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Yuval Yaron

Publications and source records attributed to Yuval Yaron.

At least 19 recordsLinked to original sources
PubMed2003

The clinical application of spectral karyotyping (SKY) in the analysis of prenatally diagnosed extra structurally abnormal chromosomes (ESACs).

OBJECTIVE: The prenatal detection of de novo extra structurally abnormal chromosomes (ESACs) presents a challenge because the associated risk for congenital anomaly ranges from 100% to practically none, depending on the chromosomal origin. Despite the use of standard cytogenetic techniques and even fluorescence in situ hybridization (FISH), the origin of some ESACs often remains elusive. Spectral karyotyping (SKY) is a molecular cytogenetic technique based on the simultaneous analysis of all chromosomes using a unique probe mix that allows the rapid identification of all chromosomes in 24 colors. The purpose of this study was to evaluate the use of SKY in the characterization of prenatally diagnosed de novo ESACs. METHODS: This series includes five cases of de novo ESACs detected prenatally in routine amniocentesis samples performed for advanced maternal age. Cases of inherited ESACs or ESACs defined by standard cytogenetic techniques were excluded. RESULTS: SKY analysis yielded valuable information, particularly in cases of nonsatellited ESACs: a der(18) and a ring(Y). In a case of a unisatellited der(15), SKY corroborated data obtained by standard cytogenetic techniques and FISH. Finally, in two cases of small bisatellited chromosomes, SKY was noncontributory. CONCLUSIONS: While SKY may be a valuable tool in some cases, especially nonsatellited and ring ESACs, it does have limitations and should be used judiciously in conjunction with other cytogenetic techniques.

Adult↗
PubMed2003

Combined cytogenetic and array-based comparative genomic hybridization analyses of Wilms tumors: amplification and overexpression of the multidrug resistance associated protein 1 gene (MRP1) in a metachronous tumor.

Tumor samples from a variety of Wilms tumors (WT) obtained from three patients were analyzed by cytogenetic and array-based comparative genomic hybridization (CGH) methods. The tumors represented different stages of tumorigenesis and included a unilateral primary WT and contralateral nephrogenic rest (case 1), a primary WT and a contralateral metachronous WT (case 2), and a recurrent WT with lung metastases (case 3). All six specimens exhibited abnormal karyotypes characteristic of different WT levels of progression. Array-based CGH examinations of 57 genes that are commonly amplified in various cancers revealed a 2.6-fold genomic amplification of the multidrug resistance-associated protein 1 (MRP1) gene in the metachronous WT, but no amplification in the primary tumor. This sole amplification event in our series was also confirmed by Southern blot analysis. Furthermore, quantitative reverse transcriptase polymerase chain reaction showed a sixfold overexpression of the MRP1 gene in this metachronous WT relative to the primary tumor. Our findings suggest that for most of the genes examined in this series genomic amplification does not play a role in WT pathogenesis. Isolated amplification and overexpression of the MRP1 gene in the metachronous WT, however, suggest that this gene may be an important factor in the development and progression of metachronous tumors.

Blotting, Southern↗
PubMed2003

Two novel translocations, t(2;4)(q35;q31) and t(X;12)(q22;q24), as the only karyotypic abnormalities in a malignant peripheral nerve sheath tumor of the skull base.

Malignant peripheral nerve sheath tumor (MPNST) is a rare neoplasm that originates from Schwann cells and comprises 5%-10% of soft tissue sarcomas. Cytogenetic analysis of this tumor has shown a highly complex karyotype, and no single chromosomal aberration has been reported to date. We combined spectral karyotyping analysis and G-banding for cytogenetic characterization of this unique tumor, which originated in the anterior skull base. We report the simultaneous occurrence of a t(2;4)(q35;q31) and a t(X;12)(q22;q24) as the only chromosomal abnormalities in this tumor. To the best of our knowledge, apparently balanced translocations have not been identified previously in MPNST.

Adult↗
PubMed2003

Screening for familial dysautonomia in Israel: evidence for higher carrier rate among Polish Ashkenazi Jews.

