A somatic origin of homologous Robertsonian translocations and isochromosomes

One t(14q14q), three t(15q15q), two t(21q21q), and two t(22q22q) nonmosaic, apparently balanced, de novo Robertsonian translocation cases were investigated with polymorphic markers to establish the origin of the translocated chromosomes. Four cases had results indicative of an isochromosome: one t(14q14q) case with mild mental retardation and maternal uniparental disomy (UPD) for chromosome 14, one t(15q15q) case with the Prader-Willi syndrome and UPD(15), a phenotypically normal carrier of t(22q22q) with maternal UPD(22), and a phenotypically normal t(21q21q) case of paternal UPD(21). All UPD cases showed complete homozygosity throughout the involved chromosome, which is supportive of a postmeiotic origin. In the remaining four cases, maternal and paternal inheritance of the involved chromosome was found, which unambiguously implies a somatic origin. One t(15q15q) female had a child with a ring chromosome 15, which was also of probable postmeiotic origin as recombination between grandparental haplotypes had occurred prior to ring formation. UPD might be expected to result from de novo Robertsonian translocations of meiotic origin; however, all de novo homologous translocation cases, so far reported, with UPD of chromosomes 14, 15, 21, or 22 have been isochromosomes. These data provide the first direct evidence that nonmosaic Robertsonian translocations, as well as isochromosomes, are commonly the result of a mitotic exchange

Short report. The AIDIT and IMPACT conference 2006: Outcomes and future directions

IMPACT (Identification of Men with a genetic predisposition to ProstAte Cancer: Targeted screening in BRCA1/2 mutation carriers and controls) is an international collaboration investigating the utility of targeted prostate-specific antigen (PSA) screening for men at increased risk of prostate cancer due to inherited predisposition. Although the majority of prostate cancer occurs sporadically, it is recognized that family history plays a role in a significant number of cases: a family history either of prostate cancer alone, or of other cancers including breast and ovarian cancer. Evidence of the link between single genes and prostate cancer risk is strongest for the BRCA1 and BRCA2 genes, with BRCA2 in particular thought to lead to a relative risk of 4.65 (95%CI 3.48-6.22). This relative risk may be as high as 7.33 in men under the age of 65 years

Germline hMSH2 and hMLH1 gene mutations in incomplete HNPCC families

Hereditary non-polyposis colon cancer (HNPCC) is a common hereditary disease characterized by a predisposition to an early onset of colorectal cancer. The majority of the HNPCC families carry germline mutations of either hMSH2 or hMLH1 genes, whereas germline mutations of hPMS1 and hPMS2 genes have rarely been observed. Almost all of the germline mutations reported so far concern typical HNPCC families. However, there are families that display aggregations of colon cancer even though they do not fulfil all HNPCC criteria (incomplete HNPCC families) as well as sporadic cases of early onset colon cancers that could be related to germline mutations of these genes. Therefore, we screened germline mutations of hMSH2 and hMLH1 genes in 3 groups of patients from France and Turkey: typical HNPCC (n = 3), incomplete HNPCC (n = 9) and young patients without apparent familial history (n = 7). By in vitro synthesis of protein assay, heteroduplex analysis and direct genomic sequencing, we identified 1 family with hMSH2 mutation and 5 families with hMLH1 mutations. Two of the 3 HNPCC families (66%) displayed hMLH1 germline mutations. Interestingly, 4 of 9 families with incomplete HNPCC (44%) also displayed mutations of hMSH2 or hMLH1 genes. In contrast, no germline mutation of these genes was found in 7 young patients. Our results show that germline mutations of hMSH2 and hMLH1 genes contribute to a significant fraction of familial predisposition to colon cancer cases that do not fulfil all diagnostic criteria of HNPCC. © 1997 Wiley-Liss, Inc

Complete gonadal dysgenesis 46,XY (Swyer syndrome) in two sisters and their mother's maternal aunt with a female phenotype.

OBJECTIVE: To present a familial case of Swyer syndrome. DESIGN: Case report. SETTING: Academic medical center. PATIENT(S): Two sisters with a main complaint of primary amenorrhea and another case, their mother's maternal aunt with the same history of primary amenorrhea but married with no consanguinity and no children. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The patients were studied from clinical, endocrinologic, and genetic perspectives. RESULT(S): Chromosome analyses revealed a 46,XY male karyotype with no detectable mosaicism in both sisters and their mother's maternal aunt. Molecular studies of sex-determining region Y and molecular investigation undertaken for the two sisters revealed SRY negativity. CONCLUSION(S): Gonadal dysgenesis can also be inherited as an X-linked disorder, and evidence exists from familial studies of perhaps autosomal inheritance

their mother's maternal aunt with a female phenotype

Objective: To present a familial case of Swyer syndrome.Design: Case report.Setting: Academic medical center.Patient(s): Two sisters with a main complaint of primary amenorrhea and another case, their mother's maternal aunt with the same history of primary amenorrhea but married with no consanguinity and no children.Intervention(s): None.Main Outcome Measure(s): The patients were studied from clinical, endocrinologic, and genetic perspectives.Result(s): Chromosome analyses revealed a 46, XY male karyotype with no detectable mosaicism in both sisters and their mother's maternal aunt. Molecular studies of sex-determining region Y and molecular investigation undertaken for the two sisters revealed SRY negativity.Conclusion(s): Gonadal dysgenesis can also be inherited as an X-linked disorder, and evidence exists from familial studies of perhaps autosomal inheritance. (Fertil Steril (R) 2011; 95: 1786. e1-e3. (C) 2011 by American Society for Reproductive Medicine.