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One of the key roles performed by pathologists is determination of the presence or absence of tumor cells in clinical samples. This is the basis for most approaches to staging, monitoring response to treatment, and detecting relapse of neoplasia and, as such, is a critical step in determining the course of patient management. Pathologists have utilized a variety of approaches, continually seeking to improve performance and thus patient outcome. The literature reflects this quest, including reports assessing the increased sensitivity afforded by step sectioning, immunohistochemistry, flow cytometry, and, more recently, molecular approaches for the detection of tumor cells in blood, bone marrow, and lymph node samples. The goal is, of course, the more accurate detection of disease spread and, ultimately, better patient care. [ABSTRACT FROM AUTHOR]

Molecular pathology cannot be discussed without including the translational nature of the clinical practice. While the number of Food and Drug Administration (FDA)-cleared or FDA-approved molecular pathology in vitro diagnostic test kits and analyte-specific reagents is increasing, the development of commercial test kits and reagents does not keep pace with the clinically useful genomic information generated by basic, translational, and clinical research. In the genomic in vitro diagnostic testing arena, the molecular pathology laboratory stands at the interface between science and medicine. With existing molecular biology methods, the vast majority of genomic discoveries linking genomic sequences or variations to disease states or risk can be translated into clinical tests in the molecular pathology laboratory. The laboratory director and personnel must understand the regulations and standards that govern this translational process to ensure that the high quality of clinical practice is assured. [ABSTRACT FROM AUTHOR]

Histocompatibility antigens were first described by Snell, using inbred strains of mice. Later, Dausset, Payne, Van Rood, and others discovered that in humans antibodies to white blood cell antigens can be induced after pregnancy or transfusion. These antibodies provided the tools to define the human leukocyte antigens (HLA) (References 1-3 and references therein). Recently, using molecular methods, researchers have defined hundreds of different HLA alleles. The HLA genes reside within a genetic complex referred to as the major histocompatibility complex (MHC). The MHC comprises about 4 megabases (Mb) on the short arm of chromosome 6 (6p21.3). The MHC contains the most polymorphic coding sequences in the human genome. HLA genetic diversity accounts for more than 10% of all genetic diversity observed in the human genome. HLA molecules provide the molecular basis for immunologic self-recognition, and many HLA genes encode proteins that function within immune regulatory networks. [ABSTRACT FROM AUTHOR]

Currently more than 800 laboratories perform nucleic acid-based tests of human samples for the identification of genetic diseases, malignancies, infectious organisms, patient or sample identification, and human leukocyte antigen (HLA) typing.1 The operation of a clinical molecular pathology laboratory requires integration of expertise in medical, scientific, and clinical molecular pathology, resources including facilities, equipment, and personnel, and skills in organization, administration, management, and communication. Quality service is achieved by adherence to clinical laboratory regulations, from specimen collection and processing to reporting of patient results. This chapter reviews fundamental knowledge important for the management and operation of a clinical molecular pathology laboratory. [ABSTRACT FROM AUTHOR]

Analysis of identity through DNA typing has its origins in forensic identity testing and parentage testing. These same analyses also have found tremendous clinical utility in pathology laboratories for a variety of sample identification applications.1-9 These applications include identification of mislabeled specimens of all types, identification of histologic "floaters" in surgical pathology specimens, and detection of maternal cell contamination in prenatal specimens. The scientific principles and technologies of identity testing are described in the preceding chapters. This chapter focuses on sample issues and result interpretation, which are specific to sample identification and related applications of identity testing in the clinical laboratory. [ABSTRACT FROM AUTHOR]

Methods to determine parentage and other relationships between individuals are not new. An early reference is found in Kings (3: 16-27), in which Solomon uses the threat of dividing the child to determine maternity. The application of scientific methods to this problem followed the discovery of the ABO blood group. Laws recognizing the possible exclusion of parentage by blood group testing were enacted by some states as early as 1935. Between 1940 and 1960, as additional blood group systems were defined and shown to follow Mendelian inheritance, more tests to exclude paternity were introduced. When appropriate reagents and methods were used, these red blood cell (RBC) group marker systems were reliable; however, the distribution of these markers in most populations limited the chance that a falsely accused man could be excluded. Subsequently, in the 1960s and 1970s, the discovery of polymorphic protein and red cell enzyme systems resulted in new markers that increased the power of the testing. The introduction of human leukocyte antigen (HLA)-A,B typing further expanded the possibility of excluding most falsely accused men.1 [ABSTRACT FROM AUTHOR]

