Abstract

Aims

Sudden arrhythmic death syndrome (SADS) occurs when a person suffers a sudden, unexpected death, with no cause found at postmortem examination. We aimed to describe the cardiac screening outcomes in a population of relatives of SADS victims

Methods and results

Prospective and retrospective cohort study of consecutive families attending the Family Heart Screening clinic at the Mater Misericordiae Hospital in Dublin, Ireland, from January 2007 to September 2011. Family members of SADS victims underwent a standard screening protocol. Adjunct clinical and postmortem information was sought on the proband. Families who had an existing diagnosis, or where the proband had epilepsy, were excluded. Of 115 families identified, 73 were found to fit inclusion criteria and were retained for analysis, with data available on 262 relatives. Over half of the screened family members were female, and the mean age was 38.6 years (standard deviation 15.6). In 22 of 73 families (30%), and 36 of 262 family members (13.7%), a potentially inheritable cause of SADS was detected. Of the population screened, 32 patients (12.2%) were treated with medication, and 5 (1.9%) have received implantable cardiac defibrillators. Of the five families with long QT syndrome (LQTS) who had a pathogenic gene mutation identified, three carried two such mutations.

Conclusion

In keeping with international estimates, 30% of families of SADS victims were found to have a potentially inherited cardiac disease. The most common positive finding was LQTS. Advances in postmortem standards and genetic studies may assist in achieving more diagnoses in these families.

What's new?

• This series shows that the diagnostic yield from family-based screening in a sudden arrhythmic death syndrome (SADS) population was a positive finding in 30% of families.

• Medical therapy only was indicated in the majority of the 12% of screened patients who received a clinical diagnosis of an inherited cardiac disease. In contrast to potential concerns, the requirement for implantable cardiac defibrillator therapy in screened relatives was low. Implantable cardiac defibrillators were implanted in five patients in this series (1.9% of all screened patients).

• Of the five LQT families who were found to have a pathogenic gene mutation, three families had more than one potentially pathogenic genetic variant identified in family members. Clinicians and geneticists must consider digenic LQT in families where an SADS death has occurred.

Introduction

Sudden cardiac death (SCD) is a common mode of death, with the estimated SCD incidence varying between 50 to 100 deaths per 100 000 population in Europe and North America.1 Furthermore, regional estimates of the incidence of out-of hospital cardiac arrests requiring emergency service call-out can be as great as 173 events per 100 000 person-years.2 In Ireland, SCD has a reported incidence of 51.2/100 000.3 While the commonest cause of SCD is atherosclerotic cardiovascular disease, there is a subset of sudden, unexpected deaths in which no postmortem findings including toxicological investigations can identify the cause of death. This may be called sudden arrhthmic death syndrome or SADS.4 The incidence of SADS in persons aged 4–64 years has been estimated as 0.16 events per 100 000 person-years,4 whereas the incidence of SADS in persons aged 14–35 years in Ireland has recently been reported to be 0.76 per 100 000 population-years.5

The causes of SADS can include cardiac conditions such as the ion channelopathies and cardiomyopathies. These are genetic conditions, and evidence of these conditions may be found in relatives of the deceased. Using a structured screening protocol, cardiac screening in close relatives of SADS victims can identify inheritable cardiac diseases in up to 40% of families.6–9 Furthermore, incorporating genetic screening with a ‘molecular autopsy’ can increase the identification of inheritable cardiac disease in SADS families.9,10 These diagnoses have important implications for families and individuals. However, the extent to which the findings of current studies can be extrapolated to different populations is unclear.

This study aims to examine the prevalence of hitherto undiagnosed inherited cardiac disease found in consecutive SADS families presenting to an inherited cardiac diseases clinic in the Republic of Ireland, using a standard clinical screening protocol. We describe our current SADS screening protocol, in the context of the published protocols of other international groups.

