RESEARCH ARTICLE

The Consequences of Consanguinity on the Rates ofMalformations and Major Medical Conditions at Birthand in Early Childhood in Inbred PopulationsJo€el Zlotogora1* and Stavit A. Shalev2

1Department of Community Genetic, Public Health Services, and Hebrew University, Jerusalem, Israel2Genetic Institute, Ha’Emek Medical Center, Afula, and Rappaport School of Medicine, Technion, Haifa, Israel

Received 25 April 2010; Accepted 12 May 2010

The rate of malformations and major medical conditions in early

childhood was analyzed in a single village according to the degree

of relationship between the parents. In the village, 70–80% of the

marriages are between descendants of the founders and therefore

consanguineous. In the period 1992–2003, in 99 of 2,610

children, a major malformation was diagnosed at birth and seven

additional fetuses were aborted because of a severe malforma-

tion. A significant medical condition was diagnosed in 38 addi-

tional children in early childhood. The total of 144 cases with

malformations or a major medical condition represented

5.52% (95% CI: 4.64–6.4) of the live births. Three

malformations/disorders were relatively frequent: Down syn-

drome, esophageal atresia, and profound deafness. The rate of

malformations and significant medical conditions was 7.77% (95

CI: 5.68–9.86) when the parents were first cousins and 3.63%

(95% CI: 2.11–5.15) when they were not related (P¼ 0.002,

Fisher’s exact test). Offspring of parents that were second cousins

or closer but less than first cousin had a risk that was similar to

the one of offspring of couples that were more distantly related.

We propose therefore, that in inbred populations, all the couples

that are not related as first cousins but in which the spouses

are both descendants of the founders should be considered as

related. The high prevalence of profound deafness in the village is

due to mutations in the Connexin 26 gene, while the relatively

high frequency of Down syndrome is not explained by maternal

age only. � 2010 Wiley-Liss, Inc.

Key words: consanguinity; inbred populations; malformations;

deafness; esophageal atresia; Down syndrome

INTRODUCTION

Consanguineous marriages have always been frequent and in the

last century much emphasis was focused on their possible adverse

health outcomes [Bittles and Black, 2010]. However, many of the

studies that have been conducted on consanguinity have often

lacked adequate controls [Khlat and Khoury, 1991]. Therefore, the

present study was performed in a well-defined population, a

Muslim village in Israel of 11,000 inhabitants founded about

300 years ago by few ancestors. In a 10 km distance from the village

is located a large Arab town as well as several other Arab villages.

This village was chosen at random in 1995 as the site for a pilot

project implementing genetic counseling in the Arab community.

Since the beginning of the project the data have been entered into a

pedigree computer program (Reunion, Leister Production, Inc.)

and are constantly updated being used for clinical and for research

purposes [Zlotogora et al., 2002, 2006].

The purpose of the study was to determine the rate of malfor-

mations and major medical conditions in early childhood accord-

ing to the degree of relationship between the parents.

SUBJECTS AND METHODS

For the analysis we included all couples in which at least one spouse

was born in the village and still living in it at the time of the study.

The year of birth of the women was used as a reference since it is

the date most frequently recorded in the database. It was

almost always possible to determine the exact relationship between

the spouses when both partners were descended from the

*Correspondence to:

Jo€el Zlotogora, Department of Community Genetics, Building 67 Sheba

Medical Center, Ramat Gan, Israel. E-mail: joelz@cc.huji.ac.il

Published online 15 July 2010 in Wiley InterScience

(www.interscience.wiley.com)

DOI 10.1002/ajmg.a.33537

How to Cite this Article:Zlotogora J, Shalev SA. 2010. The

consequences of consanguinity on the rates of

malformations and major medical conditions

at birth and in early childhood in inbred

populations.

Am J Med Genet Part A 152A:2023–2028.

� 2010 Wiley-Liss, Inc. 2023

founders. In this patriarchal community, a woman is almost always

living with her husband family. When a man marries a woman

from another village, the couple generally lives in the husband’s

village.

The database was initiated by gathering information through

personal interviews with families in the village, and is updated

yearly since 1992, including all the live births in the village and

malformations diagnosed at birth with data from the Israeli registry

of malformations in live newborn infants [Zlotogora et al., 2003].

The medical information was collected from the family physicians

in the village, and the Genetic Institute of Ha’Emek Hospital. In

recent years, the data obtained in genetic consultations are con-

stantly updated. Because of the geographical location of the village

and the personal links which have developed since the beginning of

the project between the authors and the physicians working in the

village, almost all the referrals from the village are to the Genetic

Institute either for genetic counseling or genetic and prenatal tests.

