family study of atrial septal defect · tricular septal defect. amother with a secundum defect and...

J. med. Genet. (1969). 6, 255.

A Family Study of Atrial Septal DefectELSPETH M. WILLIAMSON

From Southampton Children's Hospital, Southampton

Family studies, largely based on questionnaires, ofpatients suffering from atrial septal defect haveshown a small but significant increase in the numberof close relatives affected by congenital heart mal-formation (Campbell and Polani, 1961; Lamy, deGrouchy, and Schweisguth, 1957). A more recentfamily study, where available parents and sibs ofaffected patients were interviewed and clinicallyexamined, revealed a higher proportion of affectedrelatives (Nora, McNamara, and Fraser, 1967b).A further series seemed worth while, particularlyone giving information on the occurrence of cardiacmalformation in offspring of patients with atrialseptal defect. The results of such a study are re-ported here.

Method and MaterialRecords of the Wessex Cardiothoracic Centre were

searched and an attempt was made to trace those patientswho had attended the Centre during the period January1960-1966, in whom the diagnosis of atrial septal defectwas made by clinical methods and electrocardiographicfindings, and confirmed by cardiac catheterization, sur-gery, or necropsy. Those living far overseas were ex-cluded, as were those patients who had died and whoseparents were not available for interview. A particulareffort was made to trace adult patients in order to gaininformation about their offspring. To obtain a homo-geneous group, patients were excluded if a final diagnosisof ostium primum defect was reached, or if the atrialseptal defect formed only a minor component of a morecomplex lesion.

Eventually 136 patients were invited to participate inthe study. One did not wish to co-operate, so 135patients from 131 families were included as indexpatients. These patients and their families were visitedand a full social and family history elicited. Whereverpossible, parents, sibs, and offspring were examined.No relative was included as suffering from congenitalheart malformation unless there was confirmatory evi-dence from hospital records or death certificate.The index patients were grouped according to the

cardiological diagnosis (Table 1).

Received March 4, 1969.

TABLE ICARDIAC MALFORMATION IN INDEX PATIENTS

Total Male Female

Group I: ostium secundum defect only 99 30 69Group II: ostium secundum defect with

other cardiovascular anomaly 25 10 15Group III: sinus venosus type defect 11 7 4

Total index patients 135 47 88

Group I comprised 99 patients (30 male and 69 female)in whom an ostium secundum defect was the onlycardiovascular malformation.

Group II comprised 25 patients (10 males and 15female) in whom an ostium secundum defect was associ-ated with some other cardiovascular abnormality.Anomalous venous drainage, pulmonary valve stenosis,and ventricular septal defect were the most commonassociated anomalies, but aortic coarctation, persistentductus arteriosus, mitral stenosis, and subaortic stenosiswere also found.

Group III comprised 11 patients (7 male and 4 female)in whom a sinus venosus type defect was diagnosed.These were all associated with some degree of anomalousvenous drainage.A female preponderance was found among the index

patients, giving a sex ratio of 0-53. This preponderancewas most marked among the patients with isolated secun-dum defects.

Associated Non-cardiac Malformations in IndexPatients. One index patient had Down's syndromeand two were educationally subnormal. Three childrenhad strabismus, one had accessory nipples, and oneaccessory auricles. One child had had an operation forpyloric stenosis. Minor skeletal abnormalities includedtwo bifid ribs in a boy, and triphalangeal, finger-likethumbs in a girl, similar to those described by Holt andOram (1960) associated with atrial septal defect. Neitherthe parents nor the sibs of this index patient had a simi-lar thumb or cardiac abnormality.

Twins. Four of the index patients were one of twins;in no case was the co-twin affected. One pair was of un-like sex and one female pair was known to be dizygotic.In the other two female pairs there was insufficientevidence to determine zygosity.

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Elspeth M. Williamson

ResultsSummaries of the families are given in Appen-

dixes A, B, and C.

(1) 78 Index Patients whose Mothers wereInterviewed. These index patients were dis-tributed as follows. Group I: 53 patients (20 maleand 33 female); Group II: 19 patients (10 male and9 female); Group III: 6 patients (5 male and 1

female).Maternal and Environmental Factors. The dis-

tribution of index patients by maternal age and birthorder (Tables II and III) was compared with theRegistrar General's figures for the relevant year ofbirth. (The index patient with Down's syndromewas excluded because of the known association be-tween this syndrome and high maternal age.) Theresults showed no significant variation from theexpected distribution.The social class of each index patient was deter-

mined by the father's employment according to theRegistrar General's classification of occupation(1960). A high proportion of parents in the armedservices was noted, due probably to the presence oflarge naval and military bases within the region,

but no other significant variation from the distribu-tion in the general population was noted (Table IV).The season of birth of each index patient was

tabulated (Table V). The results showed no vari-ation from the expected distribution.