Methods

The Family Heart Screening Clinic at the Mater Misericordiae University Hospital performs protocol-driven family-based screening for inheritable cardiac diseases since 2007. Families attended the clinic by hospital-, general practitioner-, or self-referral.

Inclusion and exclusion criteria

For this analysis, a SADS death was defined as a sudden, unexpected death in a person with no prior known cardiac disease, last seen well within 12 h of the death, and within 1 h of the onset of symptoms (if any), in whom a full postmortem examination including toxicology investigations could not identify the cause of death.10 Families were excluded from this analysis if postmortem information were not available, or if there was an existing family diagnosis of an inheritable cardiac disease, or if the proband had epilepsy. Deaths in probands aged under one year were categorised as sudden infant death syndrome (SIDS), and were not included. If cardiac abnormalities were detected at postmortem review, such as unsuspected arrhythmogenic right ventricular cardiomyopathy (ARVC) or hypertrophic cardiomyopathy (HCM), families underwent screening, but were not included in this analysis.

Screening protocol

Family members of SADS victims underwent a standard protocol of screening tests (Figure 1). Firstly, adjunct clinical and postmortem information was sought on the proband, including full postmortem report and copies of any ante-mortem cardiac tests [such as an elecrocardiogram (ECG)]. Family information was sought as to the circumstances of the proband's death, and his or her medical and medication history. For families where the postmortem information was incomplete or not available, clinical screening was undertaken but not reported here, as the SADS death could not be verified. A three-level family pedigree was generated, to identify any pattern of inheritance in family members, and to look for any clues as to the aetiology of the SADS death, such as a family history of deafness, epilepsy, and pacemaker insertion for conduction system disease. All patients underwent a 12-lead ECG, 24-hour Holter monitor with automated QT analysis, transthoracic ECHO, and a treadmill exercise test (Bruce protocol). Further testing was undertaken as indicated by the findings of this initial screen. This included signal-averaged ECG (if there was any suspicion of ARVC), cardiac magnetic resonance imaging (MRI) scanning (if findings suggestive of ARVC or HCM were noted), and ajmaline provocation testing for the Brugada syndrome (BrS; offered in families where no other cause of death was detected, and/or the proband died is his or her sleep, and/or findings of a type 2 Brugada ECG were detected in a family member).

Figure 1

Screening protocol for first-degree relatives of victims of SADS in the Family Heart Screening Clinic at the Mater Misericordiae University Hospital, Dublin. 

Figure 1

Screening protocol for first-degree relatives of victims of SADS in the Family Heart Screening Clinic at the Mater Misericordiae University Hospital, Dublin. 

Standard diagnostic criteria were used for the conditions sought.11–20 Long QT syndrome (LQTS) was defined as probable LQTS using the Schwartz criteria.11 Brugada syndrome was diagnosed as ≥2 mm coved-type ST elevation in V1 and V2 on a standard ECG tracing, either spontaneously or on drug (ajmaline) provocation test.12 Catecholaminergic polymorphic ventricular tachycardia (CPVT) was diagnosed in patients who had a treadmill exercise test finding of increasing ventricular ectopy on incremental execise, with polymorphic or bidirectional couplets, salvos, or non-sustained or sustained VT, with an otherwise normal heart.13,14 Early repolarization (ER) was defined as J-point elevation, either notched or S-wave slurring into the ST-segment, with J-point or ST-segment elevation of ≥0.1 mV in the inferior ECG leads, lateral ECG leads, or both.15 Hypertrophic cardiomyopathy was defined as unexplained left ventricular maximal wall thickness of ≥15 mm.16 If one family member were diagnosed with HCM, diagnostic criteria for HCM were applied to other family members according to the published guidelines.17 Dilated cardiomyopathy (DCM) was diagnosed as an unexplained increase in left ventricular diastolic diameter in diastole of >112% (predicted by Henry's formula) and a fractional shortening ≤25%.18 Arrhythmogenic right ventricular cardiomyopathy was defined using revised 2010 Task Force criteria.19 Left ventricular non-compaction (LVNC) was defined by echocardiographic criteria of Jenni et al.20 In patients in whom a clinical diagnosis was made, referral was made to the Irish National Centre for Medical Genetics, through which genetic counselling and genetic testing were performed as per the Heart Rhythm UK (HRUK) guidelines.21 Extracted DNA was sent to Diagnostic Laboratories with UK Clinical Pathology Accreditation, and standard protocols were used to determine pathogenicity.22 Data on screening visits were gathered both retrospectively (from July 2007 to December 2009) and prospectively (from January 2010 to July 2011), using clinic logs to identify cases. Data were collected from patient and family charts into a password-protected spreadsheet, with analyses performed both at patient- and family-level. This study received ethical approval from the Mater Misericordiae University Hospital Research Ethics Committee, and the study was performed with due regard to the principles of the Declaration of Helsinki. Statistical analysis was performed with Intercooled Stata 11 (StataCorp, Texas).

