American Journal of Medical Genetics 137A:342 (2005)

Research LetterIs There an Increased Birth Defect Risk to Children Bornto Offspring of First Cousin Parents?Joel Zlotogora*

Department of Community Genetics, Public Health Services, Ministry of Health, Israel

To the Editor:

Approximately 3–5% of all live newborns have a medicallysignificant birth defect [Baird, 1999]. Consanguineous mar-riages are at an increased risk for birth defects and/or geneticdiseases, and in first cousin marriages this risk is twice higherthan the one of non-related couples [Zlotogora, 2002]. Onequestion often raised during genetic counseling in inbredpopulations is, whether there is an increased risk formalformations in future children if the spouses are not relatedbut one of them is the offspring of closely related parents. Insuch cases, according to the Mendelian basis of inheritance, thecounseling is that the risk is similar to the one of thepopulation. However, in the last years, the complexity ofgenetics became more evident and in many, unexpectedobservations have been made.

In the last decade, we have been involved in the study of twoMuslim Arab villages, one located in the lower Galilee, theother located near Jerusalem, both with high consanguinityrates. Data from individuals born in the villages werecollected through oral interviews and entered into a computerdatabase (Reunion, Leister productions, Inc.). All relevantdetails on significant diseases and malformations werecollected by direct interviews or examinations, from medicalfiles or from the genetic clinic and merged with thegenealogical file. Since 1992, the data on birth defects andgenetic diseases are close to complete and, therefore, thepresent study includes children born in each of the villageafter 1991. Because of the complex relationships between theindividuals born in each of the villages, the couples were

classified as related as first cousins or closer (FC), distantlyrelated (NFC) and not related when one of the spouses wasfrom another village. Since in most of the cases when a womanmarries outside the village she leaves the village to live withher husband’s family, the comparison between the rates ofmalformations/diseases was made in each of the villagesamong children of couples that were distantly related (NFC).One group included the children of couples in which one ofthe spouses was the offspring of a first cousin marriage andthe second group included children of couples in which thespouses were offspring of distantly related parents. Asubgroup included children of the couples in which only thewoman as the offspring of a first cousin marriage.

In the villages, there were no significant differences betweenthe rate of malformations/diseases among the children born tograndparents who were related as first cousin or closer andthose born to distantly related couples (Table I). The sameobservation was made when only the children born to a motheroffspring of first cousins were considered. Therefore, it appearsthat, as expected intuitionally, the offspring of first cousinmarriages are not at an increased risk for birth defects.However a note of caution should be made since the numbers ofchildren examined do not allow for distinction between thedifferent birth defects and it may be that some effect exists forsome type of defects only. Another important question thatcould not be examined in the present study is, whether thechildren born to a mother offspring of first cousins are at anincreased risk for late onset frequent diseases such ashypertension, diabetes, or malignancies. This question isparticularly relevant in view of the recent discussions

concerning the importance of different factors in the pregnancyfor her grandchildren.

REFERENCES

Baird PA. 1999. Prenatal screening and the reduction of birth defects inpopulations. Community Genet 2:9–17.

Zlotogora J. 2002. What is the birth defect risk associated with consangui-neous marriages? Am J Med Genet 109A:70–71.

TABLE I. Congenital Malformations and/or Genetic Diseases Among Offspring of First Cousins and Other Consanguineous Parents inthe Two Villages

Nliveborn

Malformations and/orgenetic diseases Percentage

Total 3,625 146 4%Children born to a parent who was the offspring of first cousins and married to a

distant relative (NFC)1,084 42 3.9%

Children born to a mother who was the offspring of first cousins and married to adistant relative (NFC)

508 20 3.9%

Other children born to parents who were FC 841 38 4.5%a

Other children born to parents who were NFC 1,700 66 3.9%

aAs previously demonstrated [Zlotogora, 2002], there is an increased risk for a malformation and/or genetic disease in the offspring of marriages when theparents are related. The risk in offspring of first cousin parents (4.5%) is only slightly higher than offspring of parents distantly related (3.5%) and thedifference is not significant.

*Correspondence to: Joel Zlotogora, M.D., Ph.D., Department ofCommunity Genetics, Public Health Services, Ministry of Health,Building 67, Sheba Medical Center, Tel Hashomer, Ramat Gan,52621, Israel. E-mail: joelz@cc.huji.ac.il

Received 5 December 2004; Accepted 5 June 2005

DOI 10.1002/ajmg.a.30905

� 2005 Wiley-Liss, Inc.