Maternal health during the relevant pregnancy:during the first trimester of pregnancy two mothershad rubella and one had measles. Vaginal bleedingwas reported by two mothers during early pregnancy(2 6%o). This is similar to the finding of Turnbulland Walker (1956) of 2-4% threatened abortion inall pregnancies. One mother admitted trying toprocure an abortion with purgatives.

Sibs of These 78 Index Patients. Stillbirths, abor-tions, normal, and affected sibs occurring within thefamily (excluding the index patient) are tabulated inTable VI. The figures have been scrutinized, andno significant differences are revealed in the results ofthe pregnancies before the index patient and thoseafter the index patient; nor were there differencesbetween the families where the index patient wasmale and the families where the index patient was

female. Thus the total figures are considered.The 212 pregnancies resulted in 22 abortions(10 30%). This figure does not differ significantly

TABLE IIMATERNAL AGE AT BIRTH OF INDEX PATIENTS

MaternalAge (yr.) < 20 20-24 25-29 30-34 35-39 40 + TotalGroup 1 20 9 15 6 1 Observed 52

2-8837 15-1583 16-2804 10-4733 5-5153 1-6890 Expected 52

Group 2 2 6 5 2 2 Observed 19II 1-2736 5-7263 6-0266 3-6450 1-7846 0-5439 Expected 19

Group 0 1 2 1 1 1 Observed 6III 0-3457 1-7534 1-9273 1-1373 0-6399 0-1964 Expected 6

Total 3 23 17 21 9 4 Observed 774 5030 22-6380 24-2343 15-2556 7-9398 2-4293 Expected 77

X2 = 5-9717.

TABLE IIIPARITY OF MOTHERS AT BIRTH OF INDEX PATIENTS

Previous Live Births

0 1 2 3 4 5 + Total

Group 19 13 9 5 1 5 Observed 52I 20-826 15-559 7 790 3-681 1-842 2-302 Expected 52

Group 7 8 3 1 0 0 Observed 19II 7 403 5-651 2-957 1-433 0-715 0-841 Expected 19

Group 3 2 0 0 0 1 Observed 6III 2-379 1-845 0-901 0-414 0-205 0-256 Expected 6

Total 29 23 12 6 1 6 Observed 7730-608 23-055 11-648 5-528 2-762 3-399 Expected 77

Xs' = 3-390.

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A Family Study of Atrial Septal Defect

TABLE IVSOCIAL CLASS OF INDEX PATIENTS

Social Class_________________ - ArmedI II III IV V Forces

Group I 2 12 22 10 1 6Group II 0 5 5 5 1 3Group III 0 0 5 0 0 1

Total 2 17 32 15 2 10

General population(Southampton) 1 98 10 21 37 72 7-55 10 54

TABLE VSEASON OF BIRTH OF INDEX PATIENTS

Jan.-Mar. Apr.-June July-Sept. Oct.-Dec.

Group I 9 19 11 14Group II 5 4 3 6Group III 0 0 2 4

Total 14 23 16 24

from the 150% estimated as the expected abortionrate among all pregnancies by Warburton andFraser (1964). Seven stillbirths resulted from the190 pregnancies that proceeded beyond 28 weeks'gestation; two of these were due to non-cardiacmalformation (one anencephalic and one meningo-myelocele), two were due to toxaemia in the mother,two were due to obstetric trauma, and in one casethe cause was unknown.

Besides the two stillbirths due to major malfor-mation of the central nervous system, one sib had a

severe scoliosis, one had a cleft palate, and one hadDown's syndrome. Five instances of major mal-

formations among 190 sibs (2 6%) is similar to therandom expectation of about 2-5% of all births(McKeown and Record, 1960).There were 12 sibs (5 male and 7 female) found

