Anencephaly in Japan: paternal age, maternal age and birth order

The statistical association between incidence of anencephaly and paternal age, maternal age and birth order was analysed in 1815 cases of foetal deaths with anencephaly reported during 1975--6. The birth order association was confirmed with an extremely high degree of statistical significance.     

Polyglandular autoimmune syndrome type I among Iranian Jews.

Polyglandular autoimmune syndrome (PAS) has been well characterised and the accepted criteria for diagnosis are the presence of at least two of the three major components: hypoparathyroidism (HPT), candidiasis, and adrenal insufficiency (AI). HPT may, however, be the only manifestation of the syndrome. Iranian Jews, having a high rate of consanguinity, appear to be a community in which PAS type I is frequent. We report on 19 families of patients with HPT from the Iranian Jewish community assuming that they are in fact affected with PAS type I. In the 19 families, 23 patients were affected, including 11 males and 12 females. All the patients but one had HPT (96%), and most were diagnosed by the age of 20 years (91%). AI was diagnosed in five of our patients; in all cases but one it appeared after HPT. Mild oral candidiasis was present in four patients and six of the patients (three males and three females) had hypogonadism. Other features of the syndrome found in some of our patients were pernicious anaemia, hypothyroidism, and alopecia. The disease is autosomal recessive and the calculated prevalence among the Iranian Jews is 1:6500 to 1:9000. The disease is also found with a very high incidence among Finns. A comparison of the symptoms between the two groups showed clinical differences including the relative rarity of candidiasis and absence of keratopathy among the Iranian Jews.     

Anencephaly: a retrospective analysis in Singapore. 1976 to 1980.

Records of 93 cases of anencephaly from three maternity hospitals in Singapore between 1976 and 1980 were analysed. The incidence was 0.54 per 1000 births. No significant correlation between anencephaly and local seasonal conditions could be found for Singapore.     

Incidence of familial dysautonomia in Israel 1977–1981

The incidence of all diagnosed cases of familial dysautonomia in Israel among Ashkenazi Jews from 1977-1981 was 27/100,000 or 1/3703. This incidence is higher than that previously reported in Israel in 1967 or 8.3/100,000 (1/12,048) (Moses et al. 1967). It is also higher than that of North American Ashkenazi Jews in 1970, when the rate was 5-10/100,000 (1/10,000-20,000) (Brunt & McKusick 1970). This higher incidence could be explained by current awareness of the diagnosis, or by the emergence of more cases.     

A Mutation Analysis of the Phenylalanine Hydroxylase (PAH) Gene in the Israeli Population

Hyperphenylalaninemia (HPA) is a group of diseases characterized by a persistent elevation of phenylalanine levels in tissues and biological fluids. The most frequent form is phenylalanine hydroxylase deficiency, causing phenylketonuria (PKU). Among 159 Israeli patients (Jews, Muslim and Christian Arabs and Druze) with HPA, in whom at least one of the mutations was characterized, a total of 43 different mutations were detected, including seven novel ones. PKU was very rare among Ashkenazi Jews and relatively frequent among Jews from Yemen, the Caucasian Mountains, Bukhara and Tunisia. The mutations responsible for the high frequency were: exon3del (Yemenite Jews), L48S (Tunisian Jews) and E178G, P281L and L48S (Jews from the Caucasian Mountains and Bukhara). Among the non‐Jewish Israeli citizens, the disease was relatively frequent in the Negev and in the Nazareth vicinity, and in many localities a unique mutation was detected, often in a single family. While marked genetic heterogeneity was observed in the Arab and Jewish populations, only one mutation A300S, was frequent in all of the communities. Several of the other frequent mutations were shared by the non‐Ashkenazi Jews and Arabs; none were mutual to Ashkenazi Jews and Arabs.     

Differences between the events preceding spina bifida and anencephaly.

It is usually held that there is a time continuum in the formation of monoxygotic (MZ) twins which is indexed by their placentation, running from dichorionic to monochorionic diamniotic to monochorionic monoamniotic and conjoined pairs. There is good evidence that this continuum is characterised by a continuum of predisposition to anencephaly, slightly raised in dichorionic pairs but very high in some sorts of conjoined pairs. Although MZ twins, especially monoamniotic and conjoined pairs, are peculiarly liable to anencephaly, they are not particularly susceptible to spina bifida. Among twin pairs concordant for anencephaly or spina bifida, there are strikingly few concordant in the sense of one twin having anencephaly and the other spina bifida, in contrast with the numbers of pairs concordant for the same malformation. The prevalence of anencephaly in double monsters varies with the type of monster, being high in diprosopus. These findings may be explained by the timing of embryonic events.     

