Mordechai Shohat

Since the identification of the MEFV gene 198 mutations have been identified, not all of which are pathologic. The screening methods used in Israel to test patients suspected of having FMF include a kit that tests for the five main mutations (M694V, V726A, M680Ic/g, M694I, E148Q), and the sequencing of MEFV exon 10 in combination with restriction analysis for detecting additional mutations To determine the contribution of testing Ifor five additional mutations - A744S, K695R, M680Ic/t, R761H and P369S - to the molecular diagnosis of patients clinically suspected of having FMF. A total of 1637 patients were tested for FMF mutations by sequencing exon 10 and performing restriction analysis for mutations E148Q and P369S. Nearly half the patients (812, 49.6%) did not have any detectable mutations, 581 (35.5%) had one mutation, 241 (14.7%) had two mutations, of whom 122 were homozygous and 119 compound heterozygous, and 3 had three mutations. Testing for the additional five mutations enabled us to identify 46 patients who would have been missedby the molecular diagnosis kit and 22 patients in whom only one mutation would have been found. Altogether, 4.3%of the patients would not have been diagnosed correctly had only the kit that tests for the five main mutations been used. This study suggests that testing for the additional five mutations as well as the five main mutations in patients with a clinical presentation of FMF adds significantly to the molecular diagnosis of FMF in the Israeli population.

Long QT syndrome is an inherited cardiac disease, associated with malignant arrhythmias and sudden cardiac death. To map and identify the gene responsible for LQTS in an Israeli family. A large family was screened for LQTS after one of them was successfully resuscitated from ventricular fibrillation. The DNA was examined for suspicious loci by whole genome screening and the coding region of the LQT2 gene was sequenced. Nine family members, 6 males and 3 females, age (median and interquartile range) 26 years (13, 46), who were characterized by a unique T wave pattern were diagnosed as carrying the mutant gene. The LQTS-causing gene was mapped to chromosome 7 with the A614V mutation. All of the affected members in the family were correctly identified by electrocardiogram. Corrected QT duration was inversely associated with age in the affected family members and decreased with age. Careful inspection of the ECG can correctly identify LQTS in some families. Genetic analysis is needed to confirm the diagnosis and enable the correct therapy in this disease.

Fanconi anemia complementation group C and Bloom syndrome, rare autosomal recessive disorders marked by chromosome instability, are especially prevalent in the Ashkenazi* Jewish community. A single predominant mutation for each has been reported in Ahshkenazi Jews: c.711+4A-->T (IVS4 +4 A-->T) in FACC and BLM(Ash) in Bloom syndrome. Individuals affected by either of these syndromes are characterized by susceptibility for developing malignancies, and we questioned whether heterozygote carriers have a similarly increased risk. To estimate the cancer rate among FACC and BLM(Ash) carriers and their families over three previous generations in unselected Ashkenazi Jewish individuals. We studied 42 FACC carriers, 28 BLM(Ash) carriers and 43 controls. The control subjects were Ashkenazi Jews participating in our prenatal genetic screening program who tested negative for FACC and BLM(Ash). All subjects filled out a questionnaire regarding their own and a three-generation family history of cancer. The prevalence rates of cancer among relatives of FACC, BLM(Ash) and controls were computed and compared using the chi-square test. In 463 relatives of FACC carriers, 45 malignancies were reported (9.7%) including 10 breast (2.2%) and 13 colon cancers (2.8%). Among 326 relatives of BLM(Ash) carriers there were 30 malignancies (9.2%) including 7 breast (2.1%) and 4 colon cancers (1.2%). Controls consisted of 503 family members with 63 reported malignancies (12.5%) including 11 breast (2.2%) and 11 colon cancers (2.2%). We found no significantly increased prevalence of malignancies among carriers in at least three generations compared to the controls.

Objectives A case of prenatally diagnosed trisomy 11 mosaicism with a normal outcome is reported and the medical literature on prenatal detection of this finding is reviewed. Methods Proportion of cells with trisomy 11 was evaluated in amniocytes, fetal blood lymphocytes, newborn fibroblasts and urinary epithelial cells. Karyotype studies and fluorescence in situ hybridization analysis using the 11q13LS1 CCND1 probe were performed. Results Trisomy 11 level III mosaicism of 26% was detected in amniotic fluid cells. Periumbilical blood sampling showed a normal fetal karyotype. No fetal structural abnormalities were noted on ultrasound scan. The infant was spontaneously delivered and had normal physical findings at birth. No evidence of trisomic cells was found on extensive postnatal evaluation, implying an extraembryonic origin. Molecular analysis excluded uniparental disomy of chromosome 11. At 1 year of age, the baby is developing normally. Conclusions Only three reports on trisomy 11 mosaicism identified at amniocentesis have been published previously, all with a normal outcome. Additional cases of prenatally diagnosed mosaicism for trisomy 11 are necessary to assess more accurately the clinical significance of this finding. Copyright © 2006 John Wiley & Sons, Ltd.