to have a congenital cardiac lesion among the 190(6-3%). Four families each had two affected chil-dren. In two of these families the lesion was iden-tical; two sisters had an ostium secundum defectand a small ventricular septal defect (No. 71 and 72),and a brother and sister had ostium secundum de-fects (No. 16 and 45). In a third family the lesionswere similar, a girl with an isolated secundum defectand her brother with a similar septal defect and anassociated aortic coarctation (No. 34 and 60). Inthe fourth family, the index patient (No. 47) had anisolated ostium secundum defect and her brotherhad a ventricular septal defect. In a further familythere were six affected children. The indexpatient (No. 17) had an ostium secundum defect,one brother and one sister had atrial and ventricularseptal defects, one brother had a ventricular septaldefect with mitral stenosis, and a further brotherhad a ventricular septal defect with coarctation ofthe aorta. A fourth brother had left ventricularcardiomyopathy.Among the 17 half-sibs of index patients, one was

affected with a cardiac malformation. The maleindex patient (No. 54) with a secundum defect andsubaortic stenosis had a paternal half-brother withsubaortic stenosis.

(2) Findings in Series as a Whole.Sibs of Remaining Index Patients. The other

57 index patients (12 male and 45 female) were

TABLE VIRESULTS OF PREGNANCIES IN MOTHERS OF INDEX PATIENTS

Sex of Unaffected Sibs Affected SibsIndex Stillborn AbortionPatient Male Female Male Female

Group IM Born before index patient 1 6 24 17 4 2

Born after index patient 0 1 10 5 0 0F Born before index patient 1 4 21 16 0 0

Born after index patient 0 4 15 23 3 0Group IIM Born before index patient 3 2 2 6 0 1

Bom after index patient 0 0 4 5 0 0F Born before index patient 1 3 0 3 0 1

Born after index patient 0 2 6 2 0 1Group IIIM Born before and after

and F index patient 1 0 8 4 0 0

Total pregnancies: 212 7 22 90 81 7 5

Half-sibsBorn before index patient 0 0 4 4 1 0Born after index patient 1 0 4 3 0 0

Total pregnancies: 17 1 0 8 7 |1 0

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questioned about their sibs. Close family informa-tion was incomplete, but 4 sibs with proven con-genital heart malformations were found among 204known sibs (1-90%).

Parental Consanguinity. The parents of indexpatient No. 127 were first cousins, and those of indexpatient No. 49 were second cousins, None of thefive sisters in the sibships was affected with con-genital heart malformation, nor was the one brother.

Offspring of Index Patients. Among the adultindex patients, 35 females and 10 males had off-spring. They were distributed as follows. GroupI: 8 males and 27 females; Group II: 5 females;Group III: 2 males and 3 females.The results of the pregnancies are tabulated in

Table VII. There was a total of 121 pregnanciesresulting in 110 live births, 1 stillbirth, and 10abortions (8 5%). Three of these children hadnon-cardiac congenital malformations, i.e. hydro-cephalus, fragilitas ossium, and a giant naevus(2-7%). These figures show no significant increaseover the expected incidence of stillbirth, abortion,and congenital non-cardiac malformation in thegeneral population.

Congenital cardiac lesions were found in 10 of the111 offspring (9%). These 10 affected children (6male and 4 female) were all among the 82 born toaffected mothers, none of the 29 children born toaffected fathers being themselves affected. Twomothers with isolated secundum defects (No. 87and 88) each had an affected daughter, one with anidentical lesion to herself and the other with a ven-

tricular septal defect. A mother with a secundumdefect and anomalous venous drainage (No. 117)bore a daughter who at necropsy was found to havemitral stenosis, aortic coarctation, and a persistentductus arteriosus. A mother with a sinus venosus

type defect (No. 121) bore a son with a ventricularseptal defect, and one mother with an isolatedsecundum defect (No. 89) bore 5 affected boys andone affected daughter. One of her sons (No. 17)had an identical lesion to hers, and the lesions

found in her other offspring have been describedearlier in the results section.

Congenital Heart Malformation in Further Rela-tives. One father and one mother of index patientswith ostium secundum defects had identical lesionsto their children (No. 15 and 17). One othermother and two fathers had suggestive historiesand clinical signs but had not been fully investigated.Among 29 grandchildren, 2 were known to beaffected, and in 1063 first cousins one was found tohave an ostium secundum defect and another diedof congenital heart disease thought to be a septaldefect. Among 322 nephews and nieces, one had anostium secundum defect and another a more com-plex lesion.

