J Genet Counsel DOI 10.1007/s10897-014-9776-6
ORIGINAL RESEARCH
Reduced Uptake of Family Screening in Genotype-Negative Versus Genotype-Positive Long QT Syndrome Mikael Hanninen & George J. Klein & Zachary Laksman & Susan S. Conacher & Allan C. Skanes & Raymond Yee & Lorne J. Gula & Peter Leong-Sit & Jaimie Manlucu & Andrew D. Krahn
Received: 31 October 2013 / Accepted: 12 September 2014 # National Society of Genetic Counselors, Inc. 2014
Abstract The acceptance and yield of family screening in genotype-negative long QT syndrome (LQTS) remains incompletely characterized. In this study of family screening for phenotype-definite Long QT Syndrome (LQTS, Schwartz score ≥3.5), probands at a regional Inherited Cardiac Arrhythmia clinic were reviewed. All LQTS patients were offered education by a qualified genetic counselor, along with materials for family screening including electronic and paper correspondence to provide to family members. Thirty-eight qualifying probands were identified and 20 of these had family members who participated in cascade screening. The acceptance of screening was found to be lower among families without a known pathogenic mutation (33 vs. 77 %, p=0.02). A total of 52 relatives were screened; fewer relatives were screened per index case when the proband was genotypenegative (1.7 vs. 3.1, p=0.02). The clinical yield of screening appeared to be similar irrespective of gene testing results (38 vs. 33 %, p=0.69). Additional efforts to promote family screening among gene-negative long QT families may be warranted. Keywords Long QT syndrome . Gene negative . Family screening . Cascade screening Electronic supplementary material The online version of this article (doi:10.1007/s10897-014-9776-6) contains supplementary material, which is available to authorized users. M. Hanninen Division of Cardiology, Grey Nuns Hospital, Edmonton, AB, Canada G. J. Klein : Z. Laksman : S. S. Conacher : A. C. Skanes : R. Yee : L. J. Gula : P. Leong-Sit : J. Manlucu Division of Cardiology, Western University, London, ON, Canada A. D. Krahn (*) Division of Cardiology, University of British Columbia, Vancouver, BC, Canada e-mail: [email protected]
Introduction Genetically-mediated Long QT Syndrome (LQTS) is a leading cause of sudden death in young patients and is estimated to affect approximately 1 in 2500 individuals (Schwartz et al. 2009). Abnormalities on a resting 12-lead ECG are often the first clue that a patient may be affected by this condition. When LQTS is recognized prior to the development of symptoms and patients comply with medical recommendations, the prognosis is excellent. On the other hand, the natural history among untreated patients is frequently characterized by recurrent exercise-induced syncope and eventual sudden death (Ackerman et al. 2011). Comprehensive genetic testing is recommended in patients with a strong clinical likelihood of long QT syndrome (LQTS), asymptomatic QTc prolongation >500 ms (in adults) or for relatives of an index case following identification of a Long QT causative mutation (Ackerman et al. 2011 and Gollob et al. 2011). However, the interpretation of genetic testing results can be complex and a source of confusion for patients and their families (Ingles et al. 2011 and Kapa et al. 2009). Despite major advances in our understanding of LQTS genetic testing (Tzou and Gerstenfeld 2009), one quarter of patients referred for LQTS genetic testing are genotypenegative (Kapplinger et al. 2009). Although the nonuniformity of clinical assessment and misdiagnosis of LQTS mimickers or phenocopies may explain some of this discrepancy (Tester et al. 2005, Choi et al. 2004 and Medlock et al. 2012), it is likely that either undiscovered monogenic genes or yet uncharacterized polygenic interactions (which would be expected to have complex inheritance patterns) account for at least some of these gene-negative, phenotype positive patients. It is generally understood among clinicians that a negative genetic test does not exclude the diagnosis of LQTS in a patient with an unequivocal phenotype (Shimizu, 2005), but
Hanninen et al.
we have often observed that patients and their families express a degree of relief upon learning that they are genotype negative. This may result in relatively fewer relatives of gene negative probands presenting for clinical screening (Kapa et al. 2009). We sought to investigate whether differences exist in the acceptance of family screening and the frequency of LQTS diagnosis among relatives of genotype-positive and genotype-negative families.
