Retinoblastoma (Rb) is a childhood tumor (~1 in 20,000 live births) developing in the retina due to mutations in the RB1 gene. Identification of the oncogenic mutations in the RB1 gene is important for the clinical management and for genetic counseling to families with a child or a parent affected with the tumor. Here we present our experience in detecting the pathogenic mutations in blood samples, from 150 unrelated Rb patients and highlight the relevant counseling issues. Mutation screening in the RB1 gene was based on Sanger sequencing, mosaicism of recurrent CpG transition mutations was detected by allele specific PCR and multiplex ligation dependent probe amplification for detecting of large deletions/duplications. The overall detection rate of mutations in our cohort was 55 % (82/150). In the familial cases it was 100 % (17/17), in bilateral and unilateral-multifocal sporadic cases 91 % (50/55), and in the unilateral sporadic cases 19 % (15/78). Nonsense mutations and small deletions or insertions that results in transcripts with premature termination codons that are subject to nonsense mediated decay were the most frequent, detected in 50/82 (61 %) of the patients. The rest were large deletions detected in 14/82 (17 %), splice site mutations detected in 11/82 (13 %), missense mutations in four patients and mutations in the promoter sequence in three patients. Mutation mosaicism ranging from 10 to 30 % was detected by allele specific PCR in ten patients, 9 % (5/55) of patients with bilateral tumor and 33 % (5/15) of the patients with unilateral tumor. In three patients rare variants were detected as the only finding which was also detected in other healthy family members. Allele specific amplification of recurrent mutations raises in our cohort the identification rate from 82 to 91 % in the sporadic bilateral cases and from 13 to 19 % in the unilateral sporadic cases. Most mosaic cases could not be identified by Sanger sequencing and therefore screening for recurrent CpG transition mutations by allele specific amplification is of utmost importance. Molecular screening is important for the genetic counseling regarding the risk for tumor development and the relevance for prenatal diagnosis but in several families is accompanied by detecting rare variants that might be rare polymorphisms or low penetrant mutations.

Bardet–Biedl syndrome (BBS) is known to be caused by numerous mutations that occur in at least 15 of the BBS genes. As the disease follows an autosomal recessive pattern of inheritance, carrier screening can be performed for at‐risk couples, but the number of potential mutation sites to screen can be daunting. Ethnic studies can help to narrow this range by highlighting mutations that are present at higher percentages in certain populations. In this article, the carrier frequency for two mutations that occur in the BBS2 gene, c.311A>C and c.1895G>C were studied in individuals of Ashkenazi Jewish descent in order to advise on including them in existing mutation panels for this population. Carrier screenings were performed on individuals from the Ashkenazi Jewish population using a combination of TaqMan genotyping assays followed by real‐time polymerase chain reaction (PCR) and allelic discrimination, and allele‐specific PCR confirmed by restriction analysis. The combined results indicated carrier frequencies of 0.473% (±0.0071%) for the c.311A>C mutation and 0.261% (±0.0064%) for the c.1895G>C mutation. On the basis of these frequencies, we believe that the two mutations should be considered for inclusion in screening panels for the Ashkenazi population.

Lynch Syndrome is caused by mutations in DNA mismatch repair genes. Diagnosis is not always trivial and may be costly. Information regarding incidence, genotype-phenotype correlation, spectrum of mutations and genes involved in specific populations facilitate the diagnostic process and contribute to clinical work-up. To report gene distribution, mutations detected and co-occurrence of related syndromes in a cohort of Ashkenazi Jews in Israel. Patients were identified in dedicated high risk clinics in 3 medical centers in Israel. Diagnostic process followed a multi-step scheme. It included testing for founder mutations, tumor testing, gene sequencing and MLPA. Lynch Syndrome was defined either by positive mutation testing, or by clinical criteria and positive tumor analysis. We report a cohort of 75 Ashkenazi families suspected of Lynch Syndrome. Mutations were identified in 51/75 (68 %) families: 38 in MSH2 , 9 in MSH6 , and 4 in MLH1 . 37/51 (73 %) of these families carried one of the 3 ‘Ashkenazi’ founder mutations in MSH2 or MSH6 . Each of the other 14 families carried a private mutation. 3 (6 %) were large deletions. Only 20/51 (39 %) families were Amsterdam Criteria positive; 42 (82 %) were positive for the Bethesda guidelines and 9 (18 %) did not fulfill any Lynch Syndrome criteria. We report C-MMRD and co-occurrence of BRCA and Lynch Syndrome in our cohort. Mutation spectra and gene distribution among Ashkenazi Jews are unique. Three founder Lynch Syndrome mutations are found in 73 % families with known mutations. Among the three, MSH2 and MSH6 are the most common. These features affect the phenotype, the diagnostic process, risk estimation, and genetic counseling.

