The 22.q11.2 deletion syndrome (22q11DS) is a common genetic condition associated with 22q11.2 microdeletions and classically has included congenital heart disease (CHD) as a part of the variable expression. Some evidence has shown that relatives of those with 22q11DS might be at an increased risk of CHD in the absence of 22q11.2 deletions. We obtained a detailed family history of CHD in the first- to third-degree relatives (n = 2,639) of 104 adult probands with 22q11DS. We compared the prevalence of CHD in the relatives without 22q11.2 deletions to the published general population prevalence. We also investigated the effect of CHD in the probands on prevalence of CHD in the relatives. Of the 104 probands with 22q11DS, 14 (13.5%) had 17 relatives (17 of 2,639, 0.6%) with CHD. Of 66 probands with CHD, 15 (0.9%) of their 1,663 relatives had CHD, a significantly greater prevalence than that for the relatives of probands without CHD (0.2%, 2 of 976, p = 0.041, odds ratio 4.43, 95% confidence interval 1.03 to 40.00). In relatives of probands with CHD, the prevalence of those with severe CHD (0.36%) was significantly elevated compared to population expectations (0.061%, p = 0.007, odds ratio 5.88, 95% confidence interval 2.16 to 12.85). In conclusion, these results support a heritable susceptibility to CHD in families of probands with 22q11DS, in addition to that imparted by microdeletion 22q11.2. The occurrence of CHD in relatives might be related to the expression of CHD in the proband with 22q11DS. These findings have potential implications for the genetic counseling of families of those with 22q11DS and support the notion that interacting genetic variants might contribute to the variable expression of 22q11DS.
The 22q11.2 deletion syndrome (22q11DS) is a common, multisystem disorder associated with microdeletion 22q11.2 that occurs at an estimated prevalence of 1/4,000 live births. Congenital heart disease (CHD) is a classic feature of 22q11.2DS, found in about 40% of patients. Conotruncal anomalies such as tetralogy of Fallot (TOF), interrupted aortic arch, and truncus arteriosus have been most strongly associated. Multiple factors are thought to affect the expression of CHD in patients with 22q11DS. These include the hemizygosity of the 45 genes in the 22q11.2 deletion region and interaction of the effects of hemizygosity with genetic variants both in the intact chromosome 22 and elsewhere in the genome. In families of probands with 22q11.2 deletions, an elevated prevalence of CHD in relatives without 22q11.2 deletions would support this hypothesis of genetic interaction. Two previous pediatric studies have suggested such an elevated prevalence of CHD. However these studies involved in total just 6 first-degree relatives with CHD and did not report on the parental origin of the 22q11.2 deletion. In the present study, a well-characterized group of adults with 22q11DS was examined for a family history of CHD in their relatives without 22q11.2 deletions. We tested the hypothesis that a positive family history of CHD would be more common in the probands with CHD. We also predicted that CHD would segregate with the intact chromosome 22 in the families, consistent with the potential importance of variants in the 22q11.2 deletion region to CHD expression.
Methods
Patients monitored at our clinic for adults (>17 years) with 22q11DS (n = 131) were available for study. Those with 22q11.2 deletions who were adopted (n = 4), had an inadequate family history (n = 12), or were family members of probands (n = 11) were excluded. Most subjects were ascertained because of the presence of CHD or a psychiatric disorder. The probands and their parents provided written informed consent. The research ethics boards of the University of Toronto, Centre for Addiction and Mental Health and University Health Network approved the study.
We evaluated 104 probands with the 22q11.2 deletion, all of whom had met the clinical criteria for 22q11DS and had lifetime clinical data available, including cardiac assessments. All probands with 22q11DS had echocardiograms and/or cardiac catheterization findings available to evaluate their cardiac status. CHD was classified by structural complexity, as previously described. Among probands with 22q11DS in the present series, major CHD included TOF, pulmonary atresia, or an absent pulmonary valve. Simple CHD included ventricular septal defects, or atrial septal defects. The ethnicity of the sample was 90% white (n = 94), 4% Asian (n = 4), 2% black (n = 2), and 4% other (n = 4).
A comprehensive family history was obtained from multiple interviews with all families, and pedigrees were constructed to include the first- to third-degree relatives. A history of CHD in the relatives was confirmed by medical record review where possible. To avoid a falsely elevated recurrence rate of CHD, a history of heart murmurs or cardiac conditions that were detected later in life were not considered CHD. All available parents of probands underwent assessment for the clinical features suggestive of 22q11DS. Potential syndromal features in other relatives with CHD were determined by history or direct clinical assessment, as possible. The relatives with CHD who were confirmed (n = 8; 6 children, 1 mother, and 1 sibling) to have microdeletion 22q11.2 or were suspected (n = 6; 5 siblings and 1 uncle) to have microdeletion 22q11.2, according to the presence of syndromal features or when the 22q11.2 deletion status of one or both parents was unavailable, were excluded. Genetic testing for syndromes other than for 22q11DS and for karyotypic anomalies was not performed.
