Biomedical subjects

Yuval Yaron

Publications and source records attributed to Yuval Yaron.

At least 19 recordsLinked to original sources

PubMed2006

Circulating angiogenic proteins in trisomy 13.

OBJECTIVE: Women who are carrying a trisomy 13 fetus are more prone to develop preeclampsia. Excess circulating soluble fms-like tyrosine kinase-1 has been implicated recently in the pathogenesis of preeclampsia. Since the fms-like tyrosine kinase-1/soluble fms-like tyrosine kinase-1 gene is located on chromosome 13q12, we hypothesized that the extra copy of this gene in trisomy 13 may lead to excess circulating soluble fms-like tyrosine kinase-1, reduced free placental growth factor level, and increased soluble fms-like tyrosine kinase-1/placental growth factor ratio. This may then contribute to the increased risk of preeclampsia that has been observed in these patients. Our objective was to characterize the maternal circulating angiogenic proteins in trisomy 13 pregnancies. STUDY DESIGN: Maternal serum samples of trisomy 13, 18, 21 and normal karyotype pregnancies were obtained from first and second trimester screening programs. We chose 17 cases of trisomy 13 that were matched for maternal age, freezer storage time, and parity with 85 normal karyotype control samples. Additionally, 20 cases of trisomy 18 and 17 cases of trisomy 21 were included. Cases and control samples were assayed for levels of soluble fms-like tyrosine kinase-1 and placental growth factor by enzyme-linked immunosorbent assay in a blinded fashion. Because of the skewed distributions of soluble fms-like tyrosine kinase-1 and placental growth factor, nonparametric analytic techniques were used, and the results are reported as median and ranges. RESULTS: In early pregnancy trisomy 13 cases and control samples, the median circulating soluble fms-like tyrosine kinase-1/placental growth factor ratios were 17.0 (range, 1.2-61.3) and 6.7 (range, 0.8-62.9), respectively (P = .003). The median soluble fms-like tyrosine kinase-1/placental growth factor ratios in trisomy 18 and 21 were 4.8 (range, 0.9-53.9) and 5.1 (range, 1.0-18.1), which were not significantly different than the control samples. Furthermore, the differences between trisomy 13 and control samples were more pronounced in the second trimester specimens than in the specimens from the first trimester. CONCLUSION: These data suggest that alterations in circulating angiogenic factors may be involved intimately in the pathogenesis of preeclampsia in trisomy 13. A larger clinical study that measures these factors longitudinally and correlates them with pregnancy outcomes is needed to further establish the link between trisomy 13, altered angiogenic factors, and preeclampsia.

Angiogenic Proteins↗

PubMed2006

Detection of spinal muscular atrophy carriers by nested polymerase chain reaction of single sperm cells.

Spinal muscular atrophy (SMA) is an autosomal recessive disorder with a carrier frequency of approximately 1 in 40. Approximately 95% of patients have homozygous deletions of exon 7 and/or 8 of the SMN1 gene. Carrier testing for SMA is relatively complex and requires quantitative polymerase chain reaction (PCR) of genomic DNA to determine SMN1 copy number. The purpose of this study was to assess the feasibility of carrier testing for SMA in males, by nested PCR analysis of SMN1 deletions in single sperm cells. A nested PCR method was developed to amplify SMN1 exon 7 in single cells. Restriction enzyme digestion with DraI was used to differentiate between the highly homologous SMN1 and SMN2 genes. Single sperm cells from five known SMA carriers and six noncarriers were analyzed. Among the five carriers, a total of 132 single sperm cells were analyzed and SMN1 exon 7 deletion was detected in 68 cells (51.5%). In contrast, among the six noncarriers, a total of 136 single sperm cells were analyzed. Of these, an apparent SMN1 exon 7 deletion was detected in four sperm cells. This was interpreted as an allele dropout (ADO) rate of 2.9%. We conclude that nested PCR of SMN1 exon 7 is an accurate and reproducible method for detection of SMA male carriers with a SMN1 deletion.

Base Sequence↗

PubMed2006

Rapid prenatal diagnosis of aneuploidy for chromosomes 21, 18, 13, and X by quantitative fluorescence polymerase chain reaction.