Hematopoietic cell transplantation (HCT) has become a well-established treatment option for a variety of malignant and nonmalignant diseases. Molecular analysis of chimerism is used to monitor the levels of donor and recipient cells in patients after HCT. The clinical utility and interpretation of chimerism analysis depend on the type of bone marrow transplant used and the underlying disease. After transplantation, chimerism analysis is used to confirm engraftment of donor hematopoiesis and identify and quantify the percentage of recipient cells to guide patient management aimed at helping to prevent graft failure or relapse. [ABSTRACT FROM AUTHOR]

The beginning of the forensic DNA typing revolution was marked by the 1985 publication of a landmark article by Sir AlecJeffreys of Leicester, England, in which he coined the term "DNA fingerprint" and suggested the potential application of DNA fingerprinting in forensic investigations.1,2 Using restriction fragment length polymorphism (RFLP) analysis and DNA probes complementary to polymorphic regions of the genome called "minisatellites," he described how bar code-like patterns were produced. The autoradiographic patterns seemed to be different in every person tested; hence the term "DNA fingerprint" likened this molecular typing to an individual's unique digital fingerprint. In the same year, Jeffreys applied his revolutionary technique to resolve a paternity dispute and to help solve a double rape-homicide in England. [ABSTRACT FROM AUTHOR]

Microbiology laboratories have developed and introduced clinical molecular assays for mycobacteria during the last several years because of the need for a reliable and rapid means of diagnosing tuberculosis (TB) for public health and therapeutic reasons. Molecular tests are used for identification of mycobacteria directly in clinical specimens, for mycobacterial identification, and for determination of drug susceptibilities. [ABSTRACT FROM AUTHOR]

Bacterial infections represent important diseases worldwide despite decades of antibiotic therapy. Diverse microbial pathogens continue t rapidly evolve and present challenges for medical practice that will require ongoing refinements in laboratory-based diagnostic strategies. Since the 1970s, the steady parade of bacterial pathogen discoveries such as Legionella pneumophila, Helicobacter pylori, and Bartonella henselae have highlighted the ongoing importance of bacterial evolution in human infectious diseases. Established bacterial pathogens such as Streptococcus pyogenes and Mycobacterium tuberculosis have reemerged during the past two decades. Drugresistant pathogens including multidrug-resistant organisms spread to different geographic areas, ignoring regional boundaries with the assistance of global immigration and travel. Advances in medicine including oncology and transplantation have resulted in greater numbers of immunocompromised patients with increased risks for invasive bacterial infections. [ABSTRACT FROM AUTHOR]

Chlamydia trachomatis (CT) and Neisseria gonorrheae (GC) are presented together, not because of their similarities in disease presentation, but because of the current trend in screening samples for both simultaneously. Historically, these organisms were identified using very different laboratory methods: CT by tissue culture and GC by growth in specialized bacterial medium. However, over the past decade a revolutionary change has taken place in the approach used to detect these two sexually transmitted infections (STIs). In many instances, molecular testing, either nucleic acid hybridization or nucleic acid amplification, has replaced culture and immunoassays. [ABSTRACT FROM AUTHOR]

Respiratory tract infections are among the most common presenting complaints of patients in both hospital and community settings. They are a considerable burden in terms of both patient morbidity and public health interventions. Laboratory diagnosis of respiratory tract infections should provide guidance in therapy and prognosis, as well as useful epidemiological information reflecting trends in the community. Understanding and monitoring such trends facilitates early recognition of new infectious agents in a population. A summary of the common viruses and bacteria causing respiratory tract infections and their clinical relevance is given in Tables 41-1 and 41-2, respectively. [ABSTRACT FROM AUTHOR]

Viral infections of the central nervous system (CNS) are relatively infrequent and usually result in a benign, selflimiting disease. 1-4 However, in a small percentage of cases, viral infection of the CNS can have extremely serious consequences that result in a spectrum of permanent neurologic damage or death. Viral agents gain access to the CNS by either neuronal or hematogenous spread, and infections can occur at a multitude of sites including the spinal cord, leptomeninges, dorsal nerve roots, nerves, and brain parenchyma. Viral CNS infections are classified clinically as either meningitis or encephalitis, although a close interrelationship occurs between the two disease states.1-4 Host factors (age, sex, immune status, genetic differences) and viral factors (serotype, receptor preference, cell tropism, viral load) in concert with geographic and seasonal factors contribute to the potential for the development of CNS disease.1-4 [ABSTRACT FROM AUTHOR]