Cardiological Diagnosis in Affected First DegreeRelatives. The cardiac lesions found in the 26affected first degree relatives of index patients aretabulated in Table VIII. In 8 cases the lesionfound in the relative was identical to that in the in-dex patient, and in a further 6 relatives it waspartially so, an atrial septal defect being found in allthese 14 relatives. Among the remaining relatives,7 had ventricular septal defects, 4 in one familyshowed left ventricular cardiomyopathy, and 1 hadmitral stenosis and aortic coarctation with a patentductus arteriosus.

DiscussionFamilial aggregation of atrial septal defect is

apparent in the results of this family study. A re-currence of congenital heart malformation in 6 30%of sibs of index patients is a higher rate than wasreported by Campbell and Polani (1961) or by Noraet al. (1967b). The recurrence in 9%, of offspringof index patients in this study, and the high rate ofrecurrence in sibs is partly due to the inclusion of aremarkable family where both mother and son wereindex patients and there were six affected children(Fig.). In this particular family, left ventricularcardiomyopathy occurred in the father (I.1) and

TABLE VIIOFFSPRING OF INDEX PATIENTS

Unaffected AffectedSex of Offspring OffspringIndex Stillborn Abortion O p _ OffspnngPatient IMale Female Male Female

M Group I 0 0 14 10 0 0F Group I 0 3 32 22 5 3F Group II 0 5 4 5 0 1M Group III 0 0 4 1 0 0F Group III 1 2 6 2 1 0

Total pregnancies: 121 1 10 60 40 6 4

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TABLE VIIICARDIAC MALFORMATION IN FIRST DEGREE RELATIVES OF INDEX PATIENTS

Sex and Index No. Identical Malformation Malformation Including Malformation Including OtherAtrial Septal Defect Ventricular Septal Defect Malformation

Group IF 45 Brother, index patient 16M 16 Sister, index patient 45F 34 Brother, index patient 60, ASD

and coarctation of aortaF 47 Brother, VSDM 15 FatherF 87 DaughterF 88 Daughter, VSDF 89 Son, index patient 17 Son, ASD and VSD; daughter, Son, VSD and MS; son VSD Brother, LVC;

ASD and VSD and coarct. son, LVC;father, LVC

M 17 Mother, index patient 89 Brother, ASD and VSD; Brother, VSD and MS; Brother, LVCsister, ASD and VSD brother, VSD and coarct.

Group IIF 71 Sister, index patient 72

(ASD and VSD)F 72 Sister, index patient 71

ASD and VSDM 60 Sister, index patient 34, ASD

(ASD and coarct.)F 117 Daughter, MS,

(ASD and AVD) PDA, andcoarct.

Group IIIF 121 Son, VSD

Abbreviations: ASD-atrial septal defect; VSD-ventricular septal defect; MS-mitral stenosis; PDA-patent ductus arteriosus; coarct.-coarctation of aorta; AVD-anomalous venous drainage; LVC-left ventricular cardiomyopathy.

brother (11.2) of the index patient and in one of hersons (III.3). McKusick (1964) has described thiscondition as a single gene affect transmitted as adominant trait, and this pedigree is consistent with adominant mode of transmission with reduced pene-trance, as there is no evidence of cardiomyopathyin the index patient (II.1). The occurrence of asecond, probably unrelated, congenital cardiacdisease in this family, and the fact that this onefamily has contributed so much to the high rates ofrecurrence in first degree relatives found in thisseries, make it seem wise not to include this family

* Corgenital heart malformation> Index patient

ASD Atrial septal defectVSD Ventricular septal defectMS Mitral stenosis

I coarct. Aortic coarctationLVC Left ventricular cardiomyopathy 9V2 LVC

II ( 1938 194$ 1939ASD LVC SEYAL

DEFECT

III ; s o 1 *195 19 1959 190o 19VSD VSD LVC ASD ASD ASDMS COARCT. VSD VSD

FIG. Pedigree of index patients 17 and 89.

for the purpose of calculating the recurrence rates.Excluding this family, recurrence of congenitalheart malformation was found in 3 7% of sibs ofindex patients (a figure close to the 3 6% reportedby Nora et al., 1967b) and in 3-8% of offspring ofindex patients.