OBJECTIVE: Quantitative fluorescence polymerase chain reaction (QF-PCR) is a rapid method for detection of chromosome copy number by amplification of repeat sequences at polymorphic loci. Our objective was to assess the performance of QF-PCR in detecting common aneuploidies in prenatal diagnosis. STUDY DESIGN: The study group consisted of pregnant women referred for amniocentesis or chorionic villus sampling (CVS) due to increased risk of fetal aneuploidy. Samples were collected from known affected and normal pregnancies. These were blindly screened for trisomy of chromosomes 21, 18, 13, and sex chromosome abnormalities, using QF-PCR. DNA from uncultured amniocytes was directly extracted using a modified alkaline lysis method. DNA from CVS was extracted by the phenol-chloroform procedure. Ten short tandem repeat (STR) markers were used for detection of fetal aneuploidy and gender. The STRs were selected for high heterozygosity rates and efficiency of the PCR amplification. The forward primer of each pair was labeled with a unique fluorescent dye. Amplified products were detected by an ABI Prism 310 Genetic Analyzer and results were analyzed using GeneScan Analysis Software. RESULTS: A total of 65 amniotic fluid and CVS samples were collected from affected and normal pregnancies. Two samples were contaminated with blood and were therefore excluded from the analysis. All 29 cases of aneuploidy were correctly diagnosed by QF-PCR, including 17 cases of trisomy 21, 7 cases of trisomy 18, and 5 cases with trisomy 13. The 34 normal samples were also correctly diagnosed as such. Thus, all results were in agreement with the standard cytogenetic results. There were no false-positive or false-negative results. CONCLUSION: We conclude that QF-PCR is a rapid, reliable, and reproducible method that may be used to provide rapid results in prenatal diagnosis of aneuploidy.

Amniocentesis↗

PubMed2005

Preimplantation genetic diagnosis (PGD) for Duchenne muscular dystrophy (DMD) by triplex-nested PCR.

OBJECTIVES: Duchenne muscular dystrophy (DMD) is a lethal X-linked recessive disorder with an incidence of approximately 1 in 3500 males, caused by mutation in the DMD gene. About 2/3 of DMD cases are caused by gross DMD gene deletion mutations. The purpose of this study was to develop a series of single-cell multiplex-nested PCR protocols for preimplantation genetic diagnosis (PGD) of the most prevalent DMD deletions. METHODS: The protocols were developed on single blood leukocytes from normal males and females and patients with known DMD gene deletion. In the first reaction, 2 of 11 different primer sets (exons 4, 8, 12, 13, 17, 46, 47, 49, 50, 52 and intron 52) were used to allow the simultaneous amplification of different DMD loci and the SRY gender marker, in a single triplex-nested polymerase chain reaction (PCR). Aliquots of this reaction were then subjected to nested PCR in which each locus was amplified individually. Following the successful establishment of single-cell triplex-nested PCR in single leukocytes, the technique was employed in five clinical PGD cases. RESULTS: For each DMD locus, more than 50 single leukocytes from healthy controls and more than 100 single leukocytes from affected individuals with known deletions were analyzed. Amplification efficiency for each tested locus was 98-100%. The false-negative rates for each analysis taken separately was <1%. Taken together, however, the results of the triplex-nested PCR analysis had a false-negative rate of 0%. No contamination was detected in all wash-drop blanks tested. We subsequently performed 18 PGD cycles in 5 DMD carriers. A total of 156 embryos were biopsied and successfully analyzed. Of these, 39 affected embryos were detected and 50 unaffected embryos were transferred (mean = 2.9 +/- 1.1 embryos per cycle). These resulted in three biochemical pregnancies and three clinical pregnancies, all of which have culminated in the birth of normal offspring. CONCLUSION: Triplex-nested PCR using 2 of 11 DMD loci and the SRY gender marker allow PGD for >90% of DMD families with known deletions. These protocols are associated with a high amplification efficiency and accuracy.

Case-Control Studies↗

PubMed2004

Cytogenetic analysis of three variants of clival chordoma.

Chordoma is an uncommon malignant neoplasm derived from remnants of the embryonal notochord. The tumor arises in the sacrococcygeal region in most cases. Cytogenetic information on clival chordomas is scarce due to the low incidence of these tumors. In this study, we applied the G-banding and spectral karyotyping techniques to compare the karyotypes of three variants of clival chordoma: conventional, chondroid, and dedifferentiated. We describe a normal karyotype of a chondroid chordoma and a complex karyotype of a conventional chordoma involving chromosomes 1, 2, 3, 5, 8, 9, 11, 15, 19, 20, and X. The cytogenetic analysis of the dedifferentiated chordoma showed a polyploid complex karyotype of 71-123 chromosomes with double minutes that originated from chromosome 17.

Aged↗

PubMed2004

First-trimester nuchal translucency and maternal serum free beta-hCG and PAPP-A can detect triploidy and determine the parental origin.

OBJECTIVE: To evaluate the levels of first-trimester screening markers in triploid pregnancies and to determine the parental origin of triploidy. STUDY DESIGN: During the five-year study period, 12322 patients with singleton pregnancies underwent combined first-trimester screening using nuchal translucency (NT) and maternal serum free beta-human chorionic gonadotrophin (free beta-hCG) and pregnancy associated plasma protein-A (PAPP-A) at 10 to 14 weeks' gestation. Maternal serum markers and NT were evaluated in cases of triploidy. Molecular analysis was performed using polymorphic markers to establish the parental source of triploidy. RESULTS: Eight cases of triploidy were detected at a rate of at least 1 in 1540. All cases were electively terminated early in gestation or resulted in spontaneous miscarriage. Two patterns of first-trimester markers emerged: type I, characterized by extremely high levels of free beta-hCG and elevated NT; and type II, characterized by very low levels of PAPP-A and free beta-hCG with normal NT. Molecular analysis demonstrated that type I triploidy is of paternal origin (diandric) and type II is of maternal origin (digynic). CONCLUSIONS: On the basis of these results, it may be possible to detect triploid pregnancies in the first trimester and determine their origin using combined first-trimester screening.