The data were analyzed in 2009 in order to include diseases

appearing in the first 5 years of life; only children born before

2003 with major malformations and diseases leading to disability

were included in the study (Additional Information). To avoid the

bias of multiply affected pregnancies in families with a known

inherited syndrome or chromosomal aberration, recurrent dia-

gnoses leading to termination of pregnancy were not included in the

study (Additional Information).

RESULTS

Type of Marriages According to the Degree ofRelationshipData on the type of marriages in the village have been published

previously and are updated in Table I [Zlotogora et al., 2002]. Along

the years, the proportion of first cousin marriages declined almost

entirely due to the reduction of marriages between children of

brothers (patrilateral parallel first cousin marriages; Table I). In the

present study, aided by a new function of the computer program

allowing determination of the precise relationship between the

spouses, we could perform a more detailed analysis. The proportion

of spouses that married a 2nd cousin or a closer relative (including

first cousins) declined along the years from 52.5% to 30.3%

(P< 0.0001, Fisher’s exact test), while the proportion of those

marrying a more distant relative increased from 33.1% to 46.2%

(P< 0.02, Fisher’s exact test).

Malformations and Significant Medical ConditionsAmong Children From the Village

General incidence. In the years 1992–2003, 2,610 children were

born to parents in whom the relationship between the spouses was

known. In 99 of those children, a major malformation was diag-

TABLE I. Type of Marriages in the Village According to the Year of Birth of the Woman

1930–1939 1940–1949 1950–1959 1960–1969 1970–1979 1980–1989 TotalDouble first cousins 1 (0.7%) 5 (2.5%) 3 (0.8%) 1 (0.2%) 0 1 (0.4%) 11First cousins parallel patrilineal 19 (13.7%) 27 (13.6%) 44 (12.3%) 54 (8.5%) 50 (7.8%) 14 (6.0%) 208First cousins parallel matrilineal 2 (1.4%) 5 (2.5%) 6 (1.6%) 19 (3.0%) 17 (2.7%) 9 (3.8%) 64First cousins cross patrilineal 4 (2.9%) 5 (2.5%) 12 (3.4%) 19 (3.0%) 17 (2.7%) 7 (3.0%) 64First cousins cross matrilineal 6 (4.3%) 11 (5.6%) 12 (3.4%) 32 (5.0%) 32 (5.1%) 9 (3.8%) 96Second cousin and closer 41 (29.5%) 39 (19.7%) 62 (17.3%) 99 (15.5%) 78 (12.3%) 31 (13.2%) 350Related more distantly than second cousins 46 (33.1%) 67 (33.8%) 134 (37.5%) 222 (34.6%) 247 (38.8%) 108 (46.2%) 824Spouse from a another village 20 (14.4%) 39 (19.7%) 84 (23.5%) 193 (30.1%) 195 (30.5%) 55 (23.5%) 586Total number of marriages 139 198 357 639 636 234 2,203

The numbers are of each type of marriage during the respective interval and the percentages represent the proportion of the type of marriages during the time interval.

2024 AMERICAN JOURNAL OF MEDICAL GENETICS PART A

nosed at birth, and seven additional fetuses were aborted because of

a severe malformation. A significant medical condition was dia-

gnosed in 38 additional older children. Profound deafness and

mental retardation were the most frequent diagnoses in those

children (Additional Information). During the years 1992–2003,

144 cases with malformations or major medical conditions were

diagnosed (5.52% live births; 95% CI: 4.64–6.4). Among those

cases, three conditions were particularly frequent: Down syndrome,

esophageal atresia, and profound deafness.

Down syndrome was diagnosed in 10 instances (0.38% live births;

95% CI: 0.14–0.62), 8 being trisomy 21 and 2 unbalanced trans-

locations. Among these 10 cases, in 3 the parents were first cousins,

in 4 they were more distantly related, and in the other 3 the parents

were not related. Two Down syndrome children whose parents were

first cousins presented each with a major malformation: Hirsch-

prung disease in one and esophageal atresia in the other.

Esophageal atresia was diagnosed in 11 cases (including one child

with Down syndrome, see above; 0.42% live births; 95% CI:

0.17–0.67). In two of the families the parents were first cousins,

and in the other six they were more distantly related.

