This is the first study to examine late mortality in adults with 22q11.2DS. The results demonstrate that individuals with 22q11.2DS who survive to adulthood are at elevated risk of premature death when compared with their unaffected siblings. Calculating an odds ratio for 22q11.2DS is hampered by the empty cell for sibling deaths. An estimate calculated by artificially attributing one death to the sibling group shows an odds ratio of 21.5 (95% confidence interval 2.7 to 167.8). Notably, deaths in 22q11.2DS occurred at average age 41.5 years overall (47.3 years in those with no major CHD), much earlier than Canadian general population expectations: age 80.4 (both sexes); 78.0 (males); 82.7 (females) years.30
Indeed, the 11.8% mortality rate we observed for a relatively young adult cohort with 22q11.2DS is somewhat higher than that reported for infants (8%), predominantly related to CHD.9
This association between 22q11.2 deletions and early mortality in adults has not been previously described.
The causes of premature death in adults with 22q11.2DS are likely multifactorial and both cardiac and non-cardiac in origin. shows no unifying cause or single factor that adequately account for all deaths or all six sudden unexpected deaths. In the general adult population, premature death is often due to malignancy but there was no evidence from history or on autopsy of cancer in our sample. Despite its frequency as a lifetime feature of 22q11.2DS,3
only one death was attributed to infectious disease. Also, surgery for palatal abnormalities and obesity are common in 22q11.2DS,3
raising the possibility of sleep apnoea, but there was no direct evidence this was involved in the deaths. Neuropsychiatric disease and learning difficulties are common in 22q11.2DS and may interfere with obtaining appropriate medical care and maintaining compliance with recommended management. However, all of the patients in our cohort who died were in active medical follow-up in the Canadian universal health care system. Adults with major CHD have reduced life expectancy,25
but the oldest age at death in our study of 22q11.2DS (33.2 years) is younger than the median age for individuals surviving to adulthood with comparable CHD complexity at our centre, even though patients with genetic syndromes like 22q11.2DS would have been included. While major CHD is an important determinant of mortality in 22q11.2DS, we found that carrying a 22q11.2 deletion was the strongest predictor of mortality in adults, suggesting factors other than major CHD must be involved.
Strikingly, the most common cause of death observed was unexplained sudden death in six (6%) of 102 subjects. This uses a definition of sudden cardiac death that includes the provision that while prior conditions may be present they are not conditions that would appear fatal.20
An alternative view is to consider several of these six deaths sudden but in some way expected because of features associated with possible arrhythmogenicity—for example, atrial flutter, prolonged QT interval, major CHD—or because postmortem results were unavailable and thus there is uncertainty with respect to coronary artery disease. Taking such a conservative approach, and considering only one of these six a sudden unexpected death, the estimated rate would be 29 per 100 000 person-years in this 22q11.2DS cohort. In comparison, rates of sudden adult death syndrome (SADS) in the general population are estimated at 0.13–1.38 per 100 000 person-years.29
The fact that four of these six individuals had no major CHD suggests that, even for sudden unexpected deaths, gross underlying cardiac defects are an insufficient explanation in this cohort.
Studies of target tissue will be essential to determine possible mechanisms. Looking to the general population for clues, however, there are several plausible causes of sudden death to consider. Ventricular arrhythmias in the setting of structural coronary artery disease (CAD)31
are most common but none of the six 22q11.2DS patients with sudden unexpected deaths, including the three with postmortem results, had evidence of CAD. The unexpected and sudden nature of these deaths (including death during sleep) without any prior condition that would appear fatal makes other arrhythmic aetiologies a consideration.20
In the general population, familial ion channel abnormalities or cardiomyopathies are rare causes of SADS. However, there was no family history of sudden unexpected death in our sample and no evidence of cardiomyopathy clinically or on postmortem. Electrolyte disturbances (low calcium, magnesium and potassium) and the use of antipsychotics and other medications may be associated with a potential proarrhythmic state. Hypoxia, associated with respiratory disease and/or sleep apnoea, is another possible risk factor. As in general population samples,29
however, there was no direct evidence linking these factors to sudden death in 22q11.2DS. All 46 patients with schizophrenia and 22q11.2DS were treated with various antipsychotic medications. Six died of natural causes, three with sudden unexpected death, only one of whom had QT >460 ms. However, neither ECGs nor echocardiograms were performed on an annual basis and timing of the studies relative to the sudden unexpected deaths were variable. Serial studies may be helpful to identify the mechanism of death. Schizophrenia itself is known to be associated with sudden unexpected death28, 29, 32
and with increased mortality in general, mostly from suicide.33
The average age at natural death is older and mortality rates much lower32
than we observed in 22q11.2DS schizophrenia (44.8 years; 16%, respectively), however. Impaired autonomic activity has been reported postoperatively in two children with 22q11.2DS34
and, as for the general population,27–29
should be considered as another possible mechanism predisposing to sudden death.