Results

Of the 400 families attending the clinic during this period, 112 families were identified with either an initial referral diagnosis of SADS, or a diagnosis of SADS attributed on case review. All families underwent comprehensive cardiac screening. In total, 73 families were found to fit inclusion criteria (Figure 2). Family heart screening data were available on 262 relatives from the 73 eligible families.

Figure 2

Flow chart of the study population.

Figure 2

Flow chart of the study population.

Patients

Table 1 shows the baseline characteristics of the family members screened. In most families the proband was male, with age at death ranging from 1.5 to 60 years old. Two families had two SADS victims. Over half (55.5%) of the screened family members were female. After the standard clinic testing protocol, further testing was undertaken with ajmaline provocation test in 28 (10.6%), signal-averaged ECG in 10 (3.8%), and cardiac MRI scanning in 10 (3.8%). In total, 36 of 262 (13.7%) of family members were found to have a potentially inheritable cardiac disease on screening. Eight further family members were found to have ischaemic heart disease. The commonest condition detected was LQTS, in 24 screened family members (Figure 3), with other channelopathies such as BrS and CPVT being less commonly identified. Almost 1 patient in 10 had findings of ER on their ECG (25 patients from 18 families, 9.5% of all screened patients). Of these 18 families, no specific cause for the SADS death was found in 12 (66.7%). Three patients with ER were found to have a concomitant inherited cardiac condition (two with BrS on ajmaline testing and one with CPVT). More pronounced J-point elevation of ≥2 mV was seen in one patient in the inferior ECG leads, and in three patients in the lateral leads. Figure 4 shows an ER ECG from a first-degree relative of a SADS victim.

Table 1

Baseline characteristics of the probands and 257 screened relatives of 73 families with SADS bereavements

Baseline screening information Population 
Family member information Screening population (n = 262) 
 Male sex, n (%) 116 (44.3%) 
 Age, mean (SD*) 38.64 (15.59) 
 Relationship to proband  
  First-degree relative, n (%) 220 (84.0%) 
  Second-degree relative, n (%) 28 (10.7%) 
  Third-degree relative, n (%) 14 (5.34%) 
Proband information SADS probands (n = 73) 
 Age at death, mean (SD) 27.70 (11.07) 
 Male sex, n (%) 54 (74.0%) 
Baseline screening information Population 
Family member information Screening population (n = 262) 
 Male sex, n (%) 116 (44.3%) 
 Age, mean (SD*) 38.64 (15.59) 
 Relationship to proband  
  First-degree relative, n (%) 220 (84.0%) 
  Second-degree relative, n (%) 28 (10.7%) 
  Third-degree relative, n (%) 14 (5.34%) 
Proband information SADS probands (n = 73) 
 Age at death, mean (SD) 27.70 (11.07) 
 Male sex, n (%) 54 (74.0%) 

*Standard deviation

Figure 3

Newly diagnosed inheritable cardiac conditions in 36 relatives of victims of SADS, identified through protocol-based cardiac screening.