Adult↗

PubMed2004

Insight into the intrinsic sensitivity of the PCR assay used to detect CMV infection in amniotic fluid specimens.

BACKGROUND: PCR detection of human cytomegalovirus (HCMV) DNA in amniotic fluid (AF) is the most sensitive tool for diagnosis of fetal infection, but has sub-optimal sensitivity. It has been suggested that inhibition by AF reduces the sensitivity of this assay, however this assumption has never been thoroughly studied. Several PCR assays have been shown to improve sensitivity, but comparative studies are insufficient to choose the optimal approach. OBJECTIVES: To assess the effect of AF inhibition on PCR sensitivity and to determine the most sensitive assay for diagnosing fetal infection. STUDY DESIGN: Plasmid containing HCMV DNA was tested by PCR, in water and in non-infected AF, to assess the inhibitory effect of AF. Twenty-three AF-infected samples were tested by various PCR protocols. AF supernatant, with or without DNA extraction, and AF cells, were assayed by single-round and semi-nested PCR. Viral load was measured in the supernatant by a commercial quantitative PCR kit. RESULTS: The plasmid model demonstrated that single-round PCR was 2000-fold less sensitive in AF compared with water. Semi-nested PCR was only 10-fold less sensitive. Single-round PCR was 30% sensitive in HCMV-infected AF supernatants, and detected viral loads higher than 2.3 x 10(6) viral copies/ml. Extraction of DNA from the supernatant increased the sensitivity of this assay to 89% and the detection limit to 5.2 x 10(4) copies/ml. Semi-nested PCR performed on supernatant, with and without DNA extraction, was 96% and 100% sensitive, respectively, with a detection threshold of 3.8 x 10(3) copies/ml. Single-round and semi-nested PCR were 89% and 100% sensitive, respectively, in cells. The commercial quantitative PCR assay was 100% sensitive. CONCLUSIONS: AF supernatant is inhibitory to PCR. The two most sensitive assays were semi-nested PCR performed on DNA extracted from the supernatant and the commercial quantitative PCR kit. Of these two, the latter is standardized, non-labor-intensive, and allows minimal opportunity for contamination, thereby making it the preferred method for diagnosis.

Adult↗

PubMed2004

Prospective randomized comparison of two embryo culture systems: P1 medium by Irvine Scientific and the Cook IVF Medium.

PURPOSE: To compare the efficacy of two commercially available in vitro fertilization (IVF) and embryo culture media systems: the glucose-free P1 Medium supplemented with 20% synthetic serum substitute (SSS) (Irvine Scientific), and the Cook IVF Medium (Cook, Australia). METHODS: A prospective randomized study. Medical center-based IVF Unit affiliated to the Faculty of Medicine of Tel Aviv University. IVF patients were randomly assigned to either P1 Medium supplemented with 20% SSS (182 patients, 196 cycles) or Cook Medium (167 patients, 179 cycles). RESULTS: Fertilization rates were similar with both media (52.3 +/- 26.1 and 53.8 +/- 27.6, respectively). Likewise, no difference was found in morphological characteristics and grading of cultured embryos. However, a significantly higher proportion of the embryos incubated in the P1 Medium reached the four-cell stage on day 2 or the 6-cell stage on day 3 postfertilization, compared to those incubated in Cook Medium (54.3% vs. 41.9%, p < 0.0001). Clinical pregnancy and delivery rates were improved when oocytes and embryos were cultured in P1 Medium. Finally, Implantation rate was significantly higher in the P1 Medium Group (9.9% vs. 6%, respectively). CONCLUSIONS: Our results suggest that the P1 Medium may be associated with a higher embryo cleavage rate and improved implantation rates compared to the Cook IVF Medium.

Culture Media↗

PubMed2004

Feasibility of nuchal translucency in triplet pregnancies.

OBJECTIVE: To assess the feasibility of nuchal translucency in triplets compared with singletons. METHODS: Nuchal translucency thickness as part of routine first-trimester screening in the general population was compared between 3128 singleton pregnancies and 51 triplets (153 fetuses). Crown-rump length was also noted. The 5th, 50th, and 95th percentiles were determined and compared between the 2 groups, and regression curves of nuchal translucency measurements plotted against crown-rump length were drawn. RESULTS: The mean nuchal translucency thickness was 1.23 mm for singletons and triplets. The 5th and 95th percentiles were also the same between the 2 studied groups. The regression curves of 5th, 50th, and 95th percentiles of nuchal translucency plotted against crown-rump length of triplets and singletons overlapped. CONCLUSIONS: Nuchal translucency values and distribution are the same in triplets and singletons, validating the utility of the cutoff values.

Adult↗

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↗