HLA–DRw4 in Pemphigus Vulgaris Patients in Israel

Pemphigus vulgaris (PV) is relatively common in Jews. Three HLA antigens were significantly more frequent in 39 Israeli Jewish PV patients than in controls: A26 – 59% vs 20%; Bw38 – 61% vs 20%; and DRw4 – 90% vs 38%. The joint occurrence of A26–Bw38–DRw4 was observed in 46% of PV patients and in 10% of controls. Similar results were recently reported for Jews in the Los Angeles area. Yet, when our patient sample was grouped into Ashkenazi and non-Ashkenazi Jews, it was evident that each of the three antigens had a higher frequency both in Ashkenazi patients and controls as compared to non-Ashkenazim. The relative risk for DRw4 in Ashkenazim was 33.8 as compared to 14.4 in the total sample of Israeli PV patients. The phenotype A26–Bw38–DRw4 was present in 57% of Ashkenazi patients and in 13% of controls. Ashkenazi Jews have the highest prevalence of PV, and HLA associations were strongest with Ashkenazi PV patients. These associations were with three antigens, all of high frequency in that group.     

High frequency of congenital adrenal hyperplasia (classic 11 beta-hydroxylase deficiency) among Jews from Morocco.

Steroid 11 beta-hydroxylase deficiency is relatively frequent in Israel among North African Jews. Over a 39-year period, 38 affected individuals from 25 families were diagnosed. Nineteen families came from Morocco, and in another 2, one parent came from Morocco (80% of all parents). Demographic studies showed that most of their grandparents were born in the region of the Atlas Mountains. In Israel, the overall incidence of the disorder is estimated between 1 in 30,000 to 1 in 40,000 births, but in offspring of Moroccan Jews the ratio is 1 in 5,000 to 1 in 7,000, with an allele frequency of 1 in 70 to 1 in 84 and a carrier frequency of 1 in 35 to 1 in 42. The clinical expression is characterized by a wide range of variability in the signs of androgen and mineralocorticoid excess. Virilization in the female ranged from enlarged clitoris in the mildest forms, to markedly hypertrophied clitoris with penile urethra and fused labial-scrotal folds in the most severe forms. Hypertension causing vascular accidents and death was observed in both severe and mildly virilized patients, whereas masculinized females were sometimes normotensive. Based on historical evidence, the origin of the ancestors, and the onomastic analysis of the families surnames, we propose that the mutation of 11 beta-hydroxylase deficiency in Jews from Morocco may have originated in either the ancient Jewish settlers or the native Berber tribes who lived in the region of the Atlas Mountains in the southern region of Morocco before the destruction of the Second Temple by the Romans, in the year 70 C.E.     

High frequency of congenital adrenal hyperplasia (classic 11β-hydroxylase deficiency) among Jews from Morocco

Steroid 11β-hydroxylase deficiency is relatively frequent in Israel among North African Jews. Over a 39-year period, 38 affected individuals from 25 families were diagnosed. Nineteen families came from Morocco, and in another 2, one parent came from Morocco (80% of all parents). Demographic studies showed that most of their grandparents were born in the region of the Atlas Mountains. In Israel, the overall incidence of the disorder is estimated between 1 in 30,000 to 1 40,000 births, but in offspring of Moroccan Jews the ratio is 1 in 5,000 to 1 in 7,000, with an allele frequency of 1 in 70 to 1 in 84 and a carrier frequency of 1 in 35 to 1 in 42. The clinical expression in characterized by a wide range of variability in the signs of androgen and mineralocorticoid excess. Virilization in the female ranged from enlarged clitoris in the mildest forms, to markedly hypertrophied clitoris with penile urethra and fused labial-scrotal folds in the most severe forms. Hypertension causing vascular accidents and death was observed in both severe and mildly virilized patients, whereas masculinized females were sometimes normotensive. Based on historical evidence, the origin of the ancestors, and the onomastic analysis of the families surnames, we propose that the mutation of 11β-hydroxylase dificiency in Jews from Morocco may have originated in either the ancient Jewish settlers or the native Berber tribes who lived in the region of the Atlas Mountains in the southern region of Morocco before the destruction of the Second Temple by the Romans, in the year 70 C.E.     

