1,721,290 research outputs found
Genetic testing of cancer predisposition
No full textCancer is a multistep process determined by the occurrence of sequential genetic changes in cells of the somatic Lineage. A minority of cancer patients present with a striking tumor family history, suggestive of mendelian inheritance. It has been shown that specific familial cancer aggregations are due to mutations in cancer-predisposing genes which are transmitted through the germline. So far, more than 20 genes associated with cancer predisposition have been identified. Since the genes involved are many, currently there is no universal test for cancer predisposition. Rather, mutation detection strategies need to be tailored according to the type of gene which needs to be investigated. This is established based on clinical evaluation, on analysis of clinical documentation, and on pedigree reconstruction and interpretation. Therefore, genetic counseling is a fundamental step of cancer genetic testing. The counseling process includes also the provision of adequate information on the limits of cancer genetic tests, on the risks associated with mutations in specific genes, and on the options available for prevention and early diagnosis. Due to the complexity of these issues, scientific and professional organizations usually recommend that genetic tests for cancer predisposition be performed in institutions actively involved in research in the field. To better handle the multiple facets of familial cancer syndromes, ad hoc multidisciplinary teams ("cancer family clinics") have been established in a number of countries. While the bulk of knowledge accrued so far concerns clearcut hereditary conditions associated with high penetrance, there are growing data indicating that less penetrant mutations, and even common polymorphisms, are involved in cancer susceptibility, albeit with lower risks. Further discoveries in the field will probably lead to an exponential increase in the number of potential candidates to genetic tests. However, before these can be applied on a population scale, there is a need for improvements and standardization of management and surveillance strategies
A single mutation in the FGA locus responsible for false homozygosities and discrepancies between commercial kits in an unusual paternity test case
No full textWe report an unusual paternity test case showing multiple peculiarities. Using AmpFlSTR((R)) Profiler Plus and AmpFlSTR((R)) Identifiler PCR Amplification kits, the alleged father and the two children were apparently homozygous at the FGA locus, but using the PowerPlex((R)) 16 kit the three individuals were found to be heterozygous. Drop-out was caused by a single mutation event in the presumptive binding site of the reverse primer. In addition, three inconsistencies were detected between the daughter and the alleged father among 18 STR markers. The occurrence of the rare null allele at the FGA locus and case history suggested that the true father was the brother of the alleged father. Furthermore, a single-step repeat maternal mutation was also detected at D16S539. This puzzling case was solved by using multiple analytical approaches, including the use of different primer pairs, the use of a high number of STR markers, and the characterization of the mutation causing the "null allele.
BRACHY ECTRODACTYLY AND ABSENCE OR HYPOPLASIA OF THE FIBULA - AN AUTOSOMAL DOMINANT CONDITION WITH LOW PENETRANCE AND VARIABLE EXPRESSIVITY
No full textA complex dysostosis characterized by brachy- and/or ectrodactyly and fibular hypoplasia was found in two distantly related individuals. The proposita, aged 25 years, showed metacarpal and phalangeal hypoplasia on both hands, ectrodactyly on both feet, and nearly complete bilateral absence of the fibula. Only milder acromelic defects were detected in a second cousin. A similar pattern of skeletal involvement had been previously described in an unrelated Italian family. The peculiar segregation pattern can be explained by autosomal dominant inheritance with low penetrance and variable expressivity
Gastrointestinal manifestations in PTEN hamartoma tumor syndrome
No full textThe PTEN hamartoma tumor syndrome (PHTS) is a heterogeneous set of multisystem disorders caused by germline pathogenic variants in the PTEN tumor suppressor gene. Manifestations include developmental anomalies and proliferative lesions. Evidence of involvement of the GI tract has accrued over time, leading to the incorporation of GI manifestations (multiple hamartomas, glycogenic acanthosis and colorectal cancer) into the diagnostic criteria. Polyps of the upper and lower GI tract are found in most adult patients and in a significant fraction of children. Polyps tend to be of mixed histology, with a predominance of hamartomas and ganglioneuromas. PHTS patients are also at increased risk of colorectal cancer, and surveillance by colonoscopy is advised starting at the age of 35–40 years. A number of additional manifestations, including eosinophilic gastrointestinal disorders, have been observed in few or single cases, and their association with PHTS has yet to be determined