Myotonic dystrophy is the commonest autosomal dominant type of muscular dystrophy in adults. It is one of the trinucleotide repeat expansion disorders, and its severity correlates with the number of CTG repeats in the myotonic dystrophy gene. It has been suggested that myotonic dystrophy exhibits the phenomenon of preferential transmission of the larger mutated alleles that has been described in other trinucleotide repeat disorders. Several authors have reported that the frequency of transmission of the mutated alleles is higher than 50%—a finding that, if true, does not comply with the Mendelian laws of segregation. However, these studies were based on data from the analysis of pedigrees with ascertainment bias. In our study, we determined the frequency of transmission of mutated alleles using data from prenatal molecular studies, which are not subject to ascertainment bias. This is the first study to examine the segregation of the mutated alleles in myotonic dystrophy in pregnancy. Eighty-three fetuses were examined, 30 of 62 mothers (48.38%) and 8 of 21 fathers (38.09%) transmitted the mutated allele, giving an overall transmission rate of 45.78%. We found no evidence of statistically significant deviation of the frequency of transmission of the mutated alleles from the 50% expected in autosomal dominant disorders. This study, unlike previous ones, excludes preferential transmission in myotonic dystrophy, a finding that may be attributable to the lack of correction for ascertainment bias in previous studies and to the use of prenatal data in this study.

Second trimester maternal serum biochemical markers, introduced between 1990 and 1995, were supplemented with new ultrasound methods at 14–16 weeks and first trimester biochemical markers between 1995 and 2000. This study evaluated the effectiveness of a Down syndrome (DS) prevention program among the Israeli Jewish population between 1990 and 2000. We collected data on the total number of prenatal tests performed on Israeli Jewish women, DS cases detected prenatally and DS livebirths in Israel during these years. We also studied the use of the newer screening tests in 1990, 1992, and 2000. Between 1990 and 1995, use of chromosomal studies for DS in this population increased from 11.3% to 21.6% and the percentage of cases detected prenatally from 53% to 70%. However, between 1996 and 2000, even with the new screening methods, the utilization rate remained similar (20.7% and 19.8%, respectively) and the percentage detected prenatally decreased to 61% in 2000. The total cost per case detected increased from $47,971 in 1990 to $75,229 in 1992, and to $190,171 in 2000. Between 1990 and 1995, improvement in the percentage of cases detected prenatally was associated with a significant increase in the amniocentesis rate—both are attributed to the introduction of second trimester maternal serum biochemical marker tests. Unexpectedly, the introduction between 1995 and 2000 of new genetic methods to assess the DS risk did not improve the percentage detected or reduce the amniocentesis rate, and was accompanied by an increased cost per case detected.

To study the prevalence of cleft palate and cleft lip with or without cleft palate in an Israeli Arab town, questionnaires were sent to the parents of 1375 pupils in grades 1 and 2 in all seven primary schools in the town of Taibe, and 1281 responded. The information requested included data about siblings and members of the parental generation to give a total of 16 174, and the presence of consanguinity and history of exposure to medication, radiation, smoking or alcohol during pregnancy.There were four affected individuals among the index cases, of whom two had cleft palate only and two cleft lip with cleft palate, giving prevalence rates for each of these of 1.56/1000. Adding to these the number of affected siblings gave a total of 10 affected individuals; two with cleft palate only (0.39/1000) and eight with cleft lip with or without cleft palate (1.56/1000). Among the parental generation, of 16 reported affected individuals, two had cleft palate only (0.18/1000) and 14 cleft lip with or without cleft palate (1.26/1000). The overall prevalence rate for all 26 affected individuals was 1.6/1000; four of these had cleft palate only (0.24/1000) and 22 had cleft lip with or without cleft palate (1.36/1000). There were no cases whose mothers had been exposed to medication, radiation, smoking or alcohol during pregnancy. The effect of consanguinity was not significant (P < 0.92). This study shows that the prevalence of facial clefting in an Israeli Arab community is consistent with that in the general population worldwide.

Arthrogryposis multiplex congenita (AMC) is a heterogeneous symptom complex characterized by non‐progressive joint contractures from birth that involve more than one part of the body. In 1997, our group investigated a large Israeli Arab inbred kindred that showed autosomal recessive inheritance of AMC neuropathic type, and we mapped the gene to 5qter between markers D5S1456 and D5S498. Haplotype sharing studies revealed complete homozygosity in all affected individuals with marker D5S394, thus providing significant statistical evidence in favor of linkage. In this study, we have undertaken further fine mapping of this region of chromosome 5qter, and have examined several additional markers. All the affected individuals showed complete homozygosity for the marker D5S394, and also for three additional markers that are telomeric to marker D5S394 and situated 31766 bp, 58016 bp, and 58516 bp, respectively, from it. Analysis of the recombinant individuals has enabled us to narrow down the critical region to a distance of .442 Mb between markers D5S394 and D5S2069.