Isolated profound deafness was diagnosed in eight of the children

(0.31% live births; 95% CI: 0.1–0.52) all as a result of mutations in

the Connexin 26 gene. One child was born to first cousin parents,

and the other seven were born to distantly related parents.

Incidence of malformations and significant medical conditions

according to the relationships between the parents

Parents were first cousins (including double first cousins). Among

631 children born to parents who were first cousins 35 had a major

malformation at birth, and 3 pregnancies were terminated because

of a severe malformation (6.0%; 95% CI: 4.16–7.88). In addition, in

11 children a significant medical condition was diagnosed before

the age of 5 years (total 7.77%; 95% CI: 5.68–9.86). Of a total of

48 malformations and significant medical conditions, at least 6 were

the result of an autosomal recessive disorder (12.5%). Definite

autosomal recessive disorders represented 4 of the 11 conditions

that were diagnosed in early childhood (36.4%; Table II).

Parents not related. Among the 579 children born to non-related

parents, 13 had one major malformation at birth, and one pre-

gnancy was terminated because of a severe malformation. In

addition, in 7 children a significant medical condition was

diagnosed before the age of 5 years (total 3.6%; 95% CI:

1.17–3.67). One of these 21 significant medical conditions was the

result of a known autosomal recessive disorder. In 5 of the 7 children

in whom a significant condition was diagnosed during childhood, it

was an autosomal dominant condition, inherited from the father

who was born in the village.

Parents were related. In the group of children born to parents

originating from the founders that were not first cousins or closer,

two groups were distinguished: one in which the parents were less

than first cousins but at least second cousins, and a second group in

which the parents were more distantly related (Table II.1).

The relationship between the parents: Less than first cousins

but at least second cousins. Among 452 children born to parents

related as less than first cousins but at least second cousins, 19 had a

major malformation at birth and one pregnancy was terminated

because of a severe malformation (4.42%; 95% CI: 2.53–6.31).

In addition in 3 children a significant medical condition was

diagnosed before the age of 5 years (total 5.1%).

TABLE II. Malformations and Major Medical Conditions 1992–2003

Related as second cousinsbut less than first cousins

Relation more distantthan second cousins

All related moredistantly thanfirst cousins

TotalNumber, percentage

(95% CI) TotalNumber, percentage

(95% CI) TotalNumber,

percentage (95% CI)1. Malformations and major medical conditions when the parents are distantly related

Among live born 452 19, 4.2% (2.35–6.05) 948 32, 3.38% (2.23–4.53) 1,400 51, 3.64% (2.66–4.62)At birth þ TOP 20, 4.42% (2.53–6.31) 34, 3.59% (2.41–4.77) 54, 3.86% (2.85–4.87)Total (pregnancy and childhood) 23, 5.09% (3.06–7.12) 51, 5.38% (3.94–6.82) 74, 5.29% (4.12–6.46)

Related as first cousinsor double first cousins Non-related

All related moredistantly thanfirst cousins

TotalNumber, percentage

(95% CI) TotalNumber, percentage

(95% CI) TotalNumber, percentage

(95% CI)2. Malformations and major medical conditions 1992–2003

Among live born 631 35, 5.55% (3.76–7.34) 579 13, 2.25% (1.04–3.46) 1,400 51, 3.64% (2.66–4.62)At birth þ TOP 38, 6.02% (4.16–7.88) 14, 2.42% (1.17–3.67) 54, 3.86% (2.85–4.87)Total (pregnancy and childhood) 49, 7.77% (5.68–9.86) 21, 3.63% (2.11–5.15) 74, 5.29% (4.12–6.46)

The percentages are given with the 95% confidence interval (CI)TOP, termination of pregnancy because of severe fetal malformation.

ZLOTOGORA AND SHALEV 2025

The relationship between the parents was less than second

cousins. Among 948 children born to parents more remotely

related than second cousins, 32 had a major malformation at

birth and two pregnancies were terminated because of a severe

malformation (total 3.59%; 95% CI: 2.41–4.77). In 17 children, a

significant medical condition was diagnosed before the age of

5 years (total 5.38%).

Since for each of the parameters examined the differences among

the groups were not significant, the analysis was also performed as

one group referred to as ‘‘distantly related’’ (Table II.2). Of a total of

1,400 children born to parents distantly related, 74 malformations

and significant medical conditions were diagnosed (5.29%; 95% CI:

4.12–6.46), and at least 17 were the result of an autosomal recessive

disorder (22.7%). Definite autosomal recessive disorders repre-

sented 9 of the 20 conditions that were diagnosed in the first 5 years

of life (45%).

