Biomedical subjects
Publications and source records attributed to E Levy-Lahad.
BRCA1 and BRCA2 mutations increase breast and ovarian cancer risks substantially enough to warrant risk reduction surgery, despite variable risk estimates. Underlying this variability are methodological issues, and also complex genetic and nongenetic effects. Although many modifying factors are unidentified, known factors can already be incorporated in individualised risk prediction.
BACKGROUND: Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder caused by mutations in the neurofibromin gene. Approximately, 50% of cases are caused by de-novo mutations. Even when the NF1 mutation is known, accuracy of PGD is highly enhanced by simultaneous analysis of linked markers. In a childless couple referred to PGD, the male carried a de-novo mutation, precluding the possibility of typing relatives to establish the mutation-associated haplotype. We developed a single-sperm haplotype analysis strategy to establish the haplotype linked to the NF1 mutation. METHODS: Spermatozoa from freshly ejaculated semen were used as a substrate for multiplex PCR on single sperm. RESULTS: In addition to the NF1 mutation, six informative polymorphic markers flanking the NF1 gene (D17S1294, D17S1849, D17S841, D17S975, NF1TG2 and NF1AC5) were linked to individual alleles in single sperm from the affected male. CONCLUSIONS: Single-sperm analysis established the haplotypes of both mutant and wild-type NF1 alleles and enabled the implementation of a PGD protocol using polymorphic marker analysis. This method is generally applicable to PGD for any disease in which the haplotype of paternal mutations cannot be determined by typing relatives.
AIM: To reject one of the variants of inherited thrombophylia in a 64-year-old patient with deep thrombosis of leg veins and high hemoglobin and red cell levels. MATERIAL AND METHODS: The study was made of antithrombin III and protein C, protein S levels; resistance to activated protein C; molecular structure of DNA coding factor 5; methylenetetrahydrofolate reductase. RESULTS: The patient was diagnosed to have heterozygote factor V Leiden mutation. The replacement of arginine by glutamine in position 506 of factor V molecule raises the risk of thrombosis. This risk was aggravated by high hemoglobin, red cells, hematocrit, low volume of circulating plasma, smoking. The patient had normal levels of leukocytes and platelets, normal spleen size, slightly lowered level of erythropoietin. CONCLUSION: The presence of thrombosis in patients with erythremia or erythrocytosis rejects one of the thrombophilia forms.
BRCA1 and BRCA2 carriers are at increased risk for both breast and ovarian cancer, but estimates of lifetime risk vary widely, suggesting their penetrance is modified by other genetic and/or environmental factors. The BRCA1 and BRCA2 proteins function in DNA repair in conjunction with RAD51. A preliminary report suggested that a single nucleotide polymorphism in the 5' untranslated region of RAD51 (135C/G) increases breast cancer risk in BRCA1 and BRCA2 carriers. To investigate this effect we studied 257 female Ashkenazi Jewish carriers of one of the common BRCA1 (185delAG, 5382insC) or BRCA2 (6174delT) mutations. Of this group, 164 were affected with breast and/or ovarian cancer and 93 were unaffected. RAD51 genotyping was performed on all subjects. Among BRCA1 carriers, RAD51-135C frequency was similar in healthy and affected women [6.1% (3 of 49) and 9.9% (12 of 121), respectively], and RAD-135C did not influence age of cancer diagnosis [Hazard ratio (HR) = 1.18 for disease in RAD51-135C heterozygotes, not significant]. However, in BRCA2 carriers, RAD51-135C heterozygote frequency in affected women was 17.4% (8 of 46) compared with 4.9% (2 of 41) in unaffected women (P = 0.07). Survival analysis in BRCA2 carriers showed RAD51-135C increased risk of breast and/or ovarian cancer with an HR of 4.0 [95% confidence interval 1.6-9.8, P = 0.003]. This effect was largely due to increased breast cancer risk with an HR of 3.46 (95% confidence interval 1.3-9.2, P = 0.01) for breast cancer in BRCA2 carriers who were RAD51-135C heterozygotes. RAD51 status did not affect ovarian cancer risk. These results show RAD51-135C is a clinically significant modifier of BRCA2 penetrance, specifically in raising breast cancer risk at younger ages.
To determine whether human X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome (IPEX; MIM 304930) is the genetic equivalent of the scurfy (sf) mouse, we sequenced the human ortholog (FOXP3) of the gene mutated in scurfy mice (Foxp3), in IPEX patients. We found four non-polymorphic mutations. Each mutation affects the forkhead/winged-helix domain of the scurfin protein, indicating that the mutations may disrupt critical DNA interactions.