Viruses are particularly problematic pathogens in transplant recipients. Viral infections not only can cause disease but also can enhance susceptibility to opportunistic infections by both causing tissue injury and contributing to systemic immunosuppression. Such infections have been shown to increase the rate of graft rejection and increase the risk of cancer. The outcome of viral infections in the transplant setting is the result of a balance among infection in tissues, host antiviral immune function, and the level of immunosuppression required to maintain graft function. Diagnosis of viral infections in immunocompromised patients remains a challenge due to the need to differentiate asymptomatic infection from clinically relevant disease. [ABSTRACT FROM AUTHOR]

Viral hepatitis is believed to have existed in antiquity, with references traced back to the fifth century BC. A new era in viral hepatitis was ushered in by the landmark discovery of Australia antigen, subsequently renamed hepatitis B surface antigen (HbsAg) by Blumberg and coworkers in 1965.1 What followed was a rapid growth in information about the hepatitis B virus (HBV), development of serologic and molecular tests for HBV, understanding of the natural history and pathogenesis of infection, development and approval of antiviral therapies, and most importantly, the development of effective vaccines for prevention of HBV infection. [ABSTRACT FROM AUTHOR]

Human immunodeficiency virus types 1 and 2 (HIV-1 and HIV-2), the causative agents of the acquired immunodeficiency syndrome (AIDS), are RNA viruses belonging to the genus Lentivirus of the family Retroviridae. Like all retroviruses, replication involves reverse transcription of the RNA genome into a double-stranded DNA molecule, with subsequent integration into the host genome. This integrated retroviral DNA is referred to as the provirus. Due to this complex replicative cycle, molecular assays used in the diagnosis and management of HIV-1 infection may target either HIV-1 RNA or proviral DNA. [ABSTRACT FROM AUTHOR]

The myeloproliferative disorders (MPD) and myelodysplastic syndromes (MDS) encompass a pathologically and clinically heterogeneous group of hematologic entities that are united by their putative origin from pluripotent hematopoietic stem cells. The World Health Organization classifies these entities into three broad categories: (1) the chronic myeloproliferative diseases, (2) the myelodysplastic syndromes, and (3) the myelodysplastic/myeloproliferative diseases1 (see Table 35-1). Though all are true hematopoietic stem cell disorders characteristically associated with bone marrow hyperplasia, they are divergent in that MPD typically are associated with effective hematopoiesis, while MDS are associated with ineffective hematopoiesis, reflected by high or low peripheral blood counts, respectively. [ABSTRACT FROM AUTHOR]

There are two broad genetic changes that can be studied in T-cell lymphomas, namely, T-cell receptor (TCR) gene rearrangements and chromosomal translocations, deletions, or additions. [ABSTRACT FROM AUTHOR]

Immunodeficient patients are at an increased risk for developing lymphoproliferative disorders (LPD), including lymphomas. The World Health Organization (WHO) classification recognizes four clinical settings associated with the development of immunodeficiency-related LPDs: (1) primary immune disorders, (2) HIV infection, (3) iatrogenic immunosuppression following solid organ or allogeneic bone marrow transplantation (posttransplant lymphoproliferative disorder [PTLD]), and (4) methotrexate therapy, usually for an autoimmune disorder.1 These lesions are highly heterogeneous, largely due to the various underlying causes of the different immunodeficiencies; however, they share several features (see Table 34-1). In most instances, the LPD are related to Epstein-Barr virus (EBV or HHV-4) infection, and thus, in situations where immunocompetence can be reestablished, these EBV-driven proliferations may regress. However, the development of secondary genetic structural alterations in oncogenes and tumor suppressor genes, not all of which have been defined, results in transformation to a neoplastic process that is no longer responsive to immune modulation. [ABSTRACT FROM AUTHOR]