DISCUSSION

While modernization led to significant changes in marital oppor-

tunities, marriages within the community remain the preference

and in the village studied proportions of inter-village marriages

remained in the same range representing approximately 20–30% of

the total [Zlotogora et al., 2002]. Among Muslims consanguineous

marriages are traditional, even though not recommended in Islam.

In the Arab world, the most frequent type of consanguineous

marriages has been between first cousins and among those,

marriages between children of brothers (patrilineal parallel) have

been the preferred type of marriages for various reasons, one of

which being the avoidance of parceling the lands of the family. With

the disappearance of the advantages of this specific type of

marriages in the village, a significant decline in the total proportion

of patrilineal parallel first cousin marriages was observed, from

13.6% to 6%. The rate of the other three types of first cousin

marriages remained in a similar range during the years (Table I). A

similar decline in the prevalence of first cousin marriages has also

been observed in other Arab populations of the region [Jaber et al.,

2000; Hamamy et al., 2005; Sharkia et al., 2008; Assaf and Khawaja,

2009]. These changes are probably due to various factors, mostly the

internal changes in the society but also education programs,

including media campaigns particularly emphasizing the medical

risks of first cousin marriages. On the other hand, other advantages

of consanguinity such as the possibility for both spouses to keep

living near their close relatives, staying in the village in which they

were born, are also achieved in rural societies by marriages between

distant relatives. Indeed, in the period of the survey, while the

proportion of marriages between close relatives (2nd cousins and

closer) in the village declined from 52.5% to 30.3% (P< 0.0001,

Fisher’s exact test), the rates of distantly related marriages rose from

33.1% to 46.2% (P< 0.02, Fisher’s exact test).

Consanguinity has been identified as a risk factor for congenital

malformations and major medical conditions. Comparisons be-

tween the rates of birth defects among the offspring of first cousin

marriages and those of non-related couples were reported in several

studies from inbred communities (Table III). Large inter-study

variations in the rates of malformations are evident, mostly

secondary to differences in the type of birth defects included, the

way the data were collected (either by personal examination or

through registries), and whether the data were collected at birth or

also included follow up in early childhood. However, in each of the

studies, higher rates of birth defects were always observed among

offspring of first cousins as compared to offspring of non-related

parents from a same population. In the ‘‘Birmingham birth study’’

[Bundey and Alam, 1993] which followed offspring of 4,886 women

during their childhood, among the North European sub-popula-

tion (0.4% related) the prevalence of congenital and genetic dis-

orders was 4.3%, while among the British Pakistani children (57%

first cousins) the prevalence of congenital and genetic disorders was

7.9%. In the study by Jaber et al. [1992] in 610 children followed in a

single Israeli locality, malformations and genetic conditions were

diagnosed in 15.8% of the children of first cousin parents as

opposed to 5.8% of the children born to parents that were not

related. In our study, which was focused on a single village, among

the 2,610 children born and followed for at least 5 years, the rate of

malformations and significant medical conditions was 7.8% when

the parents were first cousins and 3.6% when they were not related

(P¼ 0.002, Fisher’s exact test). Summarizing the present data and

those from the literature it appears that the rate of malformations

during pregnancy and at birth, including or excluding conditions

diagnosed in early childhood, is approximately two to three

times higher among first cousins than in non-related couples

from the same population. This relative risk is not significantly

different from that observed for first cousin marriages in non-

inbred populations [Stoltenberg et al., 1997].

TABLE III. Malformations in Pregnancies/at Birth Different Populations

Population Total, n First cousins (%) Related (%) Not related (%)Norway [Stoltenberg et al. 1997]

Norway 1,448,766 3.4 1.6 1.5Norway, Pakistani 7,494 4.5 3.8 2.1

Turkey [Demirel et al. 1997] 3,254 2.7 2.2 0.8Israel [Jaber et al. 1992] 610 15.8 15.1–8.3 5.8–4.1Israel [Bromiker et al., 2004] 561 8.7 6–4.1 2.6Israel [Present study]

Birth 2,610 6.0 3.9 2.4Childhood 7.8 5.3 3.6

2026 AMERICAN JOURNAL OF MEDICAL GENETICS PART A

However, as discussed above, in recent decades several inbred

populations have shown a tendency of progressive decline in first

cousin marriages rates, concomitant to a rise of marriages between

more distantly related individuals [Jaber et al., 2000; Hamamy et al.,

2005; Sharkia et al., 2008]. Therefore, another important piece of

information is the estimate of the risk conferred by marriages

between more distantly related individuals in inbred communities.