PURPOSE:Congenital hyperinsulinism of infancy (OMIM# 256450) is a devastating disease most commonly caused by dominant or recessive mutations in either ABCC8 or KCNJ11, the genes that encode for the β-cell adenosine triphosphate-regulated potassium channel. A unique combination of a paternally inherited germline mutation and somatic loss-of-heterozygosity causes the focal form of the disease (Focal-congenital hyperinsulinism of infancy [Focal-CHI]), the incidence of which in genetically susceptible individuals is not known.METHODS:We genotyped 21,122 Ashkenazi Jewish individuals for two previously identified ABCC8 founder mutations and utilized a clinical database of 61 unrelated Ashkenazi patients with congenital hyperinsulinism of infancy to obtain an estimate of the risk of Focal-CHI in a genetically susceptible fetus.RESULTS:The combined mutation carrier rate in Ashkenazi Jews was 1:52, giving an estimated frequency of homozygosity or compound heterozygosity of 1:10,816 in this population. The risk of Focal-CHI is 1:540 per pregnancy in offspring of carrier fathers.CONCLUSION:We recommend that these mutations be included in the genetic screening program for the Ashkenazi Jewish population. As the risk of Focal-CHI is not expected to be mutation specific, the data reported in this study are useful for counseling all families in which the father was found to carry a recessive ABCC8 or KCNJ11 mutation.

Cytogenetic analysis of DNA from a girl with severe psychomotor retardation revealed a de novo pericentric inversion of chromosome 2: 46,XX,inv(2)(p15q24.2). In order to elucidate the possible role of the inversion in the girl's abnormal phenotype, we analyzed the inversion breakpoints. FISH analysis revealed BAC clones spanning the breakpoints at 2p and 2q of the inversion. Southern blot hybridization with DNA probes from the BAC regions was used to refine the localization of the breakpoints, followed by inverse‐PCR which enabled us to sequence the inversion breakpoints. We found a complex chromosomal rearrangement, including five breakpoints, four at 2q and one at 2p joined with minor insertions/deletions of a few bases. The breakpoint at 2p was within the NRXN1 gene that has previously been associated with autism, intellectual disabilities, and psychiatric disorders. In 2q, the breakpoints disrupted two genes, TANC1 and RBMS1; the phenotypic effect of these genes is not currently known. © 2011 Wiley‐Liss, Inc.

Mutations in DNA mismatch repair genes underlie lynch syndrome (HNPCC). Lynch syndrome resulting from mutations in MSH6 is considered to be attenuated in comparison to that caused by mutations in MLH1 and MSH2, thus more likely to be under diagnosed. In this study we report of a common mutation in the MSH6 gene in Ashkenazi Jews. Genetic counseling and diagnostic work-up for HNPCC was conducted in families who attended the high risk clinic for inherited cancer. We identified the mutation c.3984_3987dup in the MSH6 gene in 19 members of four unrelated Ashkenazi families. This mutation results in truncation of the transcript and in loss of expression of the MSH6 protein in tumors. Tumor spectrum among carriers included colon, endometrial, gastric, ovarian, urinary, and breast cancer. All but one family qualified for the Bethesda guidelines and none fulfilled the Amsterdam Criteria. Members of one family also co-inherited the c.6174delT mutation in the BRCA2 gene. The c.3984_3987dup in the MSH6 gene is a mutation leading to HNPCC among Ashkenazi Jews. This is most probably a founder mutation. In contrast to the c.1906G>C founder mutation in the MSH2 gene, tumors tend to occur later in life, and none of the families qualified for the Amsterdam criteria. c.3984_3987dup is responsible for 1/6 of the mutations identified among Ashkenazi HNPCC families in our cohort. Both mutations: c.3984_3987dup and c.1906G>C account for 61% of HNPCC Ashkenazi families in this cohort. These findings are of great importance for counseling, diagnosis, management and surveillance for Ashkenazi families with Lynch syndrome.

