Conclusion

Mutation detection in the BRCA1 and BRCA2 genes is of great clinical import but is extremely challenging from a technical standpoint. The large variety of mutation types mandates the use of multiple mutation detection methods if a sensitivity approaching 100 is desired. Methods for assessing pretest probability based on clinical presenta-tion33 can be used to determine which cases merit the highest degree of mutational analysis. Further improvements in mutation detection methods are needed to...

Clinical Utility of Testing

Prader-Willi syndrome is a disorder with many manifestations related to hypothalamic insufficiency. The major features include infantile hypotonia, hypogonadism, dysmorphic appearance, small hands and feet, hyperpha-gia and obesity, developmental delay and MR, and characteristic behavior such as temper outbursts, rigidity, and repetitive thoughts and behavior. In infancy, the differential diagnosis includes neuromuscular disorders associated with hypotonia such as congenital myotonic dystrophy....

Gaucher Disease Molecular Basis of the Disease

Gaucher disease (GD) is another prevalent autosomal recessive lysosomal storage disorder that is found with higher incidence in the Ashkenazi Jewish population. The carrier frequency is 1 in 18 in this population and 1 in 100 in other populations12 (for comprehensive review on GD, see Reference 13). A defect in the enzyme glucocerebrosidase leads to the accumulation of glucocerebrosides in lysosomal compartments in macrophage monocyte-derived cells, particularly in the liver, bone marrow,...

References

World Health Organization Classification of Tumours, Pathology and Genetics, Tumours of Haematopoetic and Lymphoid Tissues. Lyon, France IARC Press 2001. 2. Nowell PC. Progress with chronic myelogenous leukemia a personal perspective over four decades. Annu Rev Med. 2002 53 1-13. 3. Barnes DJ, Melo JV. Cytogenetic and molecular genetic aspects of chronic myeloid leukemia. Acta Haematol. 2002 108 180-202. 4. Melo JV. The diversity of BCR-ABL fusion proteins...

Patterns of Inheritance

One key use of the carefully collected and verified pedigree is determination of the most likely mode of inheritance of a condition in a family. This will have relevance to assessing recurrence risks, approaches to testing, and in some cases, even prognosis. The concept of patterns of inheritance extends from the work of Gregor Mendel, who in the 17th century described transmission of traits associated with single genetic loci.10 Transmission of human genetic conditions and traits has proven to...

Molecular Basis of Disease

Breast cancer is the most common cancer among women in Western countries, with about 180,000 new cases and 40,000 deaths occurring annually in the United States. Epidemiologic factors consistently associated with breast cancer risk include a family history of breast cancer, breast biopsy features, and hormonal risk factors such as age at menarche, parity, and age at first live birth. After female gender and age, family history of breast cancer is the most significant risk factor. In a...

HER2NEU Molecular Basis

HER2 NEU (C-erbB-2) gene amplification, HER2 protein overexpression, or both, are identified in 10 to 34 of invasive breast cancers.10 The ligand for the HER2 NEU protein receptor has not been identified, and its activation may occur through homo- and heterodimerization with other family members (EGFR, HER3, and HER4). Both morphologic and molecular techniques have been used to measure HER2 NEU status in breast cancer clinical samples (Table 24-1).11 The vast majority of these studies have...

Qualitative Detection HCV Assays

There are currently two FDA-cleared qualitative HCV RNA test kits available for diagnostic use, the Amplicor HCV test v2.0 (Roche) and the Versant HCV RNA qualitative test (Bayer). The Amplicor HCV test v2.0 is based on RT-PCR amplification of a portion of the 5' UTR and has an analytical sensitivity of 50IU ml.65 The test incorporates an internal control to detect PCR inhibitors and deoxyuridine triphosphate (dUTP) and uracil-N-glycosylase in the reaction mixture to prevent false positives due...

Clinical Characteristics

Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant colon cancer syndrome. The first description of a cancer-prone family with HNPCC dates back to the late 1800s.1 However, it was not until the work of Lynch in the 1970s that a more complete clinical picture of this disorder began to emerge.2,3 The diagnosis of HNPCC has, until recently, been based primarily on family history. As a result, reliably differentiating patients with HNPCC from those with sporadic cancer has...

The Genetic Family History

The personal and family medical pedigree has evolved from its earliest ancestors in the 15th century to its current form and has become an essential tool in many aspects of the clinical genetics evaluation. Originally used primarily to display relationship information, the pedigree was used for the first time to demonstrate inheritance of traits in the mid-19th century when Pliney Earl published on inheritance of color blindness and Francis Galton described inheritance of artistic ability and...

Hcv Rna Detection and Quantitation

Detection of HCV RNA in serum or plasma by nucleic acid amplification methods is important for confirming the diagnosis of HCV, distinguishing active from resolved infection, assessing the virologic response to therapy, and screening the blood supply. These tests are incorporated into diagnostic algorithms for HCV proposed by the National Institutes of Health,36 the CDC,37 European Association of the Study of the Liver,38 and National Academy of Clinical Biochemistry.39 The detection of HCV RNA...

Available Assays

Prior to 2001, professional recommendations limited CF carrier testing to individuals with a family history and their partners. Testing laboratories offered laboratory-developed assays using standard platforms, including reverse and forward dot blot, polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis, oligonucleotide ligation assays (OLA), sequence specific primer-polymerase chain reaction (SSP-PCR), various methods for exon scanning, and sequencing....

Preperinatal Setting

The roots of genetic counseling are often traced to prenatal diagnosis and reproductive decision making. Genetic counselors have been assisting women and couples with difficult reproductive choices for more than three decades. Typically, women referred for genetic counseling and prenatal diagnosis during pregnancy are those who are at increased risk of having a child affected by a genetic disorder. The most common indications are advanced maternal age (women > 35 years of age), abnormal...

Contributors

Associate Professor, Department of Medicine, Pediatrics, and Molecular Pharmacology, Director, Long QT Syndrome Clinic and Sudden Death Genomics Laboratory, Consultant, Pediatric Cardiology, Mayo Clinic College of Medicine, Mayo Clinic, Rochester, MN 55905, USA Scientific Director, Department of Human Genetics, Focus Diagnostics, Cypress, CA 90630, USA Professor, Department of Pathology, Director of Clinical Hematology, Associate Director, Department of Pathology, Stanford University Medical...

Bayesian Analysis Used in Risk Modification

When collected pedigrees are used to provide risk assessment, a variety of data may be relevant to the overall assessment. Numerous factors, some listed above, influence the likelihood that a given individual in the family may be affected by the condition in question or may be a carrier of the gene in question. When it is not possible to do direct diagnostic testing for the condition for example, if the causative gene is unknown , when the affected relative is not available for testing, or for...

Non Mendelian Inheritance Patterns

For a summary of non-Mendelian inheritance patterns, see Table 4-3. Chromosome abnormalities can occur sporadically or can be caused by familial transmission of duplications,deletions, or rearrangements that can result in imbalance of genetic material in the offspring.12 Due to the presence of many genes along the segment of chromosome involved, multiple phenotypic effects usually are seen. Risks to offspring of familial cases depend on parent of origin and size and location of the involved...