Studies of the maternal age and parity at the birthof the index patient and the social class of the familygave no evidence of these environmental factors be-ing involved in the aetiology of atrial septal defect.Landtmann (1965) found an increase in the numberof babies born with atrial septal defects in late sum-mer and early autumn, corresponding he suggestswith the winter occurrence of acute viral infections,which would affect the mother in early pregnancy.This finding is not confirmed in the present serieswhere no significant trend in the season of birth ofthe index patients was noted.The twins in this study showed no concordance

for atrial septal defect. Uchida and Rowe (1957)reported no increased concordance for con-genital heart malformation among monozygotictwin pairs than among dizygotic pairs. A personalstudy by Nora et al. (1967a) reported two monozy-gotic twin pairs where both twins were affected withatrial septal defect, and three dizygotic twin pairswhere only one twin was affected with atrial septaldefect. Though these figures are small, theysupport the suggestion that genetic factors are in-volved in the aetiology of atrial septal defect.

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Some families in the present series (No. 15, 87,88) suggest a dominant mode of transmission,whereas others (No. 16, 45, 71, 72) suggest a reces-sive mode. However, the over-all recurrence ratedoes not support any simple Mendelian pattern. Ithas been shown that polygenic inheritance can mimica Mendelian pattern (Edwards, 1960), and it is sug-gested that the results of the present study can beexplained on the hypothesis that the genetic pre-disposition to atrial septal defect is polygenic.

Similarity of the lesion in affected relatives ofpatients with atrial septal defect has been noticed inprevious reports (Christensen and Nelson, 1963;Carleton, Abelmann, and Hancock, 1958). In thepresent series, 4 of the 26 affected first degree rela-tives suffered from left ventricular cardiomyo-pathy and came from the one family. In the re-maining 22 first degree relatives, only 8 showed anidentical lesion to the index patient, but 14 (63-6%)had an atrial septal defect. Thus, 63 6% of the3-70/ of first degree relatives found to have a con-genital cardiac malformation had an atrial septaldefect-a recurrence of atrial septal defect in 2-35 %Oof first degree relatives.The incidence of congenital heart malformation

has been estimated to be about 6 per 1000 births,and in a Liverpool series Hay (1966) found a defectof the atrial septum in 11 7 %O of affected babies; theincidence of atrial septal defect, estimated fromthese figures, is 0 07% of births. Using the methoddescribed by Falconer (1965), with a populationincidence of 0 070, and an incidence in first degreerelatives of 2 35%/, the heritability of atrial septaldefect is about 70%O (69%/ + 9%/)The sharp fall-off in the proportion of second de-

gree relatives affected is in accordance with poly-genic injeritance (Carter, 1961, 1969), and is incontrast to the expected even halving of the propor-tion affected with each degree of relationship, if adominant gene with a reduced penetrance were in-volved. A deviation from the normal sex ratio witha preponderance of females was found, as in previ-ous studies (Campbell and Polani, 1961). Thereis, however, no evidence from the families now re-ported, that the relatives of the less commonlyaffected sex are more at risk than those of the com-monly affected sex, but the male deficit is not largeenough for any considerable increase in risk to beexpected.With polygenic inheritance, the risk of the abnor-

mality occurring within a family is increased if thereare affected close relatives. The large family in thepresent series, in which a mother and five of herchildren have septal defects, and the families de-scribed by Nora et al. (1967b) and by Campbell and

Polani (1961) with many affected members, couldrepresent families where many of the predisposinggenes are concentrated.Two consanguineous marriages among the parents

of 135 index patients is possibly higher than expec-ted in the general population, but is compatible withpolygenic inheritance (Carter, David, and Laurence,1968). None of the 6 sibs of the consanguineoussibship was affected with atrial septal defect, sothere was no recessive subgroup detectable byparental consanguinity in this series. It has beensuggested that recurrence of anomalies within a sib-ship is as likely to be due to persistence or recur-rence of environmental factors as to a common gene-tic inheritance (Yen and MacMahon, 1968). Thefinding in the present series of recurrence of atrialseptal defect as frequently in the offspring of indexpatients as in their sibs, together with Nora et al.(1967a) reporting a higher concordance in mono-zygotic twins than in dizygotic twins, indicate thatgenetic factors are of importance in the aetiologyof atrial septal defect. The figures presented inthis paper on the familial occurrence of atrial septaldefect can be explained by polygenic inheritance.

SummaryResults of a family study of 135 index patients

suffering from congenital atrial septal defect are re-ported.

Maternal age and parity, maternal health duringpregnancy, season of birth, and social class studiesgave no evidence of these environmental factors be-ing involved in aetiology.

In all, 3.70% of sibs and 3 8%° of offspring of indexpatients were affected with congenital heart malfor-mation, the cardiac lesion being an atrial septaldefect in 63%' of affected first degree relatives. Theheritability is estimated at 70%/. These findingsare compatible with the hypothesis that the pre-disposition to atrial septal defect is polygenic.