Objective To describe our 2-year experience with preimplantation genetic diagnosis (PGD) for carriers of mutations in the genes BRCA1 and BRCA2, the dilemmas incurred and the lessons learned.Methods We collected data on those carriers of BRCA1/2 mutations who applied for PGD counseling and who decided to proceed. We describe the PGD procedures that were conducted and their outcome.Results Tell carriers of BRCA1/2 Mutations applied for PGD counseling. seven were healthy, and three were BC survivors. Eight women needed in vitro fertilization (IVF) because of coexisting infertility. After counseling, six opted for the procedure and five Of them underwent PGD for the BRCA Mutation. In one of these PGD, fluorescence in situ hybridization (FISH) analysis for chromosomes 21, X and Y was also performed. Three women conceived, each in the first treatment attempt. One of them gave birth to twins. the second to a singleton and the third is currently pregnant. During the pregnancies, dilemmas concerning PGD confirmation were discussed.Conclusions PGD is an acceptable reproductive Option for BRCA Mutation carriers, especially for those who require IVF due to fertility problems. Discussion of this option should be carried out with sensitivity, taking into account the age of the woman, her health, fertility status and emotional state. Confirmatory prenatal diagnosis may not always he encouraged. Copyright (C) 2009 John Wiley & Sons, Ltd.

Introduction Several epidemiologic studies have provided suggestive evidence of a link between coetaneous malignant melanoma (CMM) and breast cancer. The Breast Cancer Linkage Consortium (BCLC) reported approximately 2.6-fold increase in the risk for CMM among BRCA2 carrier families. Methods To evaluate the role of BRCA1/2 mutations in CMM, we screened 92 Jewish patients of Ashkenazi origin diagnosed with CMM for the three Ashkenazi founder mutations: 185delAG and 5382insC in the BRCA1 and 6174delT in the BRCA2 gene. Information about personal demography, family history of cancer, and occupational and lifestyle history was collected. Results Thirty-seven of 92 (40.2%) CMM patients reported a family history of cancer in a first-degree relative. In 14 patients, history of breast cancer (BC) was recorded; however, no family had features associated with BRCA carrier status (i.e., young age at BC onset, history of several BC cases or ovarian cancer in the family). None of the patients were found to carry any of these three mutations. Conclusion Our results suggest a limited role for the three Ashkenazi BRCA founder mutations in CMM risk among the Ashkenazi Jewish population. Therefore, screening patients with CMM for these BRCA1/2 mutations is not warranted.

Placental mesenchymal dysplasia (PMD) is a distinct placental phenotype that has often been misdiagnosed as partial hydatiform mole. PMD placentas are typically larger than average (placentomegaly) and show cystic areas with absence of trophoblast hyperplasia. IUGR and fetal or neonatal death are common in PMD but it also may be associated with normal fetus. Neonatal diabetes mellitus is a rare disorder with reporting incidence of 1/400,000–500,000 live births. Transient neonatal diabetes mellitus (TNDM) is characterized by neonatal hyperglycemia that resolves within the first few months and may relapse in adolescence. In some of these cases defects in the paternal chromosome 6 are involved. To the best of our knowledge, placentomegaly and PMD were not reported in association with TNDM. Herein we report a case of TNDM with PMD and pat(UPD6), and discuss the possible connection between these two entities.