Familial dysautonomia (FD) is an autosomal recessive disorder characterized by hereditary sensory and autonomic neuropathies. Although extremely rare in most populations, FD is common among Ashkenazi Jews (AJ), with a calculated carrier frequency of 1 in 30, based on disease prevalence. The gene for FD was recently identified as IKBKAP. One major mutation (IVS2 + 6T --> C) is responsible in >99.5% of cases among AJ. The purpose of this study was to determine the actual frequency of FD carriers in the AJ population in Israel and to determine whether carriers are more frequent among a subpopulation of AJ from Poland. The study group included 1267 Jews of Ashkenazi origin who were referred for routine DNA screening tests. These included 1100 individuals who were full AJ and 167 who were part AJ. None had a family history of FD. Mutation analysis for (IVS2 + 6T --> C) was performed by PCR amplification followed by restriction enzyme analysis. All positive cases were confirmed by DHPLC WAVE( trade mark ). Among the 1100 full AJ tested, 34 were found to be FD carriers (1:32). The incidence of mutation carriers was significantly higher in AJ of Polish descent (1:18) compared to AJ of non-Polish descent (1:99). Among the 167 individuals who were part AJ, there were 3 carriers (1:56). The incidence of FD among AJ, particularly those of Polish background, warrants population screening. Population screening may be performed by denaturing high-performance liquid chromatography.

Base Sequence↗
PubMed2002

Multiple genes in human 20q13 chromosomal region are involved in an advanced prostate cancer xenograft.

We analyzed a prostate cancer xenograft derived from a locally advanced tumor using combined cytogenetic, array-based comparative genomic hybridization and expression analyses. This analysis revealed that genes in the 20q13 chromosomal region, CSE1L, ZNF217, MYBL2, and STK15, were significantly overexpressed in this tumor. The expression pattern of these genes was then confirmed in two large human prostate cancer microarray databases. Furthermore, the MYBL2 and STK15 have been significantly overexpressed in prostate metastases, allowing a clear distinction between localized tumors and metastases. Our data suggest these genes to be involved in advanced stages of prostate tumorigenesis and as such, they may serve as markers for tumor progression.

Adenocarcinoma↗
PubMed2002

A novel founder mutation in the RNASEL gene, 471delAAAG, is associated with prostate cancer in Ashkenazi Jews.

HPC1/RNASEL was recently identified as a candidate gene for hereditary prostate cancer. We identified a novel founder frameshift mutation in RNASEL, 471delAAAG, in Ashkenazi Jews. The mutation frequency in the Ashkenazi population, estimated on the basis of the frequency in 150 healthy young women, was 4% (95% confidence interval [CI] 1.9%-8.4%). Among Ashkenazi Jews, the mutation frequency was higher in patients with prostate cancer (PRCA) than in elderly male control individuals (6.9% vs. 2.4%; odds ratio = 3.0; 95% CI 0.6-15.3; P=.17). 471delAAAG was not detected in the 134 non-Ashkenazi patients with PRCA and control individuals tested. The median age at PRCA diagnosis did not differ significantly between the Ashkenazi carriers and noncarriers included in our study. However, carriers received diagnoses at a significantly earlier age, compared with patients with PRCA who were registered in the Israeli National Cancer Registry (65 vs. 74.4 years, respectively; P<.001). When we examined two brothers with PRCA, we found a heterozygous 471delAAAG mutation in one and a homozygous mutation in the other. Loss of heterozygosity was demonstrated in the tumor of the heterozygous sib. Taken together, these data suggest that the 471delAAAG null mutation is associated with PRCA in Ashkenazi men. However, additional studies are required to determine whether this mutation confers increased risk for PRCA in this population.

Antigens, Surface↗
PubMed2002

Clinical and screening implications of the I1307K adenomatous polyposis coli gene variant in Israeli Ashkenazi Jews with familial colorectal neoplasia. Evidence for a founder effect.

BACKGROUND: The authors previously found the I1307K adenomatous polyposis coli (APC) gene variant in 5% of Ashkenazi control participants, in 15.4% of those who had familial colorectal neoplasia, but also in 1.6% of non-Ashkenazi control participants. In this study, they evaluated its use in a screening program for familial colorectal neoplasia and examined for a founder effect. METHODS: Consecutive Ashkenazim with a personal and/or family history of colorectal neoplasia had the DNA test. Markers flanking the APC gene were examined in Ashkenazi and non-Ashkenazi I1307K carriers and noncarriers. RESULTS: Among 718 persons, I1307K occurred in 6.2% of Ashkenazi participants, in 1.5% of non-Ashkenazi control participants (P = 0.02), and in 10.7% of Ashkenazim with familial neoplasia (relative risk, 1.73 [not significant compared with controls]; 95% confidence interval, 0.7-3.2). Colorectal neoplasia was detected in carriers at a younger age (P < 0.05) without excess risk for multiple colorectal neoplasia or noncolorectal neoplasia. I1307K attributable risk for colorectal neoplasia was 0.5-0.6%. Compared with noncarriers, both Ashkenazi and non-Ashkenazi I1307K carriers had similar flanking polymorphic alleles (P < 0.01). CONCLUSIONS: I1307K is a low-penetrance genetic variant that indicates a 1.7 relative risk for neoplasia in carriers who have familial carcinoma, clinically equivalent to obtaining a family history of sporadic colorectal neoplasia and promoting early screening. I1307K is a founder genetic variant in Jews of different ethnic origin, mainly Ashkenazim, but it explains only partially their higher incidence of colorectal carcinoma.