Prevalence of myotonic dystrophy in Israeli Jewish communities: inter-community variation and founder premutations

In a comprehensive epidemiological survey among Jews living in Israel, the average prevalence of myotonic dystrophy (DM) was 15.7/10(5) (1 case in 6369) with intercommunity variations; the Ashkenazi Jews had the lowest rate, 5.7/10(5) (1 case in 17544) as compared to the rate in the Sephardim/Oriental Jews 20/10(5) (1 case in 5000) and the in the Yemenite Jews 47.3/10(5) (1 case in 2114). The rate of unrelated DM-sibships per 10(6) people of each community was used as an estimate of the transition rate from stable to unstable DMPK-(CTG)(n) alleles assuming that each transition is a beginning of a new DM sibship. This study indicated that the difference in the incidence of DM is a result of higher mutation rate in the non-Ashkenazi Jews (>50/10(6)) as compared to the rate in the Ashkenazi Jews (16.3/10(6)). The intragenic haplotype of the DM alleles was the same as that of the DM in many populations all over the world. However, two DM closely linked markers D19S207 and D19S112 were in linkage disequilibrium with the DM mutation in patients of Yemenite and Moroccan (the largest subgroup in the Sephardim Jews) extractions and not in the Ashkenazi patients. This observation indicated a common ancestral origin for the DM premutation in patients of the same ethnic origin. We concluded that the difference in the prevalence of DM among the Jewish communities is a consequence of founder premutations in the non-Ashkenazi Jewish communities.     

Short rib-polydactyly syndrome (SRPS) with anencephaly and other central nervous system anomalies: A new type of SRPS or a more severe expression of a known SRPS entity?

We describe two patients with short rib-poly-dactyly syndrome (SRPS) from two unrelated Spanish families. These patients present clinical and radiological characteristics that overlap those of the different established types of SRPS. In addition, one patient had anencephaly and the other patient had severe brain abnormalities with a family history of an older sister with anencephaly, and a brother diagnosed with SRPS. This second family is interesting in that the two affected brothers present with different clinical and radiological findings; for example, one had ovoid tibiae and the other did not. This particular family shows that intrafamiliar variation is also observed within SRPS. It remains unsettled whether these cases might be considered a new type of SRPS or a variant of an established entity or whether the differences between the SRPS represent variability or heterogeneity. Molecular studies may answer this question in the near future. © 1993 Wiley-Liss, Inc.     

Risk factors associated with neural tube defects: exposure during the first trimester of gestation

The neural tube defects (NTD) are a group of malformations of multifactorial etiology. Their high incidence in Mexico and the etiologic heterogeneity observed in several studies, prompted the present investigation with the main objective of looking for risk factors associated to NTD. We analyzed maternal exposure during the first trimester of pregnancy to different environmental factors, such as acute or chronic illnesses, immunizations, smoking, alcoholism, maternal or paternal occupation and exposure to chemicals. The sample include 360 patients with anencephaly, 249 with spina bifida and 44 with encephalocele, ascertained from a total of 230 635 live births and 4,020 stillborns, studied in the Mexican program of Registro y Vigilancia Epidemiológica de Malformaciones Congénitas Externa. Of the risk factors considered, significant differences with the control group were found for anencephaly in relation to maternal viral upper respiratory infection, hyperthermia, ingestion of analgesics, antiemetics and paternal occupation. In the case of spina bifida, significant differences were found only for viral upper respiratory infections.     

Higher than expected carrier rates for familial Mediterranean fever in various Jewish ethnic groups

Familial Mediterranean fever (FMF) is an autosomal recessive disease characterised by recurrent attacks of inflammation of serosal membranes. Amyloidosis leading to renal failure is the most severe complication in untreated patients. In Israel FMF is most frequent among Jews of North African origin. Recently the causative gene (MEFV) has been found and the common mutations characterised. The aim of this study was to investigate the carrier rates of the common MEFV mutations among 400 healthy members of four different ethnic groups (100 in each group) in Israel, and to compare the distribution of the different mutations between FMF carriers and patients. We found a high frequency of carriers among Jews from the various ethnic groups. In North African Jews it was 22%, in Iraqi Jews 39%, in Ashkenazi Jews 21%, and in Iranian Jews 6%. The distribution of the four most common MEFV mutations among healthy individuals (M694V 29%, V726A 16%, M6801 2% and E148Q 53%) was significantly different (P < 0.003) from that found in patients (M694V 84.4%, V726A 9.0%, M6801 0% and E148Q 6.6%). Six healthy asymptomatic individuals were found to carry mutations in both alleles: two homozygotes for E148Q and four compound heterozygotes E148Q/other. These results demonstrate a very high carrier rate among all Jewish ethnic groups. They confirm that mutation E148Q is associated with a milder phenotype, which explains the lower prevalence of FMF among the Ashkenazi and Iraqi Jews. This study raises the question of the need for molecular screening for M694V homozygotes in the Israeli North African Jewish community.     