The genetics and pathology of diploid complete and triploid partial hydatidiform moles have been well established. Enlarged cystic placenta often indicates an underlying etiology and is frequently associated with adverse pregnancy outcome. Several imprinted genes are strongly expressed in placental tissues and essential for normal placental growth and development. Disruption of these imprinted genes can lead to abnormal placental pathology and placental stunting or overgrowth. We present the genetic etiologies of five unusual mosaic cases of enlarged cystic placentas and report a novel etiology, mosaicism for deletion of the maternal GRB10 gene.Five mosaic placental mesenchymal dysplasia cases with discrete populations of “cystic” and “normal” villi and/or atypical p57KIP2 immunostaining were evaluated by genetic analysis; including G-banded karyotyping, fluorescence in situ hybridization (FISH), whole genome CGH + SNP microarray, conventional Sanger sequencing, and STR microsatellite analysis.Genetic etiologies ranged from genome-wide changes, including mosaic androgenetic isodisomy and mosaic diandric triploidy, to a novel microdeletion of the maternally-expressed GRB10 gene. An abnormal mosaic population of cells was also detected in the fetus in two cases.Four cases were mosaic for either diandric triploidy or an androgenetic cell population, and the enlarged cystic placentas were likely due to an excess of paternally-expressed growth promoting genes and also the absence of maternally-expressed growth restricting genes. Also we identified mosaicism for a novel microdeletion of the maternal GRB10 allele, a potent growth inhibitor, which resulted in placental overgrowth in the cystic area of one placenta. We advocate the use of ancillary techniques to investigate complex mosaic cases of enlarged cystic placentas to discover atypical genetic etiologies and to increase our understanding of the placental genome.

Hereditary non-polyposis colorectal cancer is a cancer predisposition syndrome known to be caused by heterozygous germline mutations in DNA mismatch repair genes (MMR) most commonly hMLH1, hMSH2, hMSH6. Heterozygous mutations in one of these genes confer an increased risk, mainly for colon and endometrial cancer. Recently, several publications identified that biallelic mutations in the MMR genes are associated with a more severe phenotype, including childhood malignancies and signs of neurofibromatosis type I (NF1). We report on a non-consanguineous Ashkenazi Jewish family with two affected siblings with features of NF1, colon cancer and astrocytoma at age 13 and 14. Their mother developed endometrial cancer at age 54. Their father had leukoplakia of the vocal cords with a family history of pancreatic cancer. Molecular and pathology studies were done on the tumor tissue and on genomic DNA of family members. Tumor testing demonstrated a high degree of microsatellite instability (MSI analysis), expression of MLH1 and absence of expression of both MSH2 and MSH6 proteins. A biallelic c.1906G > C (p.A636P) mutation in the hMSH2 gene was detected in the blood of one affected child. Parental genetic testing showed that each parent was heterozygote for the mutation. The c.1906G > C mutation is a founder mutation in the Ashkenazi Jewish population. To our knowledge this is the first report of homozygosity for this founder mutation.

Hereditary non-polyposis colon cancer is caused by mutations in DNA mismatch repair genes. The mutation spectrum in the Israeli population is poorly documented except for the c.1906G > C Ashkenazi founder mutation in the hMSH2 gene. To report our experience in HNPCC screening, the mutations detected and the clinical features among a cohort of Israeli patients. Diagnostic work-up was done in a multi-step process guided by clinical and ethnic information. Tumors of suspected patients were tested for microsatellite instability and immunohistochemistry. Based on tumor analyses, we proceeded to mutation screening by DHPLC followed by sequence analysis and multiplex ligase dependent probe amplification. Ashkenazi Jews were first tested for the c.1906G > C founder mutation. Of the 240 families, 24, including Arabs and Jews from different ethnic origins, were tested positive. All tumors that lost expression of mismatch repair proteins also showed microsatellite instability. There was evidence for involvement of hMSH2 (15) hMLH1 (6) and hMSH6 (3) genes. Mutations were identified in 17/24 (71%) patients: 6 Ashkenazi families harbored the c.1906G > C mutation. Eleven other mutations (2 nonsense, 3 splice site and 6 small deletions) were detected. Three of the mutations are novel. No gross deletions or insertions were detected. This is the first report that characterizes the profile of HNPCC in a cohort of patients in Israel. Tumor testing indicated that the 3 main MMR genes are involved, and that mutation spectrum is broad.