We describe an unusual family with a fatal genetic syndrome of neonatal diabetes mellitus (DM), enteropathy, endocrinopathy, and severe infections with variable thrombocytopenia. All affected individuals are male; X-linked inheritance is likely. The most common clinical features are neonatal DM, inanition, and enteropathy; a variety of other autoimmune phenomena are less frequent. Clinical variability within and among families is common, including lack of one or more cardinal features. The syndrome is usually fatal, but survival is sometimes possible with immunosuppressive therapy. Clinical variability and frequent new mutations may contribute to poor recognition and underreporting of similar cases.
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The objective was to compare the contribution to perinatal bilirubinemia of hemolysis and UDP-glucuronosyltransferase (UGT) gene promoter polymorphism, seen in Gilbert's syndrome, between glucose-6-phosphate dehydrogenase (G-6-PD)-deficient and -normal neonates. Serum total bilirubin (STB) values from 52 G-6-PD-deficient and 166 G-6-PD-normal term, male neonates, sampled within 3 h of delivery (first sample) and on d 3 (second sample), were analyzed in relation to blood carboxyhemoglobin corrected for inspired CO (COHbc), an accurate index of hemolysis, and UGT promoter genotype. COHbc values (% total Hb) were greater in G-6-PD-deficient neonates than controls: first sample 1.00 +/- 0.25% versus 0.84 +/- 0.24%, p < 0.0001; second sample 0.83 +/- 0.20% versus 0.76 +/- 0.19%, p = 0.002. First sample COHbc and STB values did not correlate in either the G-6-PD-deficient or control groups, whereas second sample COHbc values correlated significantly with corresponding STB values in the control population only (r = 0.28, p = 0.0007). At second sampling, there was a higher allele frequency of the variant UGT promoter among those with STB values > or =75th percentile than those <75th among the G-6-PD-deficient neonates (0.60 versus 0.33, respectively, p = 0.025), but not controls (0.31 versus 0.40, respectively, p = 0.24). Among those infants with at least one variant UGT promoter allele, STB values were higher in the G-6-PD-deficient neonates than controls at second sampling only (181 +/- 56 microM versus 149 +/- 46 microM, respectively, p = 0.03). Both within and between the G-6-PD-deficient and control groups, our data demonstrate changing and differing contributions of hemolysis and UGT promoter polymorphism to bilirubinemia during the first 3 d of life.
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An inherited risk for thrombosis, including mutant thermolabile variant of methylenetetrahydrofolate reductase (MTHFR), factor V Leiden, or prothrombin may be the co-factor(s) for avascular necrosis (AVN) in patients with sickle cell disease. Similarly, heterozygosity for factor V Leiden is sufficient to explain the increased blood viscosity observed in children with Legg-Calve-Perthes disease who develop AVN. Because there are no laboratory tests or clinical markers that are helpful in predicting which patients with Gaucher disease may develop AVN, the current study was undertaken to ascertain if there exists an inherited predilection to hypercoagulability in patients with Gaucher disease and AVN. Analysis was performed on genomic DNA extracted from 56 adult patients with type I Gaucher disease. In this cohort of Ashkenazi Jewish patients, the frequency of mutations in the MTHFR, prothrombin, and factor V Leiden genes was found to be low, as was the presence of anticardiolipin antibodies; and none was correlated with increased incidence of AVN. Splenectomy, that may be a predisposing factor to AVN in patients with Gaucher disease, was factored out. Hence the presence of any of the above thrombophilic factors, and which by extension may be risk factors for AVN in other diseases, are not more common in patients with Gaucher disease who develop AVN. Studies in larger cohorts and possibly inclusion of additional factors may be needed to ascertain whether a correlation exists.
We asked whether UDP glucuronosyltransferase (UGT) gene promoter polymorphism (Gilbert's syndrome) would increase hyperbilirubinaemia in direct Coombs' negative ABO-incompatible neonates, as seen in other combinations with this condition. 40 ABO-incompatible and 344 ABO-compatible controls had an allele frequency of 0.35 for the variant promoter gene. The incidence of hyperbilirubinaemia was significantly higher only in the former who were also homozygotes for the variant UGT promoter, compared with ABO-incompatible babies homozygous for the normal UGT promoter (43% vs 0, p=0.02), and with ABO-compatible controls of all UGT genotypes combined (relative risk 5.65, 95% CI 2.23-14.31). Gilbert's syndrome is a determining factor for neonatal hyperbilirubinaemia ABO incompatibility.
