Purpose of review-More than forty different individual genes have been implicated in the inheritance of dilated cardiomyopathy. For a subset of these genes, mutations can lead to a spectrum of cardiomyopathy that extends to hypertrophic cardiomyopathy and left ventricular noncompaction. In nearly all cases, there is an increased risk of arrhythmias. With some genetic mutations, extracardiac manifestations are likely to be present. The precise genetic etiology can usually not be discerned from the cardiac and/or extracardiac manifestations and requires molecular genetic diagnosis for prognostic determination and cardiac care.Recent findings-Newer technologies are influencing genetic testing, especially cardiomyopathy genetic testing, where an increased number of genes are now routinely being tested simultaneously. While this approach to testing multiple genes is increasing the diagnostic yield, the analysis of multiple genes in one test is also resulting in a large amount of genetic information of unclear significance.Summary-Genetic testing is highly useful in the care of patients and families, since it guides diagnosis, influences care and aids in prognosis. However, the large amount of benign human genetic variation may complicate genetic results, and often requires a skilled team to accurately interpret the findings.
BackgroundLamins A and C, encoded by the LMNA gene, are filamentous proteins that form the core scaffold of the nuclear lamina. Dominant LMNA gene mutations cause multiple human diseases including cardiac and skeletal myopathies. The nuclear lamina is thought to regulate gene expression by its direct interaction with chromatin. LMNA gene mutations may mediate disease by disrupting normal gene expression.Methods/FindingsTo investigate the hypothesis that mutant lamin A/C changes the lamina's ability to interact with chromatin, we studied gene misexpression resulting from the cardiomyopathic LMNA E161K mutation and correlated this with changes in chromosome positioning. We identified clusters of misexpressed genes and examined the nuclear positioning of two such genomic clusters, each harboring genes relevant to striated muscle disease including LMO7 and MBNL2. Both gene clusters were found to be more centrally positioned in LMNA-mutant nuclei. Additionally, these loci were less compacted. In LMNA mutant heart and fibroblasts, we found that chromosome 13 had a disproportionately high fraction of misexpressed genes. Using three-dimensional fluorescence in situ hybridization we found that the entire territory of chromosome 13 was displaced towards the center of the nucleus in LMNA mutant fibroblasts. Additional cardiomyopathic LMNA gene mutations were also shown to have abnormal positioning of chromosome 13, although in the opposite direction.ConclusionsThese data support a model in which LMNA mutations perturb the intranuclear positioning and compaction of chromosomal domains and provide a mechanism by which gene expression may be altered.
Purpose: About half of unaffected BRCA1/2 carriers have a negative family history, confounding efforts toward presymptomatic carrier identification. Ovarian cancer is preventable for known carriers but is otherwise highly lethal. Cost-effectiveness and gains in life expectancy are important factors in evaluating the desirability of population-based genetic screening, currently the only viable strategy to identify carriers with unrevealing family histories. Methods: Cost-utility analysis for a population-based genetic screening program offered to American Ashkenazi Jewish women aged 35-55 years measuring cancer incidence, life expectancy, and cost. Results: Our model predicts that a genetic screening program would result in 2811 fewer cases of ovarian cancer, with a life expectancy gain of 1.83 quality-adjusted life years among carriers. At a cost of $460 for founder mutation testing, the cost of the program is $8300 (discounted) per year of quality-adjusted life gained. Conclusion:In populations with a high prevalence of BRCA1/2 founder mutations, genetic screening may be cost-effective when compared with recommended public health interventions such as mammographic screening. We advocate the initiation of a dialogue among Jewish stakeholders, genetics professionals, and public health leaders to determine whether a population-based BRCA1/2 genetic screening program should be pursued. Genet Med 2009:11(9):629 -639. Key Words: BRCA1, BRCA2, decision analysis, ovarian carcinoma, population-based genetic screeningA n inherited predisposition to hereditary breast and ovarian cancer should be heralded by a strong cancer family history, but surprisingly often, it is not. Incomplete penetrance, sexlimited expression, limited family structure, and incomplete family history information all contribute to the frequent observation of hereditary cancer cases, which lack premonitory clues. Female BRCA1/2 carriers who are unaware of their genetic status cannot undertake recommended measures such as early mammography and breast magnetic resonance imaging (MRI) or avail themselves of risk-reducing salpingo-oophorectomy after completion of childbearing. Women with nonscreen detected, early-onset breast cancer and those who develop ovarian cancer can be expected to face much higher morbidity and mortality than if they were undergoing high-risk management.An underlying assumption in clinical cancer genetics is that by maximizing the efficiency of the referral pipeline through such means as physician and patient education and computerized family history tools, most unaffected BRCA1/2 carriers could be identified before developing cancer. High-risk management could then be instituted in a family-centered manner to reduce the cancer burden. Although this holds true for families with recognizable features of hereditary cancer, several studies suggest that about half of all BRCA1/2 families cannot be identified using this approach. [1][2][3][4][5][6][7][8] BRCA1/2 mutation prevalence rates have been measured in several population-based...
North American SOD1 alanine to valine mutation at codon 4 descended from two founders (Amerindian and European) 400-500 years ago.
Human autosomal recessive primary microcephaly (MCPH) is a rare genetic disorder in which affected individuals are born with reduced brain size. MCPH is genetically heterogeneous, with six loci and four genes reported to date. Mutations in the ASPM gene at the MCPH5 locus appear to be the most common cause of MCPH. For this study, 33 Pakistani families with primary microcephaly were enrolled. Genotyping using microsatellite markers linked to the six known MCPH loci showed the linkage of 18 families to the MCPH5 locus, two to the MCPH2 locus, two to the MCPH4 locus, and one to the MCPH6 locus. The remaining ten families were not linked to any of the known loci. Families linked to the MCPH5 locus were further subjected to screening of the ASPM gene with direct DNA sequencing. Two previously reported variants, 3978G>A (W1326X) and 9557C>G (S3186X), were observed in five Pakistani families. Four novel nonsynonymous sequence variants, 9118insCATT, 9238A>T (L3080X), 9539A>C (Q3180P), and 1260delTCAAGTC, were found to segregate within four families, but were not observed in 200 Pakistani control chromosomes. One of the variants, 9539A>C (Q3180P), occurred in the IQ 79 domain, but its functional significance awaits definition.
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