The B-cell lymphomas (BCLs) represent 80% to 90% of non-Hodgkin lymphomas in the Western world and include multiple lymphoma subtypes with different biologies, natural histories, morphologic characteristics, immunophenotypes, genetic features, prognoses, and responses to therapy.1 Numerous subtypes of B-cell malignancies are defined according to the World Health Organization (WHO) classification (Table 32-1). Accurate subclassification of these BCLs has always been a challenge for pathologists, resulting in early application of new techniques in genetic analysis to these tumors to improve diagnostic accuracy. Today, the genetic features of BCLs are used not only to aid in rendering an accurate primary diagnosis, but also to predict prognosis, to assess for minimal residual disease after therapy, and even to help determine optimal therapy. [ABSTRACT FROM AUTHOR]

Acute lymphoblastic leukemia (ALL) is a heterogeneous group of disorders that originates from B- and T-cell progenitors.1,2 Different B- and T-cell ALL can be recognized according to immunologic and molecular criteria.3-5 The identification of the molecular events underlying the process of leukemia transformation has provided not only important biological information,5-7 but also clinically relevant genetic markers for the identification of prognostically relevant ALL subgroups and for the molecular monitoring of minimal residual disease (MRD). For ALL, immunoglobulin (IG) and T-cell receptor (TCR) gene rearrangement studies are used as markers of clonality and for MRD detection, and the identification of different genetic variations is used to define different ALL subgroups. [ABSTRACT FROM AUTHOR]

The diagnostic entity of acute myeloid leukemia (AML) encompasses a heterogeneous group of diseases whose prognosis differs substantially according to the nature of the underlying molecular lesion and the age of the patient. AML is predominantly a disease of the elderly with a dramatic increase in incidence in individuals over 60 years of age. Traditionally, cases of AML have been classified as primary (de novo) or secondary depending on the absence or presence of recognized predisposing factors (see Table 30-1). [ABSTRACT FROM AUTHOR]

More than 18,000 people were diagnosed with and more than 13,000 died from primary brain tumors in 2003.1 The most common of the primary brain tumors is gliomas. Depending on the grade and morphologic type of glioma, newly diagnosed patients receive watchful waiting, surgical resection, radiotherapy, or chemotherapy, or some combination of these therapies. Regardless of therapy, most patients will progress and have a high risk of mortality and reduced quality of life. Thus, there has been intense interest in understanding the biology and genetics of gliomas, to provide better diagnostic tools and new therapeutic approaches. Molecular pathology markers are being identified that have been or will soon prove to be clinically useful in the practice of clinical neurooncology (see Table 27-1). [ABSTRACT FROM AUTHOR]

In 1999, the National Cancer Institute (NCI) began a funding initiative called the Director's Challenge: Toward a Molecular Classification of Tumors, with the goal of defining comprehensive profiles of molecular alterations in tumors that could be used to identify subsets of patients. These molecular profiles would provide the basis for future studies to validate the clinical utility of molecular-based classification schemes. A further goal of this initiative was the development and implementation of a plan for the timely release of the extensive data sets expected to result from these projects. At that time, it was becoming apparent that the knowledge of the entire human genome combined with rapidly improving technology for comprehensive analysis of the 20,000 to 25,000 genes and encoded proteins would provide an opportunity for a deeper understanding of the molecular basis of disease processes that would guide the evolution of improved therapies based on new diagnostic schemes. Specific molecular profiles correlate with important clinical parameters, which should allow physicians to base management decisions on the molecular characteristics of an individual patient's tumor, and improve a physician's ability to determine the primary tumor site for tumors of unknown origin at the time of their detection. [ABSTRACT FROM AUTHOR]

Duchenne and Becker muscular dystrophies (DMD and BMD) are X-linked, allelic, neuromuscular diseases characterized by progressive muscular weakness and degeneration of skeletal muscle. Duchenne muscular dystrophy is the most common X-linked recessive lethal disease, with an incidence of approximately 1 in 3,500 newborns, and approximately one third of cases are the result of new mutations.1,2 Affected children are usually wheelchair bound by the age of 12 years. As the disease progresses, contractures increasingly develop, leading to asymmetrical spinal deformities. Most patients die at about 20 years of age due to pneumonia related to chronic respiratory insufficiency. The allelic disorder BMD has a milder clinical course and slower disease progression. Becker muscular dystrophy has been estimated to occur approximately one tenth as frequently as DMD, with an incidence of about 1 in 35,000. The majority of BMD patients initially experience difficulties between 5 and 15 years of age, although an onset in the third or fourth decade or even later can occur. By definition the affected patients remain ambulatory until 16 years of age or later, thus allowing clinical distinction from patients with DMD. [ABSTRACT FROM AUTHOR]