Thanks are due to Dr. Alan Johnson, Wessex Cardio-thoracic Centre, and to Dr. Cedric Carter, M.R.C.Clinical Genetics Unit, Institute of Child Health, forhelp and advice in the preparation of this paper; to thephysicians and surgeons of the Wessex CardiothoracicCentre for access to their case reports; and to the regionalgeneral practitioners for allowing me to visit theirpatients.The family study was supported by a grant from the

British Heart Foundation.

REFERENCESCampbell, M., and Polani, P. E. (1961). Factors in the aetiology of

atrial defect. Brit. Heart_J., 23, 477.Carleton, R. A., Abelmann, W. H., and Hancock, E. W. (1958).

Familial occurrence of congenital heart disease. Report of threefamilies and review of the literature. New Engi. J7. Med., 259,1237.

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Carter, C. 0. (1961). Congenital abnormalities. In ClinicalAspectsof Genetics, p. 30. Ed. by F. Avery Jones. Pitman Medical,London.

(1969). Genetics of common disorders. Brit. med. Bull., 25,52.

, David, P. A., and Laurence, K. M. (1968). A family study ofmajor central nervous system malformations in South Wales. J.

med. Genet., 5, 81.Christensen, F. K., and Nelson, R. M. (1963). Similar congenital

heart disease in siblings. thorac. cardiovasc. Surg., 45, 592.Edwards, J. H. (1960). The simulation of Mendelism. Acta

Genet. (Basel), 10, 63.Falconer, D. S. (1965). The inheritance of liability to certain

diseases, estimated from the incidence among relatives. Ann.hum. Genet., 29, 51.

Hay, J. D. (1966). Population and clinic studies of congenital heartdisease in Liverpool. Brit. med. J., 2, 661.

Holt, M., and Oram, S. (1960). Familial heart disease with skeletalmalformations. Brit. Heart J., 22, 236.

Lamy, M., de Grouchy, J., and Schweisguth, 0. (1957). Geneticand non genetic factors in the aetiology of congenital heart disease.A study of 1188 cases. Amer._. hum. Genet., 9, 17.

Landtmann, B. (1965). Epidemiological aspects of congenitalheart disease. Acta paediat. scand., 54, 467.

McKeown, T., and Record, R. G. (1960). In Ciba FoundationSymposium on Congenital Malformations, p. 5. Ed. by G. E. W.Wolstenholme and C. M. O'Connor. Churchill, London.

McKusick, V. A. (1964). A genetical view of cardiovascular disease.Circulation, 30, 326.

Nora, J. J., Gilliland, J. C., Somerville, R. J., and McNamara, D. G.(1967a). Congenital heart disease in twins. New Engl. J. Med.,277, 568.

, McNamara, D. G., and Fraser, F. C. (1967b). Hereditaryfactors in atrial septal defect. Circulation, 35, 448.

Registrar General (1960). Classification of Occupation. H.M.S.O.,London.

Turnbull, E. P. N., and Walker, J. (1956). The outcome of preg-nancy complicated by threatened abortion. J7. Obstet. Gynaec.Brit. Emp., 63, 553.

Uchida, I. A., and Rowe, R. D. (1957). Discordant heart anomaliesin twins. Amer. J. hum. Genet., 9, 133.

Warburton, D., and Fraser, F. C. (1964). Spontaneous abortionrisks in man. Data from reproductive histories collected in aMedical Genetics Unit. ibid., 16, 1.

Yen, S., and MacMahon, B. (1968). Genetics of anencephaly andspina bifida. Lancet, 2, 623.

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262 Elspeth M. Williamson

APPENDIX AIndex Patients Whose Mothers Were Interviewed

Abbreviations: sb, stilborn; *, relative affected with congenital heart defect; ASD, atrial septal defect; VSD, ventricu-lar septal defect; MS, mitral stenosis; M. inc., mitral incompetence; PDA, persistent ductus arteriosus; PVS,pulmonary valve stenosis; AVD, anomalous venous drainage; IP, index patient.