The 22q11.2 microdeletion was confirmed in all probands by standard fluorescence in situ hybridization techniques using a TUPLE 1 (Vysis, Inc., Abbott Park, Illinois) or N25 (Oncor, Inc., Gaithesburg, Maryland) probe. Once the 22q11.2 deletion was confirmed in the proband, testing was offered to all available parents. For a study of the copy number variation in 22q11DS, DNA samples from 99 subjects (probands) with 22q11DS and 122 unaffected parents were genotyped for approximately 250,000 single nucleotide polymorphisms with the Affymetrix Gene CHIP Human mapping 250K Nspl Array (Affymetrix Inc., Santa Clara, California), as previously described. These data were used to determine the mode of 22q11.2 deletion and the parental origin of the de novo deletions, as well as the copy number variant (CNV) content. The mode of the 22q11.2 deletion within the cohort was confirmed to be de novo in 70 probands and transmitted in 5 probands. In cases in which parental DNA was unavailable for genotypic study, we assigned a “probable de novo” (n = 14) or “probable transmitted” (n = 2) deletion status according to the clinical features. We had 13 probands for whom the origin of the 22q11.2 deletion could not be determined. Among the probands with confirmed or probable de novo 22q11.2 deletions, the parental origin of the 22q11.2 deletion was determined for 74 probands, of whom 42 were of maternal origin. In the confirmed or probable transmitted group (n = 7), parental origin was maternal in 4 cases.
All statistical analyses were performed using Statistical Package for Social Sciences, version 11.5 (SPSS, Chicago, Illinois) and Statistical Analysis Systems, version 9.13 (SAS Institute, Cary, North Carolina). The chi-square or 2-tailed Fisher exact test was used to compare the categorical variables. The comparisons with the general population prevalence of any CHD (0.58%) or severe CHD (0.061%) used the data derived from combined numbers for adults and children in a large Canadian study.
Results
Of the 104 probands with 22q11DS in the present study (48 men and 56 women, mean age 33.3 ± 10.3 years), 66 (63.5%) had CHD (23 with simple CHD and 43 with major CHD). The presence of CHD in the proband was not significantly associated with the parental origin of the 22q11.2 deletion for either the de novo (maternal 29 of 42 [69%] vs paternal 17 of 32 [53%], p = 0.16) or transmitted (maternal 2 of 4 [50%] vs paternal 3 of 3 [100%], p = 0.43) groups. In addition, the probands with CHD did not exhibit de novo CNVs or any excess of novel inherited CNVs outside the 22q11.2 region (data not shown).
A total of 2,639 relatives were included in the present study, with a median of 23 relatives per proband (range 10 to 64 relatives). A total of 14 probands (13.5%), 9 with confirmed and 5 with probable de novo 22q11.2 deletions, had a positive family history of CHD of various types in a total of 17 relatives (0.64%; Table 1 ).
| Proband | Relative(s) | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Pt. No. | 22q11.2 Deletion | CHD in Proband | Relative | Degree of Relation | CHD in Relative | Severe CHD | Syndromal Features | Absence of 22q11.2 Deletion ⁎ | Relative on Same Family Side as Intact Chromosome 22 | ||
| Length (Mb) | Confirmed or Probable De Novo | Parental Origin | |||||||||
| 1 | 3 | Probable | — | 0 | Child | First | CHD unspecified | − | Developmental delay | Confirmed | − |
| 2 | 3 | Confirmed | Maternal | 0 | Sibling | First | PDA | 0 | 0 | Presumed | − |
| 3 | 3 | Confirmed | — | TA | Sibling | First | VSD | 0 | 0 | Confirmed | − |
| 4 | 3 | Probable | — | VSD | Nephew | Second | CHD unspecified | − | 0 | Confirmed | − |
| 5 | 3 | Probable | — | TOF | Niece | Second | VSD not requiring surgery | 0 | 0 | Presumed | − |
| 6 | 3 | Confirmed | Paternal | TOF | Nephew | Second | D-TGA | + | 0 | Confirmed | − |
| 6 | Maternal aunt | Second | CHD unspecified “blue baby,” died at 1 y | + | 0 | Presumed | + † | ||||
| 7 | 3 | Confirmed | Maternal | PA/VSD | Maternal aunt | Second | PDA, repaired at 8 y | 0 | 0 | Presumed | 0 |
| 8 | 3 | Confirmed | Maternal | TOF | Maternal aunt | Second | TOF, died at 18 mo without repair | + | 0 | Presumed | 0 |
| 9 | 1.5 | Confirmed | Maternal | TOF | Maternal aunt | Second | “Hole in heart,” detected in pregnancy | 0 | 0 | Presumed | 0 |
| 10 | 3 | Confirmed | Paternal | VSD, ASD | Maternal uncle | Second | 2 “holes in heart,” repaired at 12 y | 0 | 0 | Presumed | + † |
| 11 | 3 | Confirmed | Maternal | TOF | Paternal uncle | Second | “Hole in heart” not requiring surgery | 0 | 0 | Presumed | + † |
| 12 | 3 | Probable | — | TOF | Maternal aunt | Second | CHD unspecified “blue baby,” infant death | + | 0 | Presumed | − |
| 12 | Maternal uncle | Second | CHD unspecified cyanotic, died at 38 y | + | 0 | Presumed | − | ||||
| 13 | 3 | Confirmed | Paternal | VSD | Paternal first cousin | Third | CHD unspecified, died at 9 y | + | 0 | Presumed | 0 |
| 13 | Maternal first cousin | Third | “Hole in heart” | 0 | 0 | Presumed | + † | ||||
| 14 | — | Probable | — | TOF | Paternal first cousin | Third | “Hole in heart,” early childhood repair | 0 | 0 | Presumed | − |
⁎ Confirmed indicated direct testing using standard fluorescence in situ hybridization and 22q11.2 probe (n = 4); presumed indicated both parents of proband negative for 22q11.2 deletion (n = 9) and/or without features of 22q11DS (n = 4).