Variation in penetrance estimates for BRCA1/2 carriers suggests that other environmental and genetic factors may modify cancer risk in carriers. The GSTM1, T1 and P1 isoenzymes are involved in metabolism of environmental carcinogens. The GSTM1 and GSTT1 gene is absent in a substantial proportion of the population. In GSTP1, a single-nucleotide polymorphism that translates to Ile112Val was associated with lower activity. We studied the effect of these polymorphisms on breast cancer (BC) risk in BRCA1/2 carriers. A population of 320 BRCA1/2 carriers were genotyped; of them 262 were carriers of one of the three Ashkenazi founder mutations. Two hundred and eleven were affected with BC (20 also with ovarian cancer (OC)) and 109 were unaffected with BC (39 of them had OC). Risk analyses were conducted using Cox proportional hazard models adjusted for origin (Ashkenazi vs non-Ashkenazi). We found an estimated BC HR of 0.89 (95% CI 0.65-1.12, P=0.25) and 1.11 (95% CI 0.81-1.52, P=0.53) for the null alleles of GSTM1 and GSTT1, respectively. For GSTP1, HR for BC was 1.36 (95% CI 1.02-1.81, P=0.04) for individuals with Ile/Val, and 2.00 (95% CI 1.18-3.38) for carriers of the Val/Val genotype (P=0.01). An HR of 3.20 (95% CI 1.26-8.09, P=0.01), and younger age at BC onset (P=0.2), were found among Val/Val, BRCA2 carriers, but not among BRCA1 carriers. In conclusion, our results indicate significantly elevated risk for BC in carriers of BRCA2 mutations with GSTP1-Val allele with dosage effect, as implicated by higher risk in homozygous Val carriers. The GSTM1- and GSTT1-null allele did not seem to have a major effect.

The H syndrome is a recently reported autosomal-recessive disorder characterized by cutaneous hyperpigmentation, hypertrichosis, hepatosplenomegaly, heart anomalies, hearing loss, hypogonadism, short stature, hallux valgus, and fixed flexion contractures of the toe joints and the proximal interphalangeal joints. Homozygosity mapping in five consanguineous families resulted in the identification of mutations in the SLC29A3 gene, which encodes the equilibrative nucleoside transporter hENT3. Three mutations were found in 11 families of Arab and Bulgarian origin. The finding of several different mutations in a small geographic region implies that the H syndrome might be rather common. The identification of mutations in the SLC29A3 gene in patients with a mild clinical phenotype suggests that this is a largely underdiagnosed condition and strongly suggests that even oligosymptomatic individuals might have the disorder.

BACKGROUND:Charcot-Marie-Tooth type 1A (CMT1A) is an autosomal dominant polyneuropathy due to a 1.5 Mb tandem duplication in chromosome 17p11.2, containing the PMP22 gene. This mutation is not modified during inheritance.OBJECTIVES:We set forth to test the hypothesis that in a subgroup of CMT1A patients there is clinical anticipation, namely an increase in disease severity over generations.METHODS:Thirty-nine CMT1A mutation-positive patients in 16 families and 23 parent-offspring pairs were evaluated. This included 14 families with 2 generations and 2 families with 3 generations. Age of presentation was assessed by interviewing the patients and clinical severity was measured using the CMT neuropathy score (CMTNS).RESULTS:In 21/23 parent-child pairs and 14/16 families, there was an earlier age of presentation in children of genetically affected parents. The mean age of onset in the progeny was 12.61 years compared to 41.22 years in the parent generation, (p < 0.001). Mean severity in the younger generation was slightly higher than that of the parent generation. When corrected for the age difference, the trend for a worse phenotype in the younger generation became statistically significant (p < 0.02,Wilcoxon signed rank test).CONCLUSIONS:Our findings suggest that in a subgroup of CMT1A patients there is an increase in clinical severity over generations. The mechanism responsible for this observation remains unknown. Our findings should be validated on a larger cohort of CMT1A families.