MonthIndex No. and Year Matemal Paternal Male Sibs Female Sibs Half-sibs Other Affected

of Birth Age AgeM

RelativesMale

.Female __

19 10.55

Ten-child family20 5.50

One-child families21 4.4622 2.4523 11.5624 4.57

Two-child families25 1.4726 11.4727 2.5828 11.5929 12.6030 11.4331 10.4932 8.4733 8.55

Three-child families34 3.5735 1.6236 1.5937 12.5638 8.44

Four-child families39 9.56

40 12.5541 3.5442 3.6043 7.5544 6.5345 5.56

Six-child families46 11.5147 9.54

48 12.49

19631964

1940, 1944

195419601935, 1939

1961

1942, 1943, 194819501950, 1957, 19651936, 1940194019441960

1956*1958*1959*1961*

1942, 1943,1945, 1946,1948, 1949,1950

1953, 1957,1959

1940, 1941,1946Grouop I: Fema

1956

1949

19631945

1959

1959*(IP60)

19601945, 19521938

1957, 1958

1954194619491953, 19541938, 19461957*(IP16),

1960

1945, 19571957,1960*(VSD)

1951, 1952

1950, 195619601963

1957

1952, 1956

19381946, 19481950, 1961(sb)1954, 1956*(IP45)

1960*

1945, 1947, 1949,1951

1934, 1936, 1938,1944, 1947, 1949

le Index Patients

1950

1962

19421951

19651960, 19651956

1940

1960

1957, 19641949, 19511951, 19531952(sb)19371954

1938, 1939, 19421956, 1958, 1962

1949, 1953, 1955

1962

1934,1938

1956

1954

1964

1950 (sb),1951, i95.

1935

1964

1950

Father* ASD

Mother*(IP89)

First cousin* ASD

First cousin onceremoved*(IP50)

One-child famiI

Two-child fami23

Three-child fan45678

9Four-child fam,

10111213141516

Six-child famil17

Eight-child fam18

!y4.61

lies6.613.59

tilies9.478.524.574.62

10.41

11.59lies

7.486.593.483.45

12.3811.628.57

6.62

ilies2.53

23

3025

3125272423

22

34312033213825

24

39

34

37

28302323

262637223323303225

2323403335

25

223236223324

3323

21

26

3230

3525282525

24

45352341284327

30

39

36

44

34422625

272544273325503326

2829423635

18

243437324326

3925

23I

3

3

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263

Index No. Month Matemal Patenmal Male Sibs Female Sibs Half-sibs Other AffectedofdBiart Age Age -Relativesof Birth ~~~~~~~~~~~MaleFemale

Seven-child family49 4.46

Eight-child families50 10.49

51 9.57

Twins52 3.55

53 7.58

One-child family54 M. inc. 2.56

Subaort.stenosis

Two-child families55 PDA 9.6356 VSD 8.6057 DVS 2.59

Three-child families58 AVD 1.6559 AVD 8.59

60 Aortic 11.59coarct.

Four-child family61 VSD 6.60

Five-child family62 AVD j 12.64

Six-child familv63 PVS 12.55

Two-child families64 PVS 11.3365 VSD 3.6266 AVD 9.5667 PVS 10.33

Three-child families68 PVS 2.61

69 Aort. coarct. 8.5270 PVS 10.6371 VSD 11.5572 VSD 12.56

One-child family73 9.63

Two-child families74 8.58

75 9.48Four-child family

76 4.57Seven-child family

77 7.49

Three-child family78 6.48

1957

1953, 1960

1932,1937,1938,1946, 1950,1952

1945, 1955 (co-twin)

1954, 1956Group II: Mal

1963

1964

1965

1957(sb), 1962

1957, 1960Group II: Fema

1966

19631954, 19551962(sb)19581958

Group III: Ma

1948, 1950, 1952,1959, 1963

1951, 1952, 1955,1962, 1964

1954

1946

1958 (co-twin)a Index Patientst

19601962

19661943, 19461957*(IP34)

1959, 1962

1960(sb), 1955(sb)

1948, 1950, 1962l e Index Patientst

1930

19621935

1959

19561956*(IP72)1955*(IP71)

le Index Patients

1962

1942

1955, 1964 1961(sb)

1943, 1945, 1946, 1935, 19361948Group III: Female Index Patient

1952, 1960

1940, 1935, 19361949*(subaortic stenosis)

1932

First cousin onceremoved* (IP 39)

First cousin oncerem.*ASD; firstcousin oncerem.*VSD

t Associated cardiac lesion is indicated immediately after Index No.