Oncologic molecular pathology focuses on identifying and understanding molecular and genetic alterations underlying the development and progression of neoplastic processes. Mesenchymal malignancies may be classified into two pathogenetic types: sarcomas with complex genetic alterations and sarcomas with specific recurrent chromosomal translocations. The first type includes the majority of high-grade, pleomorphic mesenchymal malignancies that are characterized by complex chromosomal abnormalities, for example, malignant fibrous histiocytoma (MFH), osteogenic sarcoma, and embryonal rhabdomyosarcoma. In the second type, the sarcomas are translocation specific, that is, harboring a recurrent chromosomal translocation leading to an in-frame fusion of coding sequences from each of the two rearranged genes. The translocation results in the production of a chimeric transcript encoding a fusion protein with oncogenic activity. Histologically, the translocation-specific sarcomas are generally a monomorphic proliferation of neoplastic cells. This pathogenetic classification appears biologically relevant and is best illustrated by the sarcoma types observed in Li-Fraumeni syndrome and therapy-related malignancies. [ABSTRACT FROM AUTHOR]

The two main types of urothelial carcinoma (UC) are papillary UC (pTa) and "flat" UC (pTis), also known as noninvasive carcinoma in situ. Approximately 75% to 80% of UC are papillary and approximately 20% to 25% are CIS. Papillary tumors tend to recur but not progress to invasive cancer. CIS is aggressive and tends to progress to muscleinvasive cancer. [ABSTRACT FROM AUTHOR]

Based on current incidence rates, an American woman has a 1 in 9 chance of developing breast cancer at some time during her life.1 According to the American Cancer Societ Assistant y, in 2001, there were 192,200 new cases of invasive breast cancer and 47,100 cases of in situ disease in the United Profe States. That same year 40,200 American women died of the disease. This chapter considers the molecular pathology of breast cancer, focusing on the biomarker assays that are currently used in clinical management of the disease, excluding discussion of serum diagnostics, genetic predisposition testing, microarray-based RNA expression profiling, and micrometastasis detection, which are covered elsewhere in this book. The chapter concludes with a brief section on potential future assays, including the emerging field of pharmacogenomics. [ABSTRACT FROM AUTHOR]

Von Hippel-Lindau disease (VHLD) is an autosomal dominant cancer predisposition syndrome that gives rise to hemangioblastomas of the brain and spine, retinal angiomas, clear cell renal cell carcinoma, pheochromocytoma, endolymphatic sac tumors, tumors of the epididymis or broad ligament, and pancreatic tumors or cysts.1 The incidence of VHLD is estimated to be about 1 in 40,000 live births in the white population. Onset is typically between the second and fourth decade of life, with penetrance for the disease nearly complete by the age of 65 years. In most cases, a family history of the disorder is apparent. In about 20% of cases, however, the proband appears to have acquired a new mutation.2 [ABSTRACT FROM AUTHOR]

Preeminent among human tumor suppressor genes in functionality and importance is TP53, reflected by its well-recognized characterization as "guardian of the genome."1-5 TP53 is perhaps the most intensively studied human-cancer-associated oncoprotein, in keeping with its protean effects on critical cellular pathways, including transcriptional control of gene expression, cell cycle proliferation, DNA repair, apoptosis, and cellular maturation and differentiation.6-8 Mutational damage to TP53 is the single most common cancer DNA alteration, having been observed in more than 50% of all human cancers.9 Detection of TP53 mutation is now performed for several clinical indications including assessment of tumor biological aggressiveness, discrimination of tumor recurrence versus de novo cancer formation, determination of tumor anaplasia, and as part of a search for germline inherited mutational change associated with heightened cancer susceptibility.10,11 The emerging diagnostic and prognostic role attributed to TP53 mutation detection justifies testing in selected patients as part of the clinical molecular pathology workup of human cancer. [ABSTRACT FROM AUTHOR]

