22q11.2DS and no siblings died (p<0.0001). Survival to ages 40 and 50 years was 89.9% and 73.9%, respectively. Median age at death was 41.5 (range 18.1–68.6) years. Deaths included two (7.7%) of 26 subjects with neither major congenital heart disease (CHD) nor schizophrenia. Four of six sudden and unexpected deaths occurred in individuals with no major CHD. There was no evidence of cancer or coronary artery disease or family history of sudden death in the 12 patients who died, six of whom had autopsies. Discussion: Individuals with 22q11.2DS who survive childhood have diminished life expectancy and increased risk of sudden death not attributable to any single factor. Some sudden and/or premature deaths observed in the general population may represent undiagnosed 22q11.2DS. Increased recognition of the syndrome by family doctors, specialists and coroners will be essential to facilitate the tissue studies needed to determine underlying mechanisms.

VAMP1 Mutation Causes Dominant Hereditary Spastic Ataxia in Newfoundland Families

Our group previously described and mapped to chromosomal region 12p13 a form of dominantly inherited hereditary spastic ataxia (HSA) in three large Newfoundland (Canada) families. This report identifies vesicle-associated membrane protein 1 (VAMP1), which encodes a critical protein for synaptic exocytosis, as the responsible gene. In total, 50 affected individuals from these families and three independent probands from Ontario (Canada) share the disease phenotype together with a disruptive VAMP1 mutation that affects axa0critical donor site for the splicing of VAMP1 isoforms. This mutation leads to the loss of the only VAMP1 isoform (VAMP1A) expressed in the nervous system, thus highlighting an association between the well-studied VAMP1 and a neurological disorder. Given the variable phenotype seen in the affected individuals examined here, we believe that VAMP1 should be tested for mutations in patients with either ataxia or spastic paraplegia.

Public Attitudes About Genetic Testing in the Newborn Period

OBJECTIVEnTo measure attitudes toward newborn genetic testing in our jurisdiction.nnnDESIGNnA cross-sectional, pen-and-paper survey.nnnSETTINGnThe survey was administered to the general public and prospective parents in Eastern Canada between April 2010 and December 2010.nnnPARTICIPANTSnA total of 648 individuals completed surveys.nnnRESULTSnPositive attitudes were found toward newborn genetic testing, regardless of whether an effective treatment existed for the disorder in question or whether the disorder developed in adulthood. A majority agreed (69%) that testing should be available for any condition to assist with future reproductive decisions. Most respondents (93%) agreed parents should provide informed consent before newborn screening (NBS) was undertaken and that parents had a fundamental right to access NBS if they so choose.nnnCONCLUSIONnInterest in NBS for genetic disorders is generally high, regardless of whether an effective treatment exists. Findings lend support to the expansion of NBS panels to include those disorders currently lacking treatment but highlight consumers desire for informed consent before testing is undertaken.

Interest in newborn genetic testing: a survey of prospective parents and the general public.

PURPOSEnNewborn screening (NBS) panels continue to expand, yet there are too few data on public attitudes toward testing in the newborn period to indicate whether there is support for such testing. We measured interest in newborn testing for several autosomal recessive disorders and reasons for interest.nnnMETHODSnA cross-sectional, pen and paper survey was administered to the general public and prospective parents attending prenatal classes in Eastern Canada between April and December, 2010.nnnRESULTSnA total of 648 individuals completed surveys. Interest in newborn testing for inherited hearing loss, vision loss, and neurological disorders was high (over 80% would have their newborn tested). The attitudes of prospective parents and students were positive, but somewhat less so than members of the general public. Across all disorders, interest in testing was driven by the desire to be prepared for the birth of a child with a genetic disorder. Significantly more people would use the information from testing for fatal neurological disorders in future reproductive decisions than the information generated by newborn testing for inherited hearing or vision loss.nnnCONCLUSIONnInterest is high in newborn testing for a variety of conditions, including those for which no effective treatment exists. Findings lend support to the expansion of NBS panels to include those disorders currently lacking treatment and highlight the value of including the views of diverse stakeholders, including prospective parents, in screening policies.

Long-Term Clinical Outcome of Arrhythmogenic Right Ventricular Cardiomyopathy in Individuals With a p.S358L Mutation in TMEM43 Following Implantable Cardioverter Defibrillator Therapy

Background—We previously showed a survival benefit of the implantable cardioverter defibrillator (ICD) in males with arrhythmogenic right ventricular cardiomyopathy caused by a p.S358L mutation in TMEM43. We present long-term data (median follow-up 8.5years) after ICD for primary (PP) and secondary prophylaxis in males and females, determine whether ICD discharges for ventricular tachycardia/ventricular fibrillation were equivalent to an aborted death, and assess relevant clinical predictors. Methods and Results—We studied 24 multiplex families segregating an autosomal dominant p.S358L mutation in TMEM43. We compared survival in 148 mutation carriers with an ICD to 148 controls matched for age, sex, disease status, and family. Of 80 male mutation carriers with ICDs (median age at implantation 31 years), 61 (76%) were for PP; of 68 females (median age at implantation 43 years), 66 (97%) were for PP. In males, irrespective of indication, survival was better in the ICD groups compared with control groups (relative risk 9.3 [95% confidence interval 3.3–26] for PP and 9.7 [95% confidence interval 3.2–29.6] for secondary prophylaxis). For PP females, the relative risk was 3.6 (95% confidence interval 1.3–9.5). ICD discharge-free survival for ventricular tachycardia/ventricular fibrillation ≥240 beats per minute was equivalent to the control survival rate. Ectopy (≥1000 premature ventricular complexes/24 hours) was the only independent clinical predictor of ICD discharge in males, and no predictor was identified in females. Conclusions—ICD therapy is indicated for PP in postpubertal males and in females ≥30 years with the p.S358L TMEM43 mutation. ICD termination of rapid ventricular tachycardia/ventricular fibrillation can reasonably be considered an aborted death.

‘It had to be done’: genetic testing decisions for arrhythmogenic right ventricular cardiomyopathy

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a heritable disease of the heart muscle, causing life‐threatening ventricular arrhythmias, sudden cardiac death and/or biventricular heart failure. Little research examines ARVC genetic test decisions, despite the gravity of the condition. This qualitative study used semi‐structured interviews to explore the testing decisions of 21 individuals across 15 families segregating a well‐studied, particularly lethal form of ARVC caused by a p.S358L TMEM43 mutation. Genetic testing decisions were rarely described as ‘decisions’ per se, but rather ‘something that had to be done’. This perception was attributed to personality type or personal suspicion of carrying the TMEM43 mutation, but most often was described in the context of testing for other family members, usually children. Participants related a strong need to rule out risk, more for children than for themselves, but lingering doubts remained about personal and childrens risk for ARVC, even when gene test results were negative. Study findings highlight the interdependent nature of genetic test decisions and suggest that an individualistic conception of autonomy in genetic services may not meet the needs of affected families. Findings also suggest the need for follow‐up support of families affected by ARVC, including for those individuals testing negative for the family mutation.