Figure 3

Newly diagnosed inheritable cardiac conditions in 36 relatives of victims of SADS, identified through protocol-based cardiac screening.

Figure 4

Early repolarization changes in a first-degree relative of an SADS victim.

Figure 4

Early repolarization changes in a first-degree relative of an SADS victim.

Families and probands

Figure 5 shows the distribution of inheritable cardiac disease diagnoses in the SADS families. In 22 of 73 families (30.1%), a potentially inheritable cause of SADS was detected. Of the first-degree relatives of SADS victims, 13.2% (29/220) were found to have a potentially inheritable cardiac disease, compared with 14.3% (6/42) of second- or third-degree relatives. The mean age at death of the probands for whom a family diagnosis was made was 27.39 years (SD 14.12), compared with a mean age of 29.64 (SD 11.63) in the families where no diagnosis was made. Ten families were found to have evidence of LQTS. Of these 10 families, 5 of the probands were taking potentially QT-prolonging drugs at the time of death, with a further proband having had low potassium due to a concurrent medical problem. Two LQTS probands were participating in sports at the time of death, and two further deaths occured on waking from sleep (both in LQT2 families). Five families were found to have evidence of BrS, with four having family members diagnosed on ajmaline testing, and one further with a diagnosis of possible BrS on a molecular autopsy (SCN5A mutation), but with a negative ajmaline test in the single family member screened in our clinic. Two of the BrS probands were thought to be at rest or sleep at the time of death. Four families were found to have CPVT as the cause of death, and three of the probands in these families had deaths which occurred during sports and/or a state of increased activity.

Figure 5

Diagnoses of potentially inheritable pro-arrhythmic cardiac conditions made through family heart screening, for 22 of 73 families.

Figure 5

Diagnoses of potentially inheritable pro-arrhythmic cardiac conditions made through family heart screening, for 22 of 73 families.

One family had findings of ER on the proband's ECG as the only positive finding in that family after extensive family investigation. In four further families, a first-degree relative of the proband was found to have ER with ST elevation of ≥2 mm, two of which families had a cause found for their SADS death (one BrS and one CPVT), and two of which had no cause found.

Treatments and outcomes

All screened relatives who received a diagnosis were given disease-specific lifestyle advice and were counselled on sports participation with due regard to international guidelines.23 Thirty-two family members (12.2% of the total SADS screening population) were treated with medication, and three have received implantable loop recorders to further define their arrhythmic risk potential because of symptoms of syncope or presyncope. Three patients with BrS proceeded to electrophysiological study with programmed electrical stimulation. Five screened patients (1.9% of the total SADS screening population) have received implantable cardiac defibrillators (ICDs) because of high-risk features of their condition (4 LQTS, 1 HCM).24 To date, one has received an appropriate ICD discharge. One patient died of SCD with genetically proven CPVT after initiation of beta-blocker therapy. One patient with a normal screening evaluation later suffered an SCD. There were no treatment withdrawals.

Molecular genetic findings

Specific genetic findings by family are listed in Table 2. In our series, of 10 families with clinical findings of LQTS, 2 families was found to carry single KCNH2 gene mutations, and a further 3 families were found to have two pathogenic LQT mutations in family members in the pedigree. Five other clinically diagnosed LQT patients did not have typical mutations on initial molecular genetic testing. Of the four families with CPVT, two were found to have RyR2 mutations (one on a postmortem sample from the proband), one was gene-negative, and one has not been tested. Of the five families with BrS, one is a possible diagnosis, with a postmortem sample from the proband with a SCN5A variant which has been previously associated with BrS (Table 2). However, further information on segregation in this family is awaited. In the other families, one person did not want testing, and three were gene-negative for mutations in the SCN5A gene. In the patients found to have cardiomyopathies, genetic testing is pending.