OBJECTIVE: To determine the possible effects and incidence of BRCA1 and BRCA2 germline mutations in uterine serous papillary carcinoma. METHODS: We screened DNA from 12 women with uterine serous papillary carcinoma for BRCA1 and BRCA2 germline mutations common in the Jewish population (BRCA1-185delAG and 5382insC, BRCA2-6174delT). In women with germline mutations, tumor DNA was screened for loss of heterozygosity at the appropriate loci. RESULTS: Nine women were of Jewish Ashkenazi origin and three were non-Ashkenazi. Two of nine Ashkenazi women were carriers of germline mutations: one 185delAG mutation and one 5382insC mutation. Five women had histories of breast carcinoma before diagnosis of uterine serous papillary carcinoma. Family histories of seven women had at least one first-degree relative with malignant disease. Of those, four had at least one first-degree relative with breast, ovarian, or colon carcinoma. Both carriers had strong family histories of breast-ovarian carcinoma. Loss of heterozygosity analysis found loss of the wild-type BRCA1 allele in the primary uterine tumors. CONCLUSION: BRCA1 germline mutations were observed in two of nine of the women in this series. The loss of heterozygosity in the tumor tissue of the carriers, coupled with the high frequency of family and patient histories of breast or ovarian malignancies, suggest that uterine serous papillary carcinoma might be a manifestation of familial breast-ovarian cancer.
To gain insight into the molecular mechanisms underlying the inherited predisposition to breast cancer in non-Ashkenazi Jews, we genotyped 54 Jewish Moroccan women with breast cancer, unselected for family history of cancer, for the predominant Jewish mutations in BRCA1, BRCA2, and ATM. One patient (2%) was found to have the 185de1AG BRCA1 mutation, none was a carrier of the 6174delT BRCA2 mutation, and 2/54 (4%) were heterozygous for the ATM mutation. These rates were not significantly different from the rates in the general non-Ashkenazi population. These preliminary data may indicate that the predominant Jewish mutations in BRCA1, BRCA2, and ATM genes contribute little, if any, to breast cancer predisposition and risk among Moroccan Jews.
The identification of cancer susceptibility genes offers new avenues for selecting high-risk individuals as subjects for chemoprevention trials. Because carriers of predisposing mutations are at high risk, they are more likely to enroll and comply with chemoprevention trials, and meaningful results can be achieved with smaller numbers of participants and shorter periods of follow-up. Such studies have immediate benefits for carriers themselves, but they are also likely to result in effective chemopreventive strategies for the general population. In this review, we discuss BRCA1 and BRCA2 carriers as potential candidates for breast and ovarian cancer chemoprevention trials. The existence of a large population with a high frequency of easily identifiable BRCA1/2 mutations can provide ample opportunity for such studies. However, the possibility that tumor characteristics and hormonal profile of BRCA1/BRCA2 related cancers are not completely equivalent to cancers in the general population should be borne in mind.
OBJECTIVES: Type II endometrial carcinomas are estrogen-independent and have adverse histologic features and a substantially poorer prognosis. No risk factors have been identified. Interestingly, there is a striking clinical and histopathological similarity between serous papillary carcinomas of the ovary (OSPC), endometrium, and peritoneal cavity, suggesting a common oncogenic mechanism. Several common molecular alterations were found using molecular comparative analysis of OSPC and uterine serous papillary carcinoma (USPC). Germline mutations in the BRCA1 tumor suppressor gene predispose to breast and ovarian cancer but no association with sporadic endometrial cancer has been found. A family of Ashkenazi Jewish origin, in which one sister was first diagnosed with USPC and the second diagnosed with OSPC, led to the hypothesis that a BRCA mutation may contribute to USPC. METHODS: Genomic DNA from both patients as well as two unaffected siblings was analyzed for the three mutations common in Ashkenazi Jews. Loss of heterozygosity (LOH) analysis was performed on DNA extracted from USPC tumor tissue. RESULTS: Both affected sisters tested positive for BRCA1 5382insC germline mutation. LOH analysis confirmed the results. CONCLUSIONS: We present a breast-ovarian cancer family including two sisters with advanced serous papillary carcinomas of endometrial and ovarian origins, carrying the same BRCA1 mutation (5382insC). LOH analysis on USPC tumor DNA showed loss of the wild-type allele, suggesting a causal relationship between the germline BRCA1 mutation and USPC. We believe a study examining BRCA1 mutations in a large cohort of women with this high-risk endometrial carcinoma is warranted. A positive finding may have implications for surveillance and prophylactic surgery in carriers of BRCA1 mutations.