Adult↗
PubMed2002

Molecular analysis of the APC gene in 71 Israeli families: 17 novel mutations.

Familial adenomatous polyposis (FAP) is caused by germline mutations in the APC gene. This study included 71 Israeli families referred for molecular analysis of the APC gene. Analysis was performed by the protein truncation test (PTT) of exon 15, and if negative, by direct sequencing of exon 1 to 14. Mutations were found in 36 (50.7%) probands. Mutation detection rates depended on the pattern of referral, such that among the 40 probands referred from the Service for Hereditary Cancer the mutation detection rate was 70%, whereas among the 31 probands referred by other gastroenterologists detection rate was significantly lower (25.8%). Of the 36 mutations detected, 21 were within exon 15, 13 within exons 1 to 14 and 2 were newly-described splicing mutations in introns 9 and 14. A relatively high proportion of the mutations was detected in exon 9 (6/36), five of them newly described. Altogether, we describe here 17 new mutations. Within the two major ethnic groups in Israel, patients of Ashkenazi and non-Ashkenazi origin, there was no significant differences in the mutation detection rate or the distribution of mutations within the APC gene. No founder mutation was detected in any of these populations. Our data confirm that higher detection rates may be expected in patients referred by clinical services specializing in hereditary colon cancer. These results further underscore the importance of complete analysis of all exons and exon/intron boundaries, in order to achieve maximal detection rate in patients suspected of FAP.

Adenomatous Polyposis Coli↗
PubMed2002

MECP2 mutations in Israel: implications for molecular analysis, genetic counseling, and prenatal diagnosis in Rett syndrome.

This report describes molecular analysis of the MECP2 gene in 37 Israeli patients suspected of having Rett syndrome (RTT). The patients were from various Jewish ethnic groups and from Arabic origin. Of the 17 patients with classical RTT, bi-directional sequencing of the coding exons revealed MECP2 mutations in 14 patients. About 66% of the mutations were located in previously described hot-spots. One case presented a novel mutation (141insA). Mutation-negative patients were further analyzed by Southern blot, which detected a novel gross rearrangement in another classical case. Altogether, detection rate in classical cases was 88%. In a non-classical case, a novel missense mutation (1451G>C) was detected in an affected girl and in her normal father, suggesting that this is a non-pathogenic alteration. Another variant (1461 + 96insA) was detected in an affected girl and in her healthy mother and also in another affected girl and her healthy father, suggesting that this variant too, is non-pathogenic. No significant difference in mutation type was noted among the different ethnic groups. In one familial case, the same mutation was detected in two sibs but not in their mother, suggesting germ-line mosaicism. Our results suggest that mutation-negative cases should be further assessed for gross rearrangements and that molecular analysis of the parents is often required when previously undescribed sequence alterations are detected.

Blotting, Southern↗
PubMed2002

Decreased first trimester PAPP-A is a predictor of adverse pregnancy outcome.

OBJECTIVE: Low levels of maternal serum pregnancy associated plasma protein-A (PAPP-A) have been linked to chromosome anomalies such as trisomy 21, 13 and 18, triploidy and sex chromosome aneuploidy. Low levels of PAPP-A have also been implicated in spontaneous miscarriage. The purpose of this study was to evaluate whether low levels of first trimester PAPP-A are predictive of other adverse pregnancy outcomes. STUDY DESIGN: The study included patients with singleton pregnancies who underwent combined first trimester screening using nuchal translucency (NT) and maternal serum free beta-human chorionic gonadotrophin (free beta-hCG) and PAPP-A at 10-13 weeks' gestation. Patients with chromosome aberrations or fetal anomalies were excluded. Serum marker levels were expressed as gestational age-specific multiples of the median (MoMs). The incidences of various adverse pregnancy outcomes (spontaneous preterm labor, fetal growth restriction (FGR), proteinuric and non-proteinuric pregnancy induced hypertension (PIH), intrauterine fetal demise, oligohydramnios, spontaneous miscarriage and placental abruption) were evaluated, according to maternal PAPP-A MoM levels. RESULTS: Of the 1622 patients in the study, pregnancy complications were observed in 184 (11.3%). Patients with PAPP-A < or =0.25 MoM had significantly higher rates of FGR (RR = 3.12), proteinuric PIH (RR = 6.09), spontaneous miscarriage (RR = 8.76). No statistically significant differences were noted for other adverse outcomes evaluated Women with PAPP-A < or =0.50 MoM also had significantly higher rates of FGR (RR = 3.30) and spontaneous miscarriage (RR = 3.78). CONCLUSIONS: We conclude that decreased levels of first trimester maternal serum PAPP-A are predictive not only of chromosome anomalies but also of adverse pregnancy outcome.