Table 2

List of the genetic variants found in the SADS families who underwent genetic testing, with numbers of gene-positive patients from the study cohort

Family Clinical diagnosis Genetic result
 
Notes 
  Gene affected and nucleotide change Amino acid change Classification of variant 
LQTS KCNH2 c.2494 A>T p.Lys832X Highly likely to be pathogenic Three of three screened family members found to have this pathogenic mutation 
LQTS KCNH2 c.2145 G>A p.Ala715Ala Highly likely to be pathogenic Two of three screened family members found to have this pathogenic mutation 
3* LQTS KCNE1 c.94 C>T p.Arg32Cys Likely pathogenic Three of four screened family members with the KCNE1 variant, with one of the three a double heterozygote with a de novo KCNH2 pathogenic mutation also 
  KCNH2 c.2959_2960 del CT – Highly likely to be pathogenic  
4* LQTS KCNQ1 c.1552 C>T p.Arg518x Highly likely to be pathogenic Three of nine screened family members have the KCNQ1 pathogenic mutation, with one further family member with the KCNH2 deletion but not the KCNQ1 pathogenic mutation 
  KCNH2 Exon 2 deletion – Highly likely to be pathogenic  
5* LQTS KCNQ1 c.805 G>A p.Gly269Ser Highly likely to be pathogenic Three screened family members found to have the KCNQ1 pathogenic mutation, with one of these with the KCNE2 pathogenic mutation also 
  KCNE1 c.170 T>C p.Ile57Thr Highly likely to be pathogenic  
CPVT RYR2 c.6380 G>T p.Arg2127Leu Highly likely to be pathogenic One of three screened family members affected with this mutation. Mutation detected in extended family 
CPVT RYR2 c.1258 C>T p.Arg420Trp Likely pathogenic ‘Molecular autopsy’ finding. One of five screened family members found to have this mutation 
BrS SCN5A c.6010 T>G p.Phe2004Val Variant of uncertain significance (Class III) ‘Molecular autopsy’ finding. One family member screened locally, with no clinical disease 
Family Clinical diagnosis Genetic result
 
Notes 
  Gene affected and nucleotide change Amino acid change Classification of variant 
LQTS KCNH2 c.2494 A>T p.Lys832X Highly likely to be pathogenic Three of three screened family members found to have this pathogenic mutation 
LQTS KCNH2 c.2145 G>A p.Ala715Ala Highly likely to be pathogenic Two of three screened family members found to have this pathogenic mutation 
3* LQTS KCNE1 c.94 C>T p.Arg32Cys Likely pathogenic Three of four screened family members with the KCNE1 variant, with one of the three a double heterozygote with a de novo KCNH2 pathogenic mutation also 
  KCNH2 c.2959_2960 del CT – Highly likely to be pathogenic  
4* LQTS KCNQ1 c.1552 C>T p.Arg518x Highly likely to be pathogenic Three of nine screened family members have the KCNQ1 pathogenic mutation, with one further family member with the KCNH2 deletion but not the KCNQ1 pathogenic mutation 
  KCNH2 Exon 2 deletion – Highly likely to be pathogenic  
5* LQTS KCNQ1 c.805 G>A p.Gly269Ser Highly likely to be pathogenic Three screened family members found to have the KCNQ1 pathogenic mutation, with one of these with the KCNE2 pathogenic mutation also 
  KCNE1 c.170 T>C p.Ile57Thr Highly likely to be pathogenic  
CPVT RYR2 c.6380 G>T p.Arg2127Leu Highly likely to be pathogenic One of three screened family members affected with this mutation. Mutation detected in extended family 
CPVT RYR2 c.1258 C>T p.Arg420Trp Likely pathogenic ‘Molecular autopsy’ finding. One of five screened family members found to have this mutation 
BrS SCN5A c.6010 T>G p.Phe2004Val Variant of uncertain significance (Class III) ‘Molecular autopsy’ finding. One family member screened locally, with no clinical disease 

*For families 3–5, two gene mutations were detected

The KCNH2 mutation c.2145 G>A is most likely a splice site mutation, and the change at protein level can be designated as Ala715sp25