Neurofibromatosis type 1 and neurofibromatosis type 2 are two distinct genetic disorders that predispose to the development of tumors primarily of the nervous system (Table 21-1).1 A recently recognized third form of neurofibromatosis, known as schwannomatosis,2 is not included in this review, as molecular genetic testing is not available for this disorder. [ABSTRACT FROM AUTHOR]

Multiple endocrine neoplasia (MEN) syndromes include several types of autosomal dominant inherited familial cancer syndromes, each characterized by a different pattern of endocrine gland tumors in affected individuals. The two major types are MEN1 (Wermer syndrome) and MEN2 (Sipple syndrome). MEN1 is an autosomal dominant disorder characterized by a high frequency of peptic ulcer disease and primary endocrine abnormalities involving the parathyroids (90-97% of patients), pancreatic islets (30-80% of patients; including adenoma, prolactinoma, insulinoma, glucagonoma, gastrinoma, etc.), and anterior pituitary (15-50% of patients).1 MEN2 includes subtypes MEN2A, MEN2B, and familial medullary thyroid carcinoma (FMTC, non-MEN), with the primary clinical features of medullary thyroid carcinoma (MTC; 95% of patients), pheochromocytoma (pheo; 50% of MEN2A and MEN2B), parathyroid hyperplasia (15-30% of MEN2A and rarely in MEN2B), plus mucosal neuromas (lips and tongue), ganglioneuromas of the gastrointestinal tract, and marfanoid habitus in MEN2B only.1 The MEN2A diagnostic category characterizes approximately 60% to 90% of patients with MEN2, FMTC accounts for 5% to 35%, and MEN2B for about 5%.2 In addition, MTC and pheo may be bilateral or multifocal with an earlier age of onset than sporadic occurrence of the same tumor type. [ABSTRACT FROM AUTHOR]

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 been difficult. However, the constellation of several clinical characteristics, in addition to family history, may raise suspicion of HNPCC. [ABSTRACT FROM AUTHOR]

Familial adenomatous polyposis (FAP) is an autosomal dominantly inherited disorder that predisposes affected individuals to colon cancer through the early development of hundreds to thousands of adenomatous polyps (Figure 18-1). Florid polyposis throughout the colon will develop in 50% of affected individuals by age 16, and 95% will have polyposis by age 35.1 If left untreated, colorectal cancer is inevitable in those with FAP, with an average age at diagnosis of 39 years. The incidence of FAP is estimated to be 1 in 8,300 to 1 in 14,025 live births and represents less than 1% of all colon cancers.1 FAP is clinically diagnosed when an individual has greater than 100 colorectal adenomatous polyps. [ABSTRACT FROM AUTHOR]

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 meta-analysis of family history of breast cancer as a risk factor, the relative risk ranged from 1.5 for a second-degree relative to 3.6 for a mother and sister with breast cancer.1 Relative risks are significantly influenced by the degree of relationship of affected relatives and their age of breast cancer onset, with closer degrees of relationship and younger age of onset conveying higher risks. An analysis of family history as a risk factor using data from the Swedish Family-Cancer Database showed a populationattributable fraction of about 11%.2 [ABSTRACT FROM AUTHOR]

Osteogenesis imperfecta (OI) is a clinically heterogeneous disorder resulting from the reduced synthesis or the accumulation of abnormal type I collagen, which is a major structural component of many connective tissues including bone. Type I collagen is a trimeric molecule composed of two α1(I) chains and one α2(I) chain, encoded by the COL1A1 and COL1A2 genes, respectively. Fibrillar collagens have a long triple helical domain composed of Gly-X-Y repeats. Glycine residues at every third position are required for the formation of the triple helical domain.1 OI is predominantly inherited in an autosomal dominant fashion and is caused by a wide variety of mutational events in either the COL1A1 or COL1A2 gene. [ABSTRACT FROM AUTHOR]

Huntington disease (HD) is an autosomal dominant neurodegenerative disorder clinically characterized by the presence of choreiform movements, psychiatric sequelae, and dementia. While the majority (>90%) of HD patients become clinically symptomatic in adulthood, 5% to 10% of patients present with the juvenile-onset form of the disease, which is almost invariably associated with inheritance of the mutant allele from a symptomatic father. Unlike the adult-onset form of the disease, juvenile HD is generally characterized by the presence of progressive rigidity, seizures, ataxia, and dystonia. [ABSTRACT FROM AUTHOR]