Adult↗
PubMed2002

Third-trimester unexplained intrauterine fetal death is associated with inherited thrombophilia.

OBJECTIVE: To determine the risk of thrombophilias in women with unexplained intrauterine fetal deaths (IUFD). METHODS: All women with IUFD at 27 weeks' gestation or greater were initially assessed during a period of 26 months. Subjects with multiple pregnancies, congenital anomalies, intrauterine infection, chorioamnionitis, immune hydrops, diabetes mellitus, previous thromboembolism, and severe hypertensive disease were excluded. The remaining 40 women with unexplained IUFD (study group) were matched for age and ethnicity with 80 healthy women who had at least one normal pregnancy (control group). All participants were tested at least 2 months after delivery for mutations of factor V Leiden, prothrombin gene, methylenetetrahydrofolate reductase, and for deficiencies of protein S, protein C, and antithrombin III. They were also tested and found to be negative for anticardiolipin antibodies. RESULTS: The gestational age at delivery and birth weight were significantly lower in the study group. The prevalence of inherited thrombophilias was 42.5% in the study group compared with 15% in the control group (odds ratio 2.8, 95% confidence interval 1.5, 5.3, P =.001). The prothrombin mutation and protein S deficiency rates were significantly higher in the study group (odds ratio 2.3, 95% confidence interval 1.3, 4.0, and odds ratio 3.2, 95% confidence interval 2.4, 4.1, respectively). CONCLUSION: Third-trimester IUFD is significantly associated with thrombophilias. These findings suggest that thrombophilia work-ups should be part of IUFD investigations and may have therapeutic and prognostic implications in future pregnancies.

Adult↗
PubMed2002

The mitochondrial DNA mutation (deltamtDNA5286) in human oocytes: correlation with age and IVF outcome.

PURPOSE: To evaluate the correlation between the presence of a newly described mitochondrial DNA (mtDNA) mutation (deltamtDNA5286), patients' age, and in vitro fertilization (IVF) outcomes. METHODS: The presence of deltamtDNA5286 was analyzed by nested-primer PCR in 224 unfertilized oocytes of 81 women undergoing IVF for various reasons. Age, number of oocytes retrieved, fertilization and embryo cleavage, number of embryos transferred, and pregnancy rates were compared between patients with and without a mtDNA mutation in their oocytes. RESULTS: The 23 patients in which deltamtDNA5286 was detected in at least one oocyte were significantly younger than the other 58 with no mutations (30.9 years vs. 33.8 years, respectively, P = 0.03), and had a significantly lower fertilization rate (28.9% vs. 42.1%, respectively, P = 0.01). No other outcome variable was significantly different between the two groups. CONCLUSION(S): The mtDNA mutation deltamtDNA5286 may serve as a marker of decreased oocyte quality in IVF.

Adult↗
PubMed2002

Screening.

Historically, obstetrician/gynaecologists have utilized screening procedures as a major component of their routine clinical practice. The Papanicolaou (Pap) smear technique for cervical cancer is more than 50 years old and has saved countless lives by identifying who among the supposedly low-risk group of patients is in fact at high risk of cervical cancer. The introduction of alpha-fetoprotein screening for neural tube defects in the 1970s, low alpha-fetoprotein level for Down syndrome in the 80s, multiple markers in the 90s and now, after the millennium combined ultrasound and biochemistry for a more precise risk identification, has radically changed our approach towards optimizing the sensitivity, specificity and positive and negative predictive values of screening. As these techniques improve, old mainstays of attributable risks such as advanced maternal age will probably fade into oblivion as stand-alone criteria. The specifics of screening techniques will vary by disorder, but the general principles are important and can be applied to all new technologies as they come on line. In fact, the real 'take-home message' is that one must use these principles when looking at new technologies to understand their role in emerging practice.

Adult↗
PubMed2002

Maternal serum HCG is higher in the presence of a female fetus as early as week 3 post-fertilization.