Methods Participants Patients referred to the London Health Sciences Center Inherited Arrhythmia Clinic for LQTS evaluation from 1995–2012 were reviewed. At the time of their initial assessment, personal and family history (including pedigree construction) as well as resting and exercise ECG testing was carried out on all index referrals. Gene testing for LQTS was performed from 2007 onwards and was offered to all index cases either at the time of their initial assessment or retrospectively for those who were initially assessed prior to 2007. In addition to this data, we retrospectively analyzed all available health records including clinical correspondence, pacemaker/ implantable cardioverter-defibrillator (ICD) implant records and all available ECGs and exercise stress tests in order to generate a LQTS clinical score (Schwartz score, Supplementary Table 1) (Schwartz and Crotti 2011 and Horner et al. 2011). Index referrals with a “definite” LQTS phenotype (defined as a LQTS clinical score of ≥3.5) were identified as qualifying LQTS probands for the purposes of this study. Qualifying LQTS probands and their families were analyzed to determine which of these probands underwent family screening. In each case, family screening consisted of a personal and family history, resting and exercise ECG testing as well as family-specific gene testing. The outcome of family screening was determined by analyzing the frequency of LQTS diagnosis based on clinical criteria only (LQTS clinical score ≥3.5). This was chosen in an effort to exclude the phenotype negative gene carriers who could be identified only among genotype-positive families. All assessments (including initial assessments and family screening assessments) were carried out at a single tertiary care hospital (London Health Science Centre - University Hospital) in London, Ontario. The protocol was approved by the Health Sciences Research Ethics Board of Western University. Procedures Genetic testing was performed using commercially available comprehensive sequencing based on the panel offered at the
time of proband testing (Familion-Transgenomic, Omaha Nebraska and GeneDx, Gaithersburg Maryland, KCNQ1, KCNH2, SCN5A, KCNE1 and KCNE2 and additional genes based on generation of testing). All patients were assessed for LQT types 1–6, and varying generations of testing included types 7–13 based on availability of testing. All probands received standard genetic counseling by a qualified genetic counselor (SSC), with an emphasis on the nature, risks and benefits of genetic testing. All patients were also provided standard advice about beta-blocker therapy and about the risk of syncope or sudden death related to strenuous exercise among patients with LQTS. A formal, in-person discussion of genetic testing results was provided to probands regardless of the result and all probands were offered information to promote family screening among their first degree relatives, typically a printed and/or electronically mailed family information letter, regardless of genotype status (Fig. 2) (van der Roest et al. 2009). The inherited nature of LQTS and the risk to family members was emphasized in the information letter and during family screening assessments. Retrospective ECG analysis was performed by a certified Cardiologist with expertise in ECG interpretation from the research team, blinded to the results of genetic screening. The QT interval was measured manually from the beginning of the QRS complex to the end of the T wave. The end of the T wave was determined as the intersection point between the isoelectric baseline and the tangent line representing the maximal downward slope of the positive T wave or maximal upward slope of the negative T wave (Supplementary Figure 1) (Horner et al. 2011). The QT interval was considered the longest interval of all 12 leads, generally occurring in lead II and V5. The mean of three consecutive QT intervals was used. The corrected QT interval (QTc) was calculated using Bazett’s formula (Bazett, 1920). The resting QTc was considered normal if it was 480 ms -QTc 460–480 ms -QTc 450–460 ms (males) 4-min recovery QTc: -QTc >480 ms Other ECG features suggestive of LQTS -Torsades de pointes/SCD -T wave alternans -Notched T wave in 3 leads -Resting HR
ORIGINAL RESEARCH