LQTS Long QT syndrome BrS Brugada Syndrome

CPVT Catecholaminergic polymorphic ventricular tachycardia

Discussion

Key findings

SADS is a devastating event for families. Not only do the family suffer grief and bereavement, there is also the challenge of dealing with such a sudden death with no apparent cause.26 A recent report has suggested that the Republic of Ireland has at least as high an incidence of SADS in younger persons as other nations.5 We have shown that in an Irish setting, protocol-driven family heart screening can yield a clinical diagnosis in one-third of consecutive SADS families. This finding is in keeping with international estimates, and extends the generalisability of SADS screening from existing reports.6–10

Similar to findings from other European series,6–10 we found that the LQTS was the most common condition detected. LQTS has recently been described to be more prevalent than heretofore understood.27 The benefits to early detection of LQTS are well established: there are acceptable preventive strategies for this condition, including avoidance of QT-prolonging drugs, beta-blockade, and specific lifestyle modification advice.28 Therapy may be tailored to the individual's LQTS type and specific mutation, once it is identified.28,29 ICD therapy may be advised for those patients who have high-risk features to their LQTS.24,30

We noted clinical evidence of CPVT in four screened patients. While CPVT has been diagnosed in the past on a finding of exercise-induced polymorphic or bidirectional VT in the setting of a structurally normal heart,13 recent work suggests that using broader criteria of exercise-induced couplets and triplets in relatives of confirmed CPVT cases has a higher sensitivity and specificity for gene carrier status.14 However, it is acknowledged that at this time, optimal criteria for CPVT diagnosis have not been defined,31 and the clinical diagnosis of CPVT in those persons who do not carry a recognized CPVT-causing mutation must remain under review as further guidance documents emerge. In our series, none of the four persons with a possible or definite CPVT diagnosis had a history of syncope. The two gene-negative patients had typical non-sustained polymorphic VT on exercise test. The two gene-positive patients had ventricular couplets and triplets.

We describe a number of families in whom changes of ER were noted in individuals. Compared with the findings of a case–control study of J-point elevation in SADS relatives, our prevalence of ER was lower than that described (9.5 vs 23%).32 There is a high prevalence of early repolarization changes in healthy populations;15,32,33 however, ER with ST elevation of ≥0.2 mV is less common (prevalence of 0.3% in one study34) and is associated with a three-fold hazard ratio increase for arrhythmic and cardiovascular death.34 This growing body of evidence on the association between ER and ventricular arrhythmia presents a challenge for clinicians.35 There are no guidelines on management of the asymptomatic patient with ER and a family history of SADS at this time.

Only five patients in this series were found to require ICD implantation (1.9% of all screened patients), and this finding is in keeping with a recent report by Caldwell et al.8 Patients attending for screening from families with an SADS death understandably have high levels of anxiety regarding their own health36. However, using conventional indications for ICD implantation,24 it was seen that the majority of patients required medical therapy and/or lifestyle modifications alone.

Three families in the our series had their diagnosis established through a ‘molecular autopsy’ – a process in which a sample of frozen blood or tissue on the deceased person is analysed for the common gene mutations associated with either LQTS or CPVT. This process may provide the best evidence of which genetic change affected the proband, and clear guidance is now available on strategies for testing such samples,21 with evidence as to their utility in such conditions as LQTS.37 However, since not all potentially relevant genotypes are known, the molecular autopsy does not obviate the need for family screening. The two approaches are complementary.

Although probands with a post-mortem diagnosis of cardiomyopathy were excluded, nevertheless four patients were found to have cardiomyopathies [one each with HCM and DCM, and two with changes of LVNC. Post hoc review of the proband postmortem reports for these three families did not describe cardiomyopathy changes. This unexpected finding was also noted in another family screening study.10 It may be that sudden cardiac death was an early manifestation of the genetic defect in the proband, before macroscopic or microscopic phenotypic changes. Improved postmortem standards for sudden cardic death victims38 may assist in better definition of the proband's pathology in the future.