NF2 mutation screening by denaturing high-performance liquid chromatography and high-resolution melting analysis
No full textNeurofibromatosis type 2 (NF2) is an autosomal-dominant disorder caused by mutations in the NF2 gene and predisposing to the development of nervous system. Identification of germline mutations is essential to provide appropriate genetic counseling in NF2 patients, but it represents an extremely challenging task because the vast majority of mutations are unique and spread over the entire coding sequence. Moreover, about 30% of de novo patients are indeed mosaic, and direct sequencing can undetect mutated alleles present in a minority of cells. As most screening techniques do not meet the requirements for efficient NF2 testing, we have developed a semi-automated denaturing high-performance liquid chromatography (DHPLC) method for point mutation detection combined with a multiplex ligation-dependent probe amplification approach to screen for gene rearrangements. In addition, we have evaluated high-resolution melting analysis (HRMA) as an exon scanning procedure to identify point mutations in the NF2 gene. The results obtained in 92 NF2 patients expand the NF2 mutational spectrum and indicate DHPLC and HRMA as good systems to screen for point mutations in diseases with a heterogeneous spectrum of alterations
CDKN2A germline splicing mutation affecting both P16(ink4) and P14(arf) RNA processing in a melanoma/neurofibroma kindred
No full textThe CDKN2A locus encodes two tumor suppressor proteins, p16(lnk4) and p14(arf), through use of alternative first exons. CDKN2A mutations detected in melanoma families are usually missense or nonsense changes which mainly impair p16(lnk4) function. Large genomic deletions spanning the entire locus have been observed in Mo pedigrees with melanomas and nervous tumors. We have detected a novel splice site mutation in a family with melanomas, neurofibromas, and multiple dysplastic nevi. Both alternative mRNAs produced by the mutant allele lacked shared sequences from exon 2, which encodes a substantial portion (> 50%) of both p16(lnk4) and p14(arf) proteins. The development of neurofibromas can be explained by cooperative effects of combined inactivation of p16(ink4) and p14(arf) or, alternatively, of p14(arf) alone. (C) 2001 Wiley-Liss, Inc
Maternal-fetal flow, negative events, and preeclampsia - Role of ACE I/D polymorphism
No full textThe risk for an adverse pregnancy outcome is markedly higher in women with history of preeclampsia. This may stem from impaired placentation in early gestation and from high impedance to flow in uteroplacental circulation. The renin-angiotensin system is one of the mediators of the remodeling of spiral arteries throughout pregnancy. The D allele of the Insertion/ Deletion (I/D) polymorphism in the ACE gene has been associated with higher ACE activity, accounting for 47% of the total phenotypic variance of serum enzyme levels. To investigate whether the ACE I/D polymorphism affects maternal uteroplacental and fetal umbilical circulation and the pregnancy outcome in women with a history of preeclampsia, 106 women underwent Doppler examination of uterine arteries resistance index and umbilical artery pulsatility index at the 16th, 20th, and 24th weeks of gestation and were genotyped for the I/D polymorphism. This study found a difference in genotype distribution (P=0.0002) and allele frequency (P=0.0001) between women with and those without preeclampsia recurrence and fetal growth restriction as well as an association (P=0.0007) between DD genotype and risk of recurrent preeclampsia or fetal growth restriction. At the 16th, 20th, and 24th weeks, uterine artery resistance indexes were significantly lower in II, higher in DD, and intermediate in ID genotype carriers, whereas the umbilical artery pulsatility index values were significantly higher in the DD group in comparison to ID and II genotypes. The current study shows that the ACE I/D polymorphism affects uteroplacental and umbilical flows and the recurrence of an adverse pregnancy outcome in women with history of preeclampsia
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