The 22q11.2DS phenotype is highly variable in severity and accompanying features.3, 6
In this study, we ascertained adults with 22q11.2DS, some of whom had been diagnosed relatively early and many of whom were not identified until they were adults. Adults with schizophrenia were present at about twice the expected rate.3
Like many samples of 22q11.2DS, the rate of major CHD (38.2%) in our sample may be higher than that of an ideal epidemiological sample. Subjects not studied would include individuals with 22q11.2 deletions who died before age 17 and the many who have never been diagnosed with this under-recognised syndrome. Our results would be expected to pertain to individuals with 22q11.2DS identified largely because of characteristic features of 22q11.2DS,15, 35
but may be important even for adults not yet identified as having a 22q11.2 deletion. Larger samples would be needed to determine if patients with milder expression have significantly more favourable survival. We note, however, that 25% (cases 6, 9, 12 at ages 38.2, 48.8, 68.8 years) of the patients who died, including one of the six with sudden unexpected death, were initially found to have 22q11.2DS as transmitting parents. The mean age of adults with 22q11.2DS included in this study was relatively young, with the oldest subjects 68.6 and 57.5 years old. Thus, the long term outcome of older individuals with 22q11.2DS remains largely unknown.
Despite the involvement of coroners, only half of the subjects received postmortem examinations and thus pathologic causes of sudden death could not be assessed in three cases. All cases of sudden unexpected death require more detailed examination of cardiac conduction and right ventricular areas than is common in standard autopsies.29
Studies following larger numbers of patients with 22q11.2DS prospectively over decades will provide more details about clinical risk factors for death as an outcome of the syndrome, including possible effects of associated medical and psychiatric illnesses, medications, lifestyle and other factors. Detailed genome-wide molecular studies, under way at several centres including ours, will be needed to determine what role genetic variants play in mortality, both those within the 22q11.2 deletion region and its more than 45 genes, and in other regions of the genome.7
Our recent results suggest that genome-wide copy number variants do not appear to play a role but further studies are required.19
This study provides an initial overview of premature mortality in predominantly young to middle-aged adults with 22q11.2DS. 22q11.2DS is under-recognised, particularly in adults, has variable expressivity, commonly occurs as a spontaneous mutation, and has an estimated population prevalence of 1 in 4000.3
These features and the mortality results in this study suggest that some of the sudden unexpected deaths observed in general population samples29
may represent undiagnosed individuals with 22q11.2DS. Addition of 22q11.2 deletion studies to the molecular autopsy could clarify this.
For patients with 22q11.2DS, the results have implications for genetic counselling and long term follow-up, reinforcing the need for specialty clinics using a multidisciplinary approach.3–5, 36
In addition to suggested preliminary guidelines for the assessment and follow-up of adults with 22q11.2DS3
including calcium and magnesium monitoring, our results suggest that consideration should be given on a research basis to additional cardiac investigations—for example, serial ECGs or Holter monitoring. Further investigations of other systems could also shed light on additional possible causes of premature mortality. The results predict that rates of 22q11.2DS may be lower in older patient populations—for example, as observed in tetralogy of Fallot.35
As for all cases of premature death, the importance of autopsies cannot be overemphasised. Increased case recognition and tissue samples will be essential for elucidating the underlying pathogenesis both of 22q11.2DS itself and its associated excess mortality.