Family screening protocols

‘High-risk’ clinically based family heart screening involves an intensive panel of investigations, with input from a specialist family heart screening nurse and consultant cardiologist, as well as liaison with the national hub for medical genetics and expert pathologists. A number of authorities have published details on their cardiac screening regimens,6–10,39 with a comprehensive overview of the rationale for each screening step provided by Quarta et al.40Table 3 describes the proposed schedules of testing, as per the published protocols from 2003 onwards. Investigations in this table have been listed as either first-, second-, or third-line, based on how they appear in the published reports. However, the fundamental approach is a preliminary screen with relatively lower-cost and higher-yield investigations, with further testing based on both the initial findings and the family information. All published protocols emphasize the importance of the information collection on the family proband and the three-level family tree. Implementing a family-based clinical service means that patients' risk is assessed in the context of the family findings, and new family findings can be easily synthesized into the pedigree.

Table 3

Cardiac screening tests included in published screening protocols

Test Behr protocol (2003)6 Tan protocol (2005)7 Behr protocol (2008)10 van der Werf protocol (2010)8 Nunn and Lambiase protocol (2011)38 Caldwell protocol (2012)8 
Electrocardiogram First-line First-line First-line First-line First-line First-line 
Holter monitor First-line – First-line Performed if suspicion of ARVC First-line Performed if suspicion of LQTS 
Exercise stress test Performed ‘on a discretionary basis’ First-line First-line Performed if suspicion of premature atherosclerosis, ARVC, or no findings First-line First-line 
Echocardiograph (transthoracic) First-line First-line First-line Performed if suspicion of premature atherosclerosis, BrS, ARVC, or no findings First-line First-line 
Signal-averaged electrocardiogram (SAECG) – – Performed if suspicion of ARVC – First-line – 
Ajmaline testing – Performed if suspicion of BrS from the screening ECG Performed if normal screening and normal ECG OR suspicion of BrS Performed if suspicion of BrS Performed if suspicion of BrS from the screening ECG or the proband's mode of death Performed if suspicion of BrS from the screening ECG or the proband's mode of death 
Adrenaline testing for LQT – – – – Performed if LQT1 suspected – 
Cardiac magnetic resonance imaging – Performed if suspicion of ARVC Performed if suspicion of ARVC Performed if suspicion of ARVC Performed if echo abnormalities are detected, or suspicion of ARVC Performed if echo abnormalities are detected 
Test Behr protocol (2003)6 Tan protocol (2005)7 Behr protocol (2008)10 van der Werf protocol (2010)8 Nunn and Lambiase protocol (2011)38 Caldwell protocol (2012)8 
Electrocardiogram First-line First-line First-line First-line First-line First-line 
Holter monitor First-line – First-line Performed if suspicion of ARVC First-line Performed if suspicion of LQTS 
Exercise stress test Performed ‘on a discretionary basis’ First-line First-line Performed if suspicion of premature atherosclerosis, ARVC, or no findings First-line First-line 
Echocardiograph (transthoracic) First-line First-line First-line Performed if suspicion of premature atherosclerosis, BrS, ARVC, or no findings First-line First-line 
Signal-averaged electrocardiogram (SAECG) – – Performed if suspicion of ARVC – First-line – 
Ajmaline testing – Performed if suspicion of BrS from the screening ECG Performed if normal screening and normal ECG OR suspicion of BrS Performed if suspicion of BrS Performed if suspicion of BrS from the screening ECG or the proband's mode of death Performed if suspicion of BrS from the screening ECG or the proband's mode of death 
Adrenaline testing for LQT – – – – Performed if LQT1 suspected – 
Cardiac magnetic resonance imaging – Performed if suspicion of ARVC Performed if suspicion of ARVC Performed if suspicion of ARVC Performed if echo abnormalities are detected, or suspicion of ARVC Performed if echo abnormalities are detected 

