American Journal of Medical Genetics 56:87-89 (1995)

Major Gene Is Responsible for Anencephaly Among Iranian Jews

Joel Zlotogora Department of Human Genetics, Hadassah University Hospital, Hebrew University Hadassah Medical School, Jerusalem, Israel

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Anencephaly is relatively frequent in Jews originating from Iran, in particular when its incidence is compared to that of open spina bifida in the same population (12 cases of anencephaly out of 14 cases of neural tube defects). The high incidence of this disorder in Iranian Jews, a relatively isolated com- munity with a very high rate of consanguin- ity, suggests that anencephaly is caused by a major recessive gene. This possibility is sup- ported by the sex ratio among these pa- tients, which was significantly different from that observed for patients with anen- cephaly in other populations. 0 1995 Wiley-Liss, Inc.

JiU3Y WORDS: anencephaly, founder effect, neural tube defects

INTRODUCTION Anencephaly is the most severe congenital malfor-

mation of the human central nervous system, and its frequency varies greatly in different populations. Most cases are compatible with a multifactorial model. How- ever, some cases of anencephaly may be caused by chro- mosomal or single gene disorders. For instance, some families have been reported in which anencephaly ap- pears to segregate as an X-linked trait [Toriello et al., 1980; Toriello, 19841, while in others a mutation in a major autosomal recessive gene has been suggested [Farag et al., 1986; Shaffer et al., 19901.

Neural tube defects (NTDs) have been reported to be more frequent in some populations, e.g., anencephaly in East-Indian Sikhs [Hall et al., 1988; Searle, 19591. Reported here is an increased incidence of anencephaly among Jews originating from Iran, as well as observa- tions which support the existence of a major recessive gene in this community as a cause for anencephaly.

Received for publication June 7, 1994; revision received Sep- tember 16,1994.

Address reprint requests to Joel Zlotogora, M.D., Department of Human Genetics, Hadassah Hospital, P.O.B. 12000, Jerusalem 91120, Israel.

0 1995 Wiley-Liss, Inc.

Jews have lived in Persia for centuries, and while there is still a small Jewish community in Iran, most Jews have left the country, mostly for Israel. The Iran- ian Jewish community includes some 135,000 individu- als, and represents some 3.5% of the Jewish population in Israel [Statistical Abstracts, 19931. While the Iran- ian Jewish community is relatively isolated, it has strong ties with Babylonian Jewry. Several rare genetic diseases have been reported in both communities, while some genetic disorders were found to be frequent in only one of the communities [Goodman, 19791. The Iranian Jewish community is known for a very high de- gree of inbreeding, and in a random sample of 177 Iran- ian Jews, 21.3% had a coefficient of inbreeding of first cousins or closer [Cohen et al., 19811.

MATERIALS AND METHODS During a survey of genetic disorders among Iranian

Jews, files of most individuals who had 4 grandparents of Jewish Iranian origin were collected from the Genet- ics Clinic in Jerusalem. They represent 3-4% of all the individuals who visited the clinic. Among these fami- lies, anencephaly is the most common NTD. To analyze these observations, the files of the families who have been in the Genetics Clinic with a child or fetus with an NTD were collected, and the origin of the parents and the type of NTD were noted.

The only Genetics Clinic in the Jerusalem region is located in Hadassah Medical Center. Therefore, most Jewish families with NTDs are referred there for coun- seling and/or prenatal diagnosis.

RESULTS One hundred and sixty-nine Jewish families with at

least one proband with an NTD were identified. Among these families, anencephaly was the malformation in 93 probands, spina bifida in 66, craniorachischisis in 7, and encephalocele in 3. In 14 of the 169 families, both parents were from the Iranian Jewish community, and in 5, one parent was from Iran and the other from Iraq.

Among the 14 families in which both parents were of Iranian origin, 12 of the probands had anencephaly, and 2 had myelomeningocele. In 5 of the 12 families with anencephaly, the proband's parents were related, and in one of these 5 families, more than one child was

Statistical analyses were done using the x2 test.

88 Zlotogora

affected: 3 of 5 children (2 males and 1 female) had anencephaly. In the other 11 families with anencephaly, the proband's sibs were unaffected (40 nonaffected chil- dren and 13 spontaneous abortions). Two of the 12 probands with anencephaly (one male and one female) were related, since their mothers were sisters. In an- other family anencephaly was also present in a distant relative. Among the 12 families with anencephaly, there was a total of 15 anencephalic individuals (8 males, 5 females, and 2 fetuses in which the sex was not reported).