Reduced Uptake of Family Screening in Genotype-Negative Versus Genotype-Positive Long QT Syndrome Mikael Hanninen & George J. Klein & Zachary Laksman & Susan S. Conacher & Allan C. Skanes & Raymond Yee & Lorne J. Gula & Peter Leong-Sit & Jaimie Manlucu & Andrew D. Krahn
Received: 31 October 2013 / Accepted: 12 September 2014 # National Society of Genetic Counselors, Inc. 2014
Abstract The acceptance and yield of family screening in genotype-negative long QT syndrome (LQTS) remains incompletely characterized. In this study of family screening for phenotype-definite Long QT Syndrome (LQTS, Schwartz score ≥3.5), probands at a regional Inherited Cardiac Arrhythmia clinic were reviewed. All LQTS patients were offered education by a qualified genetic counselor, along with materials for family screening including electronic and paper correspondence to provide to family members. Thirty-eight qualifying probands were identified and 20 of these had family members who participated in cascade screening. The acceptance of screening was found to be lower among families without a known pathogenic mutation (33 vs. 77 %, p=0.02). A total of 52 relatives were screened; fewer relatives were screened per index case when the proband was genotypenegative (1.7 vs. 3.1, p=0.02). The clinical yield of screening appeared to be similar irrespective of gene testing results (38 vs. 33 %, p=0.69). Additional efforts to promote family screening among gene-negative long QT families may be warranted. Keywords Long QT syndrome . Gene negative . Family screening . Cascade screening Electronic supplementary material The online version of this article (doi:10.1007/s10897-014-9776-6) contains supplementary material, which is available to authorized users. M. Hanninen Division of Cardiology, Grey Nuns Hospital, Edmonton, AB, Canada G. J. Klein : Z. Laksman : S. S. Conacher : A. C. Skanes : R. Yee : L. J. Gula : P. Leong-Sit : J. Manlucu Division of Cardiology, Western University, London, ON, Canada A. D. Krahn (*) Division of Cardiology, University of British Columbia, Vancouver, BC, Canada e-mail: [email protected]
Introduction Genetically-mediated Long QT Syndrome (LQTS) is a leading cause of sudden death in young patients and is estimated to affect approximately 1 in 2500 individuals (Schwartz et al. 2009). Abnormalities on a resting 12-lead ECG are often the first clue that a patient may be affected by this condition. When LQTS is recognized prior to the development of symptoms and patients comply with medical recommendations, the prognosis is excellent. On the other hand, the natural history among untreated patients is frequently characterized by recurrent exercise-induced syncope and eventual sudden death (Ackerman et al. 2011). Comprehensive genetic testing is recommended in patients with a strong clinical likelihood of long QT syndrome (LQTS), asymptomatic QTc prolongation >500 ms (in adults) or for relatives of an index case following identification of a Long QT causative mutation (Ackerman et al. 2011 and Gollob et al. 2011). However, the interpretation of genetic testing results can be complex and a source of confusion for patients and their families (Ingles et al. 2011 and Kapa et al. 2009). Despite major advances in our understanding of LQTS genetic testing (Tzou and Gerstenfeld 2009), one quarter of patients referred for LQTS genetic testing are genotypenegative (Kapplinger et al. 2009). Although the nonuniformity of clinical assessment and misdiagnosis of LQTS mimickers or phenocopies may explain some of this discrepancy (Tester et al. 2005, Choi et al. 2004 and Medlock et al. 2012), it is likely that either undiscovered monogenic genes or yet uncharacterized polygenic interactions (which would be expected to have complex inheritance patterns) account for at least some of these gene-negative, phenotype positive patients. It is generally understood among clinicians that a negative genetic test does not exclude the diagnosis of LQTS in a patient with an unequivocal phenotype (Shimizu, 2005), but
Hanninen et al.
we have often observed that patients and their families express a degree of relief upon learning that they are genotype negative. This may result in relatively fewer relatives of gene negative probands presenting for clinical screening (Kapa et al. 2009). We sought to investigate whether differences exist in the acceptance of family screening and the frequency of LQTS diagnosis among relatives of genotype-positive and genotype-negative families.