During the last decade, techniques and advances in molecular genetics and genomics have yielded profound new insights into the fundamental mechanisms and genetic underpinnings for many heritable cardiovascular diseases. The resulting genotype-phenotype correlations facilitate: (1) molecular testing for the preclinical/presymptomatic identification of genetically susceptible individuals, (2) the possibility of gene-based prognosis, and (3) new opportunities for gene-specific or gene-targeted therapy including primary prevention in genotype-positive-phenotypenegative individuals. Cardiology has embraced new genetic discoveries, since sudden cardiac death (SCD) consumes more lives than any other medical condition in developed countries, with 1,000 SCDs occurring each day in the United States. Coronary artery disease (CAD) is the major cause of SCD, while other heritable processes including cardiomyopathies and the channelopathies may also predispose to fatal ventricular arrhythmias. [ABSTRACT FROM AUTHOR]

Hereditary hemochromatosis (HHC) is an autosomal recessive disorder of iron metabolism resulting from excess iron storage in the liver, skin, pancreas, heart, joints, testes, and pituitary gland. If left untreated, life-threatening complications such as cirrhosis, diabetes, liver cancer, and cardiomyopathy may result. Iron overload and the resulting clinical complications can be avoided by early diagnosis and periodic phlebotomy to reduce the body's iron stores. [ABSTRACT FROM AUTHOR]

Reduced to its simplest form, the vascular system is a series of interconnected biologic conduits filled with fluid moving under pressure. This system is subject to injury and must repair itself in order to avoid exsanguination. This latter function is provided by the hemostatic system. Thus, normal hemostasis is a reparative process and consists of three major mechanisms: (1) vasospasm, which is the main mechanism for controlling bleeding after transection/avulsion injuries of large arteries, arterioles, and veins; (2) platelet plug formation; and (3) the procoagulant system. The procoagulant system consists of the mechanisms by which fluid blood is converted into an insoluble hemostatic thrombus. While inherited or acquired disorders of all three mechanisms can cause clinically abnormal bleeding, this chapter reviews the molecular basis of inherited disorders of the procoagulant system (e. g., hemophilia A and B, von Willebrand disease). Inherited vascular and platelet disorders associated with abnormal bleeding are not discussed here. [ABSTRACT FROM AUTHOR]

Recent advances in the molecular biology of hearing and deafness are being transferred from the research laboratory to the clinical arena. This transfer of knowledge is enhancing patient care by facilitating the diagnosis of hereditary deafness. Traditionally, hereditary deafness has been distinguished from nongenetic causes of deafness by otologic, audiologic, and physical examinations, complemented by a family history and ancillary tests such as temporal bone computed tomography, urinalysis, thyroid function studies, ophthalmoscopy, and electrocardiography. Even using this test battery, an unequivocal distinction between genetic and nongenetic causes of deafness often is difficult. If comorbid conditions are identified, the deafness may fall into one of more than 400 recognized types of syndromic hearing loss, but if hearing loss segregates as the only abnormality, diagnosing the deafness as nonsyndromic and inherited is challenging.1 [ABSTRACT FROM AUTHOR]

Cystic fibrosis (CF) is the most common lethal autosomal recessive disease in whites, with an estimated incidence of 1 in 2500 to 3300 live births. Approximately 30,000 children and adults in the United States are affected and approximately 850 individuals are newly diagnosed annually, the majority less than 1 year old. For a current, comprehensive review of clinical CF and molecular diagnostics for this disorder, see http://www.genetests.org/. [ABSTRACT FROM AUTHOR]

Four fibroblast growth receptor genes, FGFR1 to FGFR4, encode receptors for the 18 (or more) fibroblast growth factors. Any of the factors can bind to any of the receptors, although there are preferences. Structurally, the receptors consist of an extracellular region, comprising three immunoglobulinlike domains, a single hydrophobic segment that spans the membrane, and a cytoplasmic tyrosine kinase domain. Binding of the fibroblast growth factor (FGF) ligand to the extracellular domain activates the intracellular tyrosine kinase domain and initiates a signaling pathway that is involved in cell division and differentiation. Mutations that cause hereditary diseases of the skeleton have been discovered in FGFR1, FGFR2, and FGFR3 but not so far in FGFR4. (The only currently reported variant in FGFR4, G388R, is associated with tumor progression and metastasis.) Different gain-offunction mutations in FGFR1, FGFR2, and FGFR3 lead to two major categories of disease, the craniosynostoses and the chondrodysplasias. mutation effects are varied, including ligand-free receptor dimerization that results in constitutive recep torsignaling, direct activation of the tyrosine kinase, and modulation of the receptor ligand binding affinity or specificity.1 [ABSTRACT FROM AUTHOR]