BACKGROUND: Maternal serum HCG (MSHCG) is higher when the fetus is a female than when it is male. This has been demonstrated in the second and third trimesters of pregnancy, and recently at 10-14 weeks gestation. In this study we assessed whether this gender-related difference can be detected as early as week 3 post-fertilization. METHODS: The IVF setting was chosen because it provides precise dating of gestational age and early sonography for the number of gestational sacs. The study included 347 IVF cycles from 335 patients. Only pregnancies with a single implanted embryo that resulted in a single live birth of known gender were included. MSHCG was measured on days 14-20 post-fertilization, and levels were expressed as gestational age-corrected multiples of the median (MoMs). The log10 MSHCG MoMs were compared according to fetal gender. RESULTS: MSHCG levels were significantly higher (18.5%) in week 3 post-fertilization in the presence of a female fetus (P < 0.0002). CONCLUSION: Because a fetal gender-related difference in MSHCG can be demonstrated as early as week 3 post-fertilization, the difference may be attributed to placental factors and not to the effects of the fetal hypothalamic-hypophyseal-gonadal axis.

Chorionic Gonadotropin↗
PubMed2002

Rett syndrome: clinical manifestations in males with MECP2 mutations.

Rett syndrome is a neurodevelopmental disorder characterized by cognitive and adaptive regression with autistic features, loss of acquired skills, and stereotypic hand movements that almost exclusively affects females. It is an X-linked dominant disorder, with presumed lethality in males. Nonetheless, there are a few descriptions of males suspected of having Rett syndrome. With the recent discovery that the MECP2 gene is responsible for most cases of Rett syndrome, it is possible to molecularly assess cases of affected males by direct sequencing analysis. We describe an Israeli family consisting of a female having classic Rett syndrome and a male sibling with severe neonatal encephalopathy. Molecular analysis revealed that both sister and brother have the same MECP2 gene mutation; however, their mother does not. This case, as well as other published studies of males with MECP2 mutations, reveals that the clinical manifestations in viable males vary from neonates with severe encephalopathy to adults with mental retardation and demonstrate genotype-phenotype correlations.

Abnormalities, Multiple↗
PubMedDate not supplied

Spontaneous abortions in couples declining multifetal pregnancy reduction.

Multifetal pregnancy reduction (MFPR) has clearly improved the outcomes of multifetal gestations. Several recent reports have also suggested improved outcomes in nonreduced cases, but there have been methodologic concerns about the denominators, i.e. have all cases been included and is there a 'hidden mortality' of unknown lost cases. Here we assessed the outcome of patients telephoning to discuss MFPR, but who chose not to have the procedure. Over a 3-year period, 446 patients had MFPR by one operator. Nineteen patients chose not to have the procedure. There were 11 preterm births, 1 term delivery, and 5 spontaneous losses (7 of 17) prior to 24 weeks, a loss rate of 35%. Two patients delivering triplets had a loss of 1 fetus/neonate. These data suggest that the loss rates of nonreduced pregnancies may be higher than generally thought, making the improvements with MFPR even bigger than generally realized.

Abortion, Spontaneous↗
PubMedDate not supplied

First trimester maternal serum free human chorionic gonadotropin as a predictor of adverse pregnancy outcome.

OBJECTIVE: The purpose of this study was to evaluate whether abnormal levels of first trimester maternal serum free human chorionic gonadotropin (beta-hCG) are predictive of adverse pregnancy outcomes. METHODS: The study included 1,622 consecutive patients with singleton pregnancies who underwent first trimester Down syndrome screening using nuchal translucency, and maternal serum free beta-hCG and pregnancy-associated plasma protein-A. Patients with fetal anomalies or chromosome aberrations were excluded from the study. The incidences of various adverse pregnancy outcomes were evaluated according to maternal serum free beta-hCG levels. Outcome variables included spontaneous miscarriage, proteinuric and non-proteinuric pregnancy-induced hypertension, fetal growth restriction, intrauterine fetal demise, spontaneous preterm delivery, oligohydramnios and placental abruption. RESULTS: No significant differences were noted between groups for any of the demographic variables. The only statistically significant result was an increase in the relative risk for spontaneous miscarriage (RR = 6.33) at free beta-hCG <0.2 multiples of the medians. No other statistically significant result was noted for the other adverse outcomes or for the overall complication rate. CONCLUSION: Low free beta-hCG is associated with a higher incidence of spontaneous miscarriage but is a poor predictor of other pregnancy complications.

Abortion, Spontaneous↗