In a large population study performed in the Norwegian registry

focusing on stillbirths and live births at gestational age of 16 weeks

or more among 1,448,766 children born to Norwegians without a

recent immigration background, the rate of malformations was

3.4% when the parents were first cousins, 1.6% when the parent

were distantly related and 1.5% when the parents were not related.

In the same study, among Norwegian Pakistani couples the rate of

malformations at birth was 4.5% for first cousins, 3.8% for distantly

related spouses, and 2.1% when the parents were not related

[Stoltenberg et al., 1997]. The observation that in an inbred

community such as the Norwegian Pakistani as opposed to non-

inbred populations, the risk at birth for couples that are distantly

related is higher than in non-related couples was confirmed here

and in several other studies [Jaber et al., 1992; Zlotogora, 2002].

However, while individuals are considered to be related only when

they are second cousin or closer, We have shown that in an inbred

community, offspring of parents that are second cousins or closer

but less than first cousin have a similar risk as offspring of parents

more distantly related (5.1% and 5.5%, respectively; P¼ 0.8). This

observation is explained by the fact that in inbred populations,

marriages within the community occurred from generation to

generation increasing the genetic resemblance between individuals

as demonstrated by the calculation of the inbreeding coefficients or

using molecular data [Bittles and Egerbladh, 2005; Woods et al.,

2006]. We propose therefore, that in inbred populations, all the

couples that are not related as first cousins but in which the spouses

are both descendants of the founders should be considered as

related. The main implication is for genetic counseling since those

couples have a higher risk than non-related couples even though

the difference is not statistically significant (5.3% and 3.6%,

respectively; P¼ 0.133).

In the period of the study, three disorders were particularly

frequent in the village, raising in each case the question of a possible

genetic cause. Indeed, all the cases of isolated profound deafness in

the village were due to recessive mutations in the gene for Connexin

26. While an increased proportion of first cousin marriages is

usually observed among the parents of individuals affected with

autosomal recessive diseases, this was not the case for connexin 26

related deafness in the village. The observation that the rate of first

cousin marriages among the parents of deaf children was not

different from the one of all the couples in the village is explained

by a 17% general carrier frequency of mutations in the connexin

26 gene in this village [Zlotogora et al., 2006]. It is that high

frequency of the mutants alleles that makes each couple in which

both spouses were born in the village at an almost similar risk

whatever the relationship. Similar observations were made for other

frequent diseases as for instance as sickle-cell anemia in Saudi

Arabia [El Mouzan et al., 2008].

The frequency of esophageal atresia between the years 1992 and

2003 was much higher in the village (0.42% live births; 95% CI:

0.17–0.67) than the one observed in the general Israeli Muslim

population (0.02% live births; 95% CI: 0.01–0.03) [Zlotogora et al.,

2003]. The possibility of a syndromic form of the malformation was

raised but was not supported after clinical re-examination of the

affected children. Since there were no instances of esophageal

atresia among the 2,114 live births in the 6 following years

(2004–2009), it may be that this was an unexplained transient

cluster of cases.

Down syndrome was the third disorder relatively frequent in the

village during the period of the study—0.38% live births (95% CI:

0.14–0.62) as opposed to 0.16% live births (95% CI: 0.12–0.20) in

the general Muslim population [Zlotogora et al., 2010]. Most of the

cases were trisomy 21, while the mean age of the women at birth in

the village was not different from the one in the Israeli Muslim

population. In Kuwait, a relatively high frequency of Down syn-

drome was linked to consanguinity as an independent factor and

the relative risk was approximately four times higher for closely

related than for non-related parents [Alfi et al., 1980; Farag and

Teebi, 1988]. However, this observation was not confirmed in other

studies [Roberts et al., 1991; Hook, 1992]. We did not observe an

increased consanguinity rate among the parents of affected cases,

and in none of the families reported here there was a recurrence of

Down syndrome or any other trisomy. In the 6-year period of

following our present study for which we have complete data

(2004–2009), trisomy 21 was diagnosed in six other instances out

of 2,114 live births (0.28%; 95% CI: 0.05–0.51). This continuing

high incidence of Down syndrome raises the possibility that it may

be a true phenomenon prompting us to continue to investigate the

existence of possible genetic factors.

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