In 15 other families, only one of the parents of the proband was of Iranian Jewish origin, while the other parent originated from another Jewish community. In 5 of these families the other parent (the father in 4) was from Iraq, and in all of them anencephaly was present in the proband (3 males, 1 female, 1 sex unknown). The proband was the only affected child in these 5 families (21 unaffected children, and 5 abortions). In the other 10 families the malformation of the proband was anen- cephaly in 6, open spina bifida in 3, and encephalocele in 1. There were no known relatives with NTDs.

Families in whom the parents were from Iran/Iran or Iran/Iraq represent 20% of total Jewish families of pa- tients with anencephaly, while they represent 3% of all the Jewish families of patients with open spina bifida (Table I). In patients with anencephaly in which the sex was known, the sex ratio was 1.8 (11 maled6 females) among the families from Iran/Iran or Iran/Iraq, while in the other Jewish families the sex ratio was 0.7 (26 maled37 females). The difference between the 2 groups was significantly different: x2 = 3.9, p = 0.01. The sex ratio was 0.82 (27 maled33 females) in patients with open spina bifida from Jewish families; a comparison could not be done with the patients from the Iranian Jewish community, since the numbers were too small.

The proportion of patients with anencephaly to those with anencephaly or spina bifida was 0.895 in the 19 families in which one of the parents was from Iran, and the other from Iran or Iraq. In Jewish families of other origins the proportion was 0.543 (x2 = 18, p < 0.005).

DISCUSSION From our observations, anencephaly appears to be

the major NTD among Iranian Jews. While there are no data on the frequency of NTDs among Iranian Jews, their incidence is relatively higher than in other Jewish communities. Families with patients with NTDs, in which one parent is from the Iranian Jewish commu- nity and the other from Iran or Iraq, accounted for some 17% of Jewish families with NTDs seen in our clinic. This is not due to an overrepresentation of Iranian Jews, since families of Iranian Jewish origin represent some 3 4 % of families who visited our clinic. The rela- tively high incidence of NTDs among Iranian Jews is due only to an increased frequency of anencephaly, since the relative incidence of open spina bifida is in the expected range.

The relatively high proportion of anencephaly among NTDs in families from Iran and Iran/Iraq was signifi- cantly different from that observed in other Jewish communities (0.895 as compared to 0.543). When one

parent was of Jewish Iranian origin and the other from Iran or Iraq, the male/fernale ratio in patients with anencephaly was 1.8, significantly different from the sex ratio in NTDs in other Jewish patients (male/ female ratio 0.7). In addition, parental consanguinity was present in 5 of the families.

Altogether, these observations suggest that the high incidence of anencephaly in families of IradIran and Iran/Iraq Jewish origin is due to the effect of a major gene. The assumption that some of the cases of anen- cephaly are due to the effects of a major gene has been already suggested, in particular with reference to an autosomal recessive gene and/or an X-linked recessive gene. In one study analyzing families of patients with anencephaly born to consanguineous parents, it was proposed that a major autosomal recessive gene was in- volved in the etiology of some of the families with anen- cephaly [Shaffer et al., 19901. Our data support the ex- istence of a major recessive gene which is relatively frequent among the Iranian Jews. The isolation of the Iranian Jewish community, as well as the high rate of consanguinity, may explain the high frequency of such an autosomal recessive gene due to a founder effect. The observation that anencephaly is also the major malformation in families in which one parent is from the Iranian Jewish community and the other parent from the Iraqi Jewish community may be explained by the close relationship between the 2 communities. Sim- ilar recessive disorders have been reported in high fre- quencies in both communities. The mutant gene ap- pears to be rarer among Iraqi Jews, as seen by the distribution of NTDs in this community (Table I).

The sex ratio among the anencephalic individuals in the families of I r a d r a n Iran/Iraq origin is significantly different from that expected in the multifactorial model [Hall et al., 19881. Instead of an excess of affected fe- males, we observed an excess of affected males. How- ever, the numbers are too small to determine whether the sex ratio is in the range expected for an autosomal disorder, or if there is a real male excess.

If anencephaly is due to an autosomal recessive gene, one would have expected to find more than one family with multiple affected children. The relative lack of af- fected children may be because of some other genetic and/or environmental factors influencing the expres- sion of the phenotype. The fact that the only family in whom more than one child was affected was living in Iran during all the pregnancies, while all the other fam- ilies were living in Israel a t the time of the pregnancies, may support the importance of environmental factors. There are no data about possible differences; however, it may be that the change in diet and in particular the content of folic acid may have played a role. A model im- plicating a major recessive gene for NTD influenced by other modifier loci was recently described in the curly- tail mouse. The curly-tail (ct) gene was mapped to dis- tal chromosome 4 in mice, which is homologous to distal l p in humans [Neumann et al., 19941.

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Anencephaly in Iranian Jews 89

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