Prevalence of Lithuanian mutation among St. Petersburg Jews with familial hypercholesterolemia

We used polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) analysis to detect LDL receptor gene defects in the St. Petersburg population. We have found a deltaG197 mutation in several patients of Jewish origin. The mutation named is shown to be responsible for one-third (7/23) of familial hypercholesterolemia (FH) cases in St. Petersburg Jews and absent in patients of Russian descent. The prevalence of a deltaG197 mutation in St. Petersburg Jews is consistent with its origin in Lithuania or Poland. The deltaG197 mutation can be easily detected in polyacrylamide minigels because of formation of specific heteroduplexes during PCR with DNA of heterozygous patients. Taken together with high prevalence of the mutation in St. Petersburg Jews, this observation provides an opportunity for DNA diagnostics of FH in this ethnic group. Hum Mutat 12:255–258, 1998. © 1998 Wiley-Liss, Inc.     

Explanations for the discrepancy between variant frequency and homozygous disease occurrence: Lessons from Ashkenazi Jewish data

Ample data on recessive disorders among Ashkenazi Jews has been gathered and published through the years. The opportunity to integrate molecular records analyzed in actual affected individuals with data derived from population-documented frequencies enables to compare these figures.We reviewed assumed pathogenic variants reported among patients in the Israeli medical genetic database (IMGD) with a carrier frequency of 1% or more among Ashkenazi Jews in gnomAD. Among the 60 assumed pathogenic variants recorded in IMGD, 15 (25%) had either a disease incidence considerably lower than expected by the calculated carrier frequency (12 variants), or the variant was not characterized in Ashkenazi Jewish patients (three variants).Possible explanations for the rarity or absence of affected individuals despite high carrier frequency include embryonic lethality, clinical variability, and incomplete and age-related penetrance, in addition to the existence of additional assumed pathogenic variants on the founder haplotype, hypomorphic variants or digenic inheritance.The discrepancy in actual versus expected number of patients calls for caution upon designing and choosing targeted genes and recessive mutations for carrier screening.     

Characterization of two Ashkenazi Jewish founder mutations in MSH6 gene causing Lynch syndrome

Founder mutations are an important cause of Lynch syndrome and facilitate genetic testing in specific ethnic populations. Two putative founder mutations in MSH6 were analyzed in 2685 colorectal cancer (CRC) cases, 337 endometrial cancer (EnCa) cases and 3310 healthy controls of Ashkenazi Jewish (AJ) descent from population-based and hospital-based case–control studies in Israel, Canada and the United States. The carriers were haplotyped and the age of the mutations was estimated. MSH6*c.3984_3987dupGTCA was found in 8/2685 CRC cases, 2/337 EnCa cases, and 1/3310 controls, consistent with a high risk of CRC (odds ratio (OR) = 9.9, 95% confidence interval (CI) = 1.2–78.9, p = 0.0079) and a very high risk of EnCa (OR = 19.6, 95% CI = 1.8–217.2, p = 0.0006). MSH6*c.3959_3962delCAAG was identified in 3/2685 CRC cases, 2/337 EnCa cases and no controls. Each mutation was observed on separate conserved haplotypes. MSH6*c.3984_3987dupGTCA and MSH6*c.3959_3962delCAAG probably arose around 585 CE and 685 CE, respectively. No carriers were identified in Sephardi Jews (450 cases and 490 controls). Truncating mutations MSH6*c.3984_3987dupGTCA and MSH6*c.3959_3962delCAAG cause Lynch syndrome and are founder mutations in Ashkenazi Jews. Together with other AJ founder mutations, they contribute substantially to the incidence of CRC and EnCa and are important tools for the early diagnosis and appropriate management of AJ Lynch syndrome patients.     

Comparative screening of FMF mutations in various communities of the Israeli society