Background: Telangiectases are abnormal dilatations of end vessels in the subpapillary plexus of the papillary dermis. Hereditary benign telangiectasia (HBT) (OMIM 187260) is a genetic skin disorder, characterized by multiple cutaneous telangiectases appearing in the first years of life in various locations. Several familial cases of HBT have been described displaying autosomal dominant inheritance. In some of the described pedigrees, telangiectases are limited to sun-exposed areas, whereas in others lesions are randomly distributed over the body. The disorder has been previously mapped to a 7Mb interval on chromosome 5q14 (CMC1 locus) in an Italian pedigree with randomly distributed telangiectases.Objectives: A large pedigree of HBT with photodistributed lesions is described. We sought to determine whether photodistributed HBT is linked to the CMC1 locus.Methods: In all, 35 family members were examined. DNA was extracted from blood and saliva samples. Linkage analysis to CMC1 locus on chromosome 5q14 was screened by using 3 polymorphic markers.Results: In all, 23 family members were found to have variable numbers of cutaneous radiating macular telangiectases, measuring I to 3 cm and distributed over the face, back of the hands, and forearms. HBT in this family is inherited in an autosomal dominant pattern with incomplete penetrance. Linkage to the CMC1 locus was excluded.Limitation: Only one family, although very large, was studied in this project.Conclusions: Clinical and genetic heterogeneity is evident in HBT. Photodistributed HBT is not related pathogenically to capillary malformations or to randomly distributed hereditary telangiectases and should be recognized as a separate entity. (J Am Acad Dermatol 2007;57:814-8.)

BACKGROUND:The risks for cancers other than breast (BC) or ovarian (OC) cancer in breast cancer gene 1 and 2 (BRCA1/2) mutation carriers were elevated in studies of carrier families. However, case-control studies did not confirm this observation.OBJECTIVE:To compare the risks for other cancers in BRCA1/2 mutation carriers and non-carriers, all affected with BC and/or OC. Both groups share risk modifiers of BC/OC, which enabled assessment of the role of BRCA1/2 mutations.METHODS:1098 Ashkenazi Jewish women affected with BC and/or OC were ascertained during 1995-2003; molecular testing revealed 229 BRCA1 and 100 BRCA2 carriers and 769 non-carriers. COX proportional hazard models were used to evaluate the risk of other cancers. Analyses were conducted including all other cancers or only those diagnosed after BC/OC diagnosis.RESULTS:The HRs for any other cancer were 2.6 (95% CI 1.7 to 4.2, p<0.001) and 1.8 (95% CI 0.95 to 3.6, p = 0.07) in BRCA1 and BRCA2 carriers, respectively. The corresponding colon cancer HRs were 3.9 (95% CI 1.3 to 12.1, p = 0.02) and 2.3 (95% CI 0.5 to 11.3, p = 0.3) in BRCA1 and BRCA2 carriers. The HR for lymphoma was 11.9 (95% CI 3.1 to 46.2, p = 0.001) in BRCA2 carriers. Risk estimates for other cancers after the onset of BC/OC were similar.CONCLUSION:A 2.5-fold increase in any other cancer and a fourfold risk of colon cancer were found among BRCA1 carriers. The corresponding HRs in BRCA2 carriers were non-significant, except for the markedly elevated risk of lymphoma. These results suggest a role for BRCA1/2 mutations in colorectal cancer risk in a subgroup of BC/OC-affected carriers.