Strengths and limitations

In this study, we provide information on a moderately large series of consecutive, well-phenotyped family members of SADS victims. Our study has some limitations. We report the findings of one centre only. However, our clinic population come from all over Ireland, with some relatives attending also from the UK. Our data are observational, and we have relatively limited follow-up data at this time. Clinical screening followed a standard protocol (Figure 1), but some family members chose not to proceed to ajmaline provocation testing for the BrS, especially if they were free of symptoms such as syncope. Furthermore, for both standard 12-lead ECGs and during ajmaline testing, standard lead positioning was used, rather than high-lead positions.41 For these reasons, our proportion of families with BrS may be an underestimate. Our study criteria excluded probands who may have suffered deaths due to ion channelopathy diseases, but who had another positive postmortem finding, or a known channelopathy, or a history of seizures with a diagnosis of epilepsy. Therefore, this study does not provide any estimate of the prevalence or mortality burden associated with inherited cardiac diseases in Ireland. However, if the clinic team felt that there was a co-existing possibility of a primary arrhythmic death, clinical screening of first-degree relatives was offered. Even with a diagnosis of epilepsy, channelopathy may be an underlying finding.42 Similarly, although these data were not reported here, screening was undertaken in families with a history of SIDS, as recent estimates have suggested that one-fifth of SIDS victims may have a pathogenic cardiac ion channel mutation.43 For some families identified in the clinic logs, complete postmortem information was not consistently available. Such circumstances may become less frequent as improvements in autopsy standards for sudden cardiac death victims improve.38 Again, clinical screening of relatives was offered, but not reported in this analysis.

There was no difference in the rates of diagnosis between the first- and higher-degree relatives. This is likely due to a self-selection bias, as persons with symptoms are more likely to attend for screening. We did not include screening results on children aged 16 and under, as our facility provides screening to adults only. Children were referred to a cardiologist with expertise in screening children, in a hospital with paediatric facilities. This report details the results of clinical screening. Molecular genetics results are not available on all reported individuals in this series. Molecular genetic services in Ireland are notably under-staffed, and due to service constraints, clinical cardiac screening may precede or be performed concomitant with cascade genetic testing. Nevertheless, cascade genetic screening and the ‘molecular autopsy’ are vital adjuncts to clinical investigation of families.

Conclusion

In keeping with international estimates of disease detection, 30% of families of SADS victims were found to have a potentially inheritable cardiac disease. The most common positive finding was LQTS. Advances in clinical screening, postmortem standards, and genetic studies may assist in achieving more diagnoses in these families.

Study approval

Ethical approval was granted for this study by the Mater Misericordiae University Hospital Research Ethics Committee. Patients were asked to give consent to the study data collection and analysis from January 2010 onwards. Patients who attended from January 2007 to December 2009 were not required to give individual consent.

Funding

No specific funding was received for this study. However the work of the Family Heart Screening Clinic is funded through charitable donations through the Mater Foundation's Mater Heart Appeal. CMcG is in receipt of a UCD Newman scholarship grant through Edwards Lifesciences. OC is in receipt of a unrestricted funding grant through Sanofi Ireland.

Acknowledgements

We would like to sincerely thank the patients who participated in this study. We gratefully acknowledge the assistance of the molecular genetics laboratory at the Oxford University Hospitals NHS Trust, and also the assistance of Ms Brenda Fleming and Mr Colin McQuade with data collection.

Conflict of interest: none declared.

Author contributions: C.McG., M.C., J.O.N, J.G. and N.G.M. designed the study. C.McG., N.H., O.C., E.K., J.O.N., J.G. and N.G.M. collected patient data. C.McG. and N.G.M. performed the data analysis. C.McG. wrote the manuscript. All authors provided comments on the manuscript.

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Author notes

Institution where work was performed: The Heart House, Mater Misericordiae University Hospital, Eccles Street, Dublin 7, Ireland.