Methods Participants Patients referred to the London Health Sciences Center Inherited Arrhythmia Clinic for LQTS evaluation from 1995–2012 were reviewed. At the time of their initial assessment, personal and family history (including pedigree construction) as well as resting and exercise ECG testing was carried out on all index referrals. Gene testing for LQTS was performed from 2007 onwards and was offered to all index cases either at the time of their initial assessment or retrospectively for those who were initially assessed prior to 2007. In addition to this data, we retrospectively analyzed all available health records including clinical correspondence, pacemaker/ implantable cardioverter-defibrillator (ICD) implant records and all available ECGs and exercise stress tests in order to generate a LQTS clinical score (Schwartz score, Supplementary Table 1) (Schwartz and Crotti 2011 and Horner et al. 2011). Index referrals with a “definite” LQTS phenotype (defined as a LQTS clinical score of ≥3.5) were identified as qualifying LQTS probands for the purposes of this study. Qualifying LQTS probands and their families were analyzed to determine which of these probands underwent family screening. In each case, family screening consisted of a personal and family history, resting and exercise ECG testing as well as family-specific gene testing. The outcome of family screening was determined by analyzing the frequency of LQTS diagnosis based on clinical criteria only (LQTS clinical score ≥3.5). This was chosen in an effort to exclude the phenotype negative gene carriers who could be identified only among genotype-positive families. All assessments (including initial assessments and family screening assessments) were carried out at a single tertiary care hospital (London Health Science Centre - University Hospital) in London, Ontario. The protocol was approved by the Health Sciences Research Ethics Board of Western University. Procedures Genetic testing was performed using commercially available comprehensive sequencing based on the panel offered at the
time of proband testing (Familion-Transgenomic, Omaha Nebraska and GeneDx, Gaithersburg Maryland, KCNQ1, KCNH2, SCN5A, KCNE1 and KCNE2 and additional genes based on generation of testing). All patients were assessed for LQT types 1–6, and varying generations of testing included types 7–13 based on availability of testing. All probands received standard genetic counseling by a qualified genetic counselor (SSC), with an emphasis on the nature, risks and benefits of genetic testing. All patients were also provided standard advice about beta-blocker therapy and about the risk of syncope or sudden death related to strenuous exercise among patients with LQTS. A formal, in-person discussion of genetic testing results was provided to probands regardless of the result and all probands were offered information to promote family screening among their first degree relatives, typically a printed and/or electronically mailed family information letter, regardless of genotype status (Fig. 2) (van der Roest et al. 2009). The inherited nature of LQTS and the risk to family members was emphasized in the information letter and during family screening assessments. Retrospective ECG analysis was performed by a certified Cardiologist with expertise in ECG interpretation from the research team, blinded to the results of genetic screening. The QT interval was measured manually from the beginning of the QRS complex to the end of the T wave. The end of the T wave was determined as the intersection point between the isoelectric baseline and the tangent line representing the maximal downward slope of the positive T wave or maximal upward slope of the negative T wave (Supplementary Figure 1) (Horner et al. 2011). The QT interval was considered the longest interval of all 12 leads, generally occurring in lead II and V5. The mean of three consecutive QT intervals was used. The corrected QT interval (QTc) was calculated using Bazett’s formula (Bazett, 1920). The resting QTc was considered normal if it was 480 ms -QTc 460–480 ms -QTc 450–460 ms (males) 4-min recovery QTc: -QTc >480 ms Other ECG features suggestive of LQTS -Torsades de pointes/SCD -T wave alternans -Notched T wave in 3 leads -Resting HR