Familial Mediterranean Fever (FMF) is an autosomal recessive disease that is widely spread in the populations of the Mediterranean region. It is characterized by recurrent fever and inflammatory attacks. A total of 1700 suspected patients, belonging to various communities in Israel: Jews (Ashkenazi and non-Ashkenazi), Arabs (Muslims and Christians) and Druze, was subjected to examination for FMF mutation screening. The patients were screened for the most common six MEFV gene mutations namely, M680I, M694V, M694I, V726A, E148Q and K695R. Fifty-five percent of the cases were confirmed to have MEFV mutations. The most common mutations among all the cases studied were M694V, E148Q and V726A. The common mutations in the respective communities were: among the Jews M694V with a frequency of 69.9% (76.8% for non-Ashkenazi Jews and 43.6% for Ashkenazi Jews), among the Arabs V726A with a frequency of 32.7% (32.7% for Muslims and 32.1% for Christians) and among Druze it was E148Q with a frequency of 52.1%. The characteristic mutation present in Jews was K695R and the one in Arabs was M680I, while no characteristic mutation was found in Druze. On the other hand, mutation E148Q was observed to have a considerable occurrence in patients of all ethnic groups studied. Furthermore, our results revealed that homozygous mutations accounted for 168 cases (18%). The homozygote mutation M694V was the most prevalent among Jews and the E148Q mutation was the most common among Druze, while, among Arabs there were three homozygous mutations having maximum prevalence, namely, V726A, M694V and M694I. Our study comprehensively provided a spectrum of FMF mutations in various communities of Israeli society.     

Genetic polymorphisms among Bukharan and Georgian Jews in Israel

Bukharan and Georgian Jews have lived in central Asia for many centuries. Approximately 30,000 Bukharan and 37,000 Georgian Jews lived in their respective countries within the USSR between 1920 and 1960. Genetic markers of blood--blood groups, isoenzymes, HLA antigens, and gamma and kappa chain allotypes--were tested in blood samples from 113 Bukharan and 134 Georgian Jews living in Israel. Estimates of inbreeding were low: alpha = 0.0088 for Bukharan and alpha = 0.0011 for Georgian Jews. G6PD deficiency was relatively rare in Bukharan (2.2%) and in Georgian Jews (6.0%), when compared to other Jews in the area. Both populations showed frequencies of some markers similar to that of other Jewish populations, but frequencies of several markers were extremely high or low. Bukharan Jews showed very high frequencies of B(0.243), cDe (0.122), JkA (0.705), HLA-A29 (0.167), A30 (0.116) and B7 (0.124), and AcPA (0.451) and very low ones of O(0.518), CDe(0.422), AcPB (0.513) and GLO1 (0.140). Very high frequencies in Georgian Jews were observed for cDE (0.189), HLA-A3 (0.194), Bw35 (0.300) and GLO1 (0.367). Yet the greatest difference between both populations was in African characters. While in Bukharan Jews Fy was very frequent (0.146) and cDe was the highest observed among Jews (0.122), neither of these markers was detected among the Georgian Jews tested. Yet, another African character, the Gm1,5,10,11,13,14,17,26 haplotype, occurred in both populations (0.028 and 0.042 in Bukharan and Georgian Jews, respectively). Distance measures for Bukharan, Georgian, Iranian, Cochin, and Libyan Jews based on 13 polymorphic loci showed the greatest distance between Cochin Jews and the other populations and the smallest distance between the Georgian and Iranian Jews.     

Ring chromosome 13: lack of distinct syndromes based on different breakpoints on 13q.

A stillborn male child with anencephaly and multiple malformations was found to have the karyotype 46,XY,r(13) (p11q21.1). The breakpoint at 13q21.1, determined by high resolution banding, is the most proximal breakpoint ever reported in patients with ring chromosome 13. In situ hybridisation with the probe L1.26 confirmed the derivation from chromosome 13 and DNA polymorphism analysis showed maternal origin of the ring chromosome. Our results, together with a review of previous reports of cases with ring chromosome 13 with identified breakpoints, could neither support the theory of distinct clinical syndromes based on different breakpoints on 13q nor correlate the severity of symptoms with instability of the ring.     

Anencephaly and limb deficiencies.

Limb deficiencies (LDs) are rarely reported in anencephalic infants. A review of 662 patients in the literature on non-neural defects in anencephaly only showed five patients with LDs. We report on eight patients with various LDs from the records of 141 necropsies of the anencephalic infants found among 495,830 births. Compared with another group of anencephalic infants reported in the literature, the patients in this group of anencephalic infants with LDs were predominantly male, their mean gestational age was younger by approximately 5 weeks, their mean birth-weight was approximately 1,400 g less, and they presented with a higher incidence of polyhydramnios during gestational development. The association of this pair of anomalies, which was 100 times more frequent than expected, seems not due to chance. Since all eight patients had other multiple congenital anomalies (MCA), in addition to anencephaly and LDs, the postmortem study should be mandatory in anencephalic infants with LDs. The most common associated anomalies were cardiovascular and renal defects. Oral clefts, diaphragmatic hernia, esophageal atresia, and imperforate anus were also observed in these infants. The recognition of LDs in anencephalic infants indicates severe and extensive disturbance of the early embryogenesis (blastogenesis), which affects the midline of the embryo.