APPENDIX A-continued

19

23

44

32

22

42

312727

193725

19

30

30

40223138

2622312627

25

23

34

35

40

26

21

25

46

36

29

313327

233740

24

32

31

41263039

3225402425

26

29

37

32

42

30

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264 Elspeth M. Williamson

APPENDIX BIndex Patients With Offspring

Abbreviations: sb, stillborn; *, relative affected with congenital heart defect; ASD, atrial septal defect; VSD, ventricu-lar septal defect; MS, mitral stenosis; M. inc., mitral incompetence; PDA, persistent ductus arteriosus; PVS,pulmonary valve stenosis; AVD, anomalous venous drainage; IP, index patient.

Month Other AffectedIndex and Year Male Sibs Female Sibs Male Offspring Female Offspring RelativesNo. of Birth

1925, 19301921, 1923, 1933

10 sibs5 brothers1948

1922, 1924, 1931

1941, 19471921(sb)1945*LVC

19301917

1926, 1930, 1934

1926, 192819471914, 19184 brothers1917, 1921

1934, 1946, 1950,1955

1 brother1924, 1926, 1930,

1942

1924, 1926, 1928,1932, 1936

5 brothers1914, 1916, 1918,

1919, 19201927, 1930, 1933,

1935, 1937, 1938,1941

1944, 19511929, 1932(sb), 1934,

1953*5 brothers1939, 1945

1930

1935

3 brothers

A)

5 brothers

19301945

1924, 1928

19331915, 1919

Group I: Maio

5 sisters (1924*ASD)

Group I: Fema

19141915, 191819361919, 191619321943, 194619124 sisters (1920*)Twins 1923

1940(sb), 1951, 1958

7 sisters1935

1940

1922, 1927, 1929,1930, 1934, 1941

4 sisters1912, 1924, 1926

1949, 1956, 1960

1 sister1935, 1937, 1942

Group II: Fema1944

1940

2 sisters

6 sisters, twin sister

Index Patients1951

1931, 1933, 1935,1941

1952, 1958

1964

1954, 1958, 1962

1951, 1960re Index Patients19631951, 19631956,* 1958*, 1959,*

1961,* 1962*(IP17)1964

1956, 196019451943, 1950, 19551952, 195519501932, 1942, 19441941, 1943

19381963

196419391963

1933, 19511936, 1938, 1940

1954

19661959

19591e Index Patientst1966

1960

1962

1957

1964

Group III: Male Index Patients1922 1949, 19541943 1961, 1963

Group III: Female Index Patients1946*(VSD), 1947,

1949, 19551951(sb), 1960, 19621944

194819491936, 1938

1950, 1954, 19631962, 1965

1957

1965*ASD1961*VSD1960*

1963, 194919391946, 1951

1927, 1937, 19401939, 194519651963

1936, 1943

1962

19371942

1949, 1950

1961

19371958

1965

1956

1960, 1962*(MS,PDA, coarct.)

1962

1958

1945

1956

Brother's son*ASDFirst cousin once

rem.*(IP85)First cousin once

rem.*(IP84)

Father*; Firstcousin*

Granddaughter*

Granddaughter*Niece*

t Associated cardiac lesion is indicated immediately after index No.

1920798081

828384

85

86

878889

90919293949596979899100101

102103

104105106

107108

109

110111

112113

114(AVD)115

(AVD)116

(AVD)117

(AVD)67 (s

Twin118

(MS)

119120

121

122123

5.194.267.09

? 308.359.46

10.22

12.26

11.4410.288.38

11.2810.1210.2211.313.143.221.312.168.088.167.373.37

7.125.39

5.346.164.43

1.132.13

3.29

2.482.32

9.111.36

2.46

12.34

8.30

2.30

ee Appendib1.32

5.2411.39

3.21

5.274.23

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APPENDIX CIndex Patients Without Offspring Whose Parents

Were Not Available for Interview

Month SibsIndex No. and Year

of Birth Male Female

Group I: Male Index PatientsOne-child family

124 2.46Three-child family

125 2.24 1926 1931

Group .: Female Index PatientsOne-child families

126 4.24127 12-09

Two-child families128 10.31 1934129 4.07 1906

Three-child family130 2.40 1948 1942

Five-or-more-child families131 7.11 1908, 1916, 1927 1910132 10.07 1891, 1900, 1911 1899, 1901133 5.95 1885, 1888, 1890, 1896

1894, 1897,1899, 1901

Twin134 9.38 1932 1934, 1938 (co-twin)

Group II: Female Index Patient135 11.20 3 brothers 3 sisters

3

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family study of atrial septal defect · tricular septal defect. amother with a secundum defect and...

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