Inborn errors of metabolism represent a highly diverse group of genetic disorders. Individually the disorders are rare. The most prevalent, phenylketonuria (PKU), affects approximately 1 in 10,000 individuals. However, because numerous metabolic disorders exist, collectively they are estimated to affect as many as 1 in 600 individuals. The clinical consequences of such disorders are broad and can be severe, with progressive neurological impairment, mental retardation (MR), organomegaly, and high morbidity. Their mode of inheritance is usually autosomal recessive but also can be Xlinked. Metabolic disorders result from defects in the individual enzymes of pathways that govern many different aspects of metabolism in distinct compartments within the cell. [ABSTRACT FROM AUTHOR]

Although the classic childhood phenotypes of many developmental disorders have been established for some time, only in the past decade have the genetic etiologies of some of these disorders been identified. Investigations of the molecular basis of these conditions have resulted in the identification of new genes, leading to insights into the function of new proteins and biochemical pathways. In addition, genetic mechanisms previously unknown in humans, such as genomic imprinting, uniparental disomy, expansion of trinucleotide repeats, and facilitation of deletions and duplications by low-copy repeats, were recognized as the causes of some of these conditions. [ABSTRACT FROM AUTHOR]

The purpose of this chapter is to describe basic and general principles of Bayesian analysis for molecular pathologists. Thomas Bayes first described the theorem named after him in an essay on "the doctrine of chances," published posthumously in 1763, and republished in 1958.1 Analyses based on Bayes' theorem are routinely applied to calculate probabilities in a wide variety of circumstances, not limited to medicine or genetics. In molecular pathology, Bayesian analysis is commonly used to calculate genetic risk, incorporating population data, pedigree information, and genetic testing results. First, Bayesian analysis will be introduced with two simple, concrete examples. In subsequent sections, the general principles illustrated by these examples are discussed and applied to more complex scenarios. For more in-depth treatments, the reader is referred to Introduction to Risk Calculation in Genetic Counseling by Young2 and The Calculation of Genetic Risks by Bridge3 as well as several articles on genetic risk assessment that include advanced Bayesian analyses, particularly for spinal muscular atrophy (SMA)4,5 and cystic fibrosis (CF). 6-9 [ABSTRACT FROM AUTHOR]

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 genius.1 [ABSTRACT FROM AUTHOR]

Molecular pathology is based on the principles, techniques, and tools of molecular biology as they are applied to diagnostic medicine in the clinical laboratory. These tools were developed in the research setting and perfected throughout the second half of the 20th century, long before the Human Genome Project was conceived. Molecular biology methods were used to elucidate the genetic and molecular basis of many diseases, and these discoveries ultimately led to the field of molecular diagnostics. Eventually the insights these tools provided for laboratory medicine were so valuable to the armamentarium of the pathologist that they were incorporated into pathology practice. Today, molecular diagnostics continues to grow rapidly as in vitro diagnostic companies develop new kits for the marketplace and as the insights into disease gained by the progress of the Human Genome Project develop into laboratory tests. [ABSTRACT FROM AUTHOR]

Genetic counseling is a relatively new and rapidly evolving healthcare service that is increasing in demand as we enter the new era of genomic medicine. Genetic counseling evolved as a combination of disciplines, medical genetics and counseling theory. The original definition of genetic counseling focused on communicating medical information and inheritance and recurrence risk to patients, along with presenting options for responding to the risk in a nondirective manner and helping patients adjust to their conditions. 1 As the practice of genetic counseling has grown over the past 30 years, so have the goals and scope of practice. [ABSTRACT FROM AUTHOR]

Molecular biology entails the analysis and study of the chemical organization of the cell. Molecules comprise the smallest chemical component capable of performing all the activities (structural or catalytic) of a substance. One or more atoms constitute each molecule. This chapter describes the physical organization of cells, cellular organelles, and molecules important in cell division, inheritance, and protein synthesis. [ABSTRACT FROM AUTHOR]