OBJECTIVES: We assessed the incidence of hyperbilirubinemia, defined as serum total bilirubin >/=15 mg/dL (256 micromol/L), in a cohort of Sephardic Jewish female neonates at risk for glucose-6-phosphate dehydrogenase (G-6-PD) deficiency with especial emphasis on the heterozygotes. We studied the roles of hemolysis by blood carboxyhemoglobin (COHb) determinations and of the variant promoter of the gene for the bilirubin-conjugating enzyme uridine 5'-diphosphate glucuronosyltransferase 1 (UGT1A1) seen in Gilbert's syndrome in the pathogenesis of the hyperbilirubinemia. METHODS: Consecutively born, healthy, term, female neonates were screened for G-6-PD deficiency and observed clinically with serum bilirubin evaluations as indicated for hyperbilirubinemia. On day 3, blood was sampled for COHb, total hemoglobin (tHb), and a mandatory serum bilirubin determination. COHb, determined by gas chromatography, was expressed as percentage of tHb and corrected for inspired carbon monoxide (COHbc). DNA was analyzed for the G-6-PD Mediterranean563T mutation and for the variant UGT1A1 gene. RESULTS: The cohort included 54 G-6-PD-deficient heterozygotes, 19 deficient homozygotes, and 112 normal homozygotes. More heterozygotes (12/54, 22%; relative risk: 2.26; 95% CI: 1.07-4.80) and deficient homozygotes (5/19, 26.3%; relative risk: 2.68; 95% CI: 1.05-6.90) developed hyperbilirubinemia, than did normal homozygotes (11/112, 9.8%). Third-day serum bilirubin values that were obtained from 144 neonates were significantly higher in both heterozygotes (11.2 +/- 3. 7 mg/dL [192 +/- 64 micromol/L]) and G-6-PD-deficient homozygotes (12.0 +/- 3.0 mg/dL [206 +/- 52 micromol/L]) than in the G-6-PD normal homozygotes (9.4 +/- 3.4 mg/dL [160 +/- 58 micromol/L). In contrast, COHbc values were higher only in G-6-PD-deficient homozygotes (0.74% +/- 0.14%) and not in heterozygotes (0.69% +/- 0. 19%, not statistically significant), compared with control values (0. 63% +/- 0.19%). High COHbc values were not a prerequisite for the development of hyperbilirubinemia in any of the G-6-PD genotypes. A greater incidence of hyperbilirubinemia was found among the G-6-PD-deficient heterozygotes, who also had the variant UGT1A1 gene, in both heterozygous (6/20, 30%) and homozygous (4/8, 50%) forms, than was found in their counterparts with the normal UGT1A1 gene (2/26, 7.7%). This effect was not seen in the G-6-PD normal homozygote group. A color reduction screening test for G-6-PD deficiency identified only 20.4% (11/54) of the heterozygotes. CONCLUSIONS: We showed that G-6-PD-deficient heterozygotes, categorically defined by DNA analysis, are at increased risk for neonatal hyperbilirubinemia. The screening test that was used was unable to detect most heterozygotes. Increased bilirubin production was not crucial to the development of hyperbilirubinemia, but presence of the variant UGT1A1 gene did confer increased risk.
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Gaucher disease is the most prevalent inherited disease among Ashkenazi Jews. It is very heterogeneous due to a large number of mutations within the glucocerebrosidase gene, whose impaired activity is the cause for this disease. Aiming at determining Gaucher carrier frequency among the Ashkenazi Jewish population in Israel, 1,208 individuals were molecularly diagnosed for six mutations known to occur among Ashkenazi Jewish Gaucher patients, using the newly developed Pronto Gaucher kit. The following mutations were tested: N370S, 84GG, IVS2+1, D409H, L444P, and V394L. Molecular testing of these mutations also allows identification of the recTL allele. The results indicated that Gaucher carrier frequency is 1:17 within the tested population. The prevalence of N370S carriers is 1:17.5. This implies that approximately 1:1225 Ashkenazi Jews will be homozygous for the N370S mutation. Actually, in our study of 1,208 individuals one was found to be homozygous for the N370S mutation. The actual number of known Ashkenazi Jewish Gaucher patients with this genotype is much lower than that expected according to the frequency of the N370S mutation, suggesting a low penetrance of this mutation. Results of loading experiments in cells homozygous for the N370S mutation, as well as cells homozygous for the L444P and the D409H mutations, exemplified this phenomenon.