† Even if the affected relative was on the same side as the origin of the intact chromosome 22 in the proband, the chance (in the case of an aunt/uncle) of sharing that intact chromosome 22 would be at most 50%.
The overall prevalence of CHD in the relatives of 22q11DS probands (0.64%) was similar to that of the general population for any CHD (0.58%, p = 0.8). However, probands with 22q11DS who themselves had CHD were more likely to have relatives with any CHD than were probands with no CHD (15 of 1,663 [0.9%] vs 2 of 976 [0.2%], p = 0.041, odds ratio [OR] 4.43, 95% confidence interval [CI] 1.03 to 40.00). In addition, 6 (40%) of the 15 relatives of the 22q11DS probands with CHD had severe and/or cyanotic CHD, significantly greater than the general population prevalence (0.36% [6 of 1,663] vs 0.061%, OR 5.88, 95% CI 2.16 to 12.85, p = 0.007). Of 11 second- and third-degree relatives with CHD, 8 (73%) were maternal relatives ( Table 1 ). In contrast to our prediction, no apparent relation was seen between the familial side (maternal or paternal) of the affected relative and that of the intact chromosome 22 ( Table 1 ).
Table 2 lists the recurrence risk for CHD in the first- to third-degree relatives of 104 22q11DS probands in our cohort and comparable data from another study of 108 probands with 22q11DS that reported nonsyndromic CHD in the first-degree relatives. The recurrence risks for first-degree relatives using the combined data for 22q11DS (n = 212 probands) and for relatives of a pediatric sample of 97 nonsyndromic patients with TOF with no 22q11.2 deletions are also included for comparison purposes ( Table 2 ). Our data suggested a greater prevalence of CHD in the aunts and uncles of 66 probands with 22q11DS and CHD than in the comparable relatives of probands with nonsyndromic forms of TOF (8 of 439 [1.82%] vs 1 of 572 [0.17%], OR 10.60, 95% CI 1.41 to 471.01, p = 0.013). Comparing only probands with TOF, we still found a greater prevalence of CHD the among aunts and uncles of the 43 probands in our sample than in the comparable relatives of those with nonsyndromic TOF (6 of 258 [2.33%] vs 1 of 572 [0.17%], OR 13.60, 95% CI 1.63 to 626.30, p = 0.004).
| 22q11DS Family Studies | Non-22q11DS TOF Family Study (Digilio et al † ) | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Present Study | Digilio et al ⁎ | Combined Samples | ||||||||
| Probands (n) | 104 (total cohort) | 66 (subgroup with CHD) | 108 | 212 | 97 | |||||
| Average proband age (years) | 33 ± 10 | 32 ± 10 | NA | NA | 6.5 | |||||
| Relation of Relatives | CHD/Total (n) | Risk (%) | CHD/Total (n) | Risk (%) | CHD/Total (n) | Risk (%) | CHD/Total (n) | Risk (%) | CHD/Total (n) | Risk (%) |
|---|---|---|---|---|---|---|---|---|---|---|
| First degree | 3/405 | 0.74 | 1/257 | 0.39 | 5/253 | 1.98 | 8/658 ‡ | 1.22 ‡ | 4/290 | 1.38 |
| Parents | 0/201 | — | 0/127 | — | 1/198 § | 0.51 | 1/399 | 0.25 | 1/194 | 0.52 |
| Siblings | 2/192 | 1.04 | 1/122 | 0.82 | 3/54 | 5.56 | 5/246 | 2.03 | 3/96 | 3.13 |
| Children | 1/12 | 8.33 | 0/8 | — | 1/1 ‡ | — | 2/13 ‡ | 15.38 ‡ | — | — |
| Second degree | 11/1276 | 0.86 | 11/806 | 1.36 | NA | NA | — | 2/960 | 0.21 | |
| Grandparents | 0/416 | — | 0/264 | — | — | — | — | 1/388 | 0.26 | |
| Aunts/uncles | 8/666 | 1.20 | 8/439 | 1.82 | — | — | — | 1/572 | 0.17 | |
| Nieces/nephews | 3/145 | 2.07 | 3/85 | 3.53 | — | — | — | — | — | |
| Half siblings | 0/49 | — | 0/18 | — | — | — | — | — | ||
| First cousins | 3/958 | 0.31 | 3/600 | 0.50 | NA | NA | — | 6/936 | 0.64 |
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