BACKGROUND:The incidence of breast cancer (BC) in Arab women is lower compared to the incidence in the Jewish population in Israel; still, it is the most common malignancy among Arab women. There is a steep rise in breast cancer incidence in the Arab population in Israel over the last 10 years that can be attributed to life style changes. But, the younger age of BC onset in Arab women compared with that of the Jewish population is suggestive of a genetic component in BC occurrence in that population.METHODS:We studied the family history of 31 women of Palestinian Arab (PA) origin affected with breast (n = 28), ovarian (n = 3) cancer. We used denaturing high performance liquid chromatography (DHPLC) to screen for mutations of BRCA1/2 in 4 women with a personal and family history highly suggestive of genetic predisposition.RESULTS:A novel BRCA1 mutation, E1373X in exon 12, was found in a patient affected with ovarian cancer. Four of her family members, 3 BC patients and a healthy individual were consequently also found to carry this mutation. Of the other 27 patients, which were screened for this specific mutation none was found to carry it.CONCLUSION:We found a novel BRCA1 mutation in a family of PA origin with a history highly compatible with BRCA1 phenotype. This mutation was not found in additional 30 PA women affected with BC or OC. Therefore full BRCA1/2 screening should be offered to patients with characteristic family history. The significance of the novel BRCA1 mutation we identified should be studied in larger population. However, it is likely that the E1373X mutation is not a founder frequent mutation in the PA population.

Most X‐linked diseases show a recessive pattern of inheritance in which female carriers are unaffected. In X‐linked retinitis pigmentosa (XLRP), however, both recessive and semi‐dominant inheritance patterns have been reported. We identified an Israeli family with semi‐dominant XLRP due to a missense mutation (p.G275S) in the RPGR gene. The mutation was previously reported in two Danish families with recessive XLRP. Obligate carriers from the two Danish families had no visual complaints and normal to slightly reduced retinal function, while those from the Israeli family suffered from high myopia, low visual acuity, constricted visual fields, and severely reduced electroretinogram (ERG) amplitudes. The disease‐related RPGR haplotype of the Israeli family was found to be different from the one found in the two Danish families, indicating that the mutation arose twice independently on different X‐chromosome backgrounds. A series of genetic analyses excluded skewed X‐inactivation pattern, chromosomal abnormalities, distorted RPGR expression level, and mutations in candidate genes as the cause for the differences in disease severity of female carriers. To the best of our knowledge, this is the first detailed analysis of an identical mutation causing either a recessive or a semi‐dominant X‐linked pattern of disease in different families. Our results indicate that an additional gene (or genes), linked to RPGR, modulate disease expression in severely affected carriers. These may be related to the high myopia concomitantly found in affected carriers from the Israeli family. © 2007 Wiley‐Liss, Inc.

Hereditary non-polyposis colorectal cancer (HNPCC) is an autosomal dominant cancer predisposition syndrome associated with a high risk for colorectal cancer (up to 80%), endometrial cancer (up to 60%), and increased risk for other malignancies, mostly ovarian and urinary system tumors. HNPCC is caused by a germline mutation in one of the mismatch repair (MMR) genes, mainly hMLH1, hMSH2 and hMSH6. The tumors present with microsatellite instability (MSI) associated with loss of heterozygosity of the affected gene, and with loss of expression of the gene product. Diagnosis of HNPCC involves tumor testing for MSI, immunohistochemistry staining and germ line mutation analysis of the suspected gene. Proper genetic counseling is based on the synthesis of the clinical, pathological and molecular data. Directed surveillance shows significant reduction in colon cancer incidence, cancer mortality and overall mortality among HNPCC patients.To establish a multidisciplinary service for patients suspected of having HNPCC.We have established a service which is based on tight collaboration between clinical departments and laboratories. The clinical work-up was conducted by a special oncogenetic clinic and the laboratory service consisted of tissue testing for MSI and immunohistochemistry, denaturing high performance liquid chromatography (DHPLC) for suspected genes, and mutation testing.The efficiency of detection of patients with HNPCC was high, completed in a multistep process. In the first year of our collaborative work, we have provided genetic counseling to over 100 families and performed suitable tests for 46 families. Among them we have identified more than 16 families with HNPCC; 4 showed absence of hMLH1, 1 showed absence of hMSH6, and 11 showed absence of hMSH2. All tumors that showed MSI also showed absence of either one of the three MMR proteins. We present the clinical, pathological and molecular features of our patients and discuss the implication of this data on future recommendations.