Mendelian Genetic Disorders Research Articles

BRCA1 and BRCA2: two genes, multiple clinical applications

The discovery of BRCA1 and BRCA2 hereditary breastovarian cancer genes was driven by a well-defined practical purpose: it was expected, that the identification of genetic causes of these diseases will allow to ascertain yet healthy women at-risk, and therefore to reduce cancer mortality through implementing relevant diagnostic and preventive programs. BRCA-associated syndrome is apparently the most common Mendelian genetic disease in humans. Studies on geographic spread of BRCA1/2 mutations revealed a number of founder alleles, thus permitting non-expensive and rapid identification of thousands of mutation carriers in genetically homogenous human communities (1). On the other hand, the majority of patients with suspicion for hereditary breast or ovarian cancer require comprehensive BRCA1/2 testing; exhaustive BRCA1/2 analysis remains complicated even for the time being, as it includes the detection of both small mutations and gross rearrangements across the entire coding regions of these genes (2). BRCA1 and BRCA2 gene alterations appear to be associated with somewhat distinct disease phenotypes, with a plethora of genetic and non-genetic factors modifying their penetrance (3,4). Diagnostic attitudes towards BRCA1/2 mutation carriers continue to evolve, given that some of the BRCAdriven cancers are notoriously difficult to detect at yet manageable stages (5,6).

ApreciseKUre: an approach of Precision Medicine in a Rare Disease

BackgroundAlkaptonuria (AKU; OMIM:203500) is a classic Mendelian genetic disorder described by Garrod already in 1902. It causes urine to turn black upon exposure to air and also leads to ochronosis as well as early osteoarthritis.Main body of the abstractOur objective is the implementation of a Precision Medicine (PM) approach to AKU. We present here a novel ApreciseKUre database facilitating the collection, integration and analysis of patient data in order to create an AKU-dedicated “PM Ecosystem” in which genetic, biochemical and clinical resources can be shared among registered researchers. In order to exploit the ApreciseKUre database, we developed an analytic method based on Pearson’s correlation coefficient and P value that generates as refreshable correlation matrix. A complete statistical analysis is obtained by associating every pair of parameters to examine the dependence between multiple variables at the same time.Short conclusionsEmploying this analytic approach, we showed that some clinically used biomarkers are not suitable as prognostic biomarkers in AKU for a more reliable patients’ clinical monitoring. We believe this database could be a good starting point for the creation of a new clinical management tool in AKU, which will lead to the development of a deeper knowledge network on the disease and will advance its treatment. Moreover, our approach can serve as a personalization model paradigm for other inborn errors of metabolism or rare diseases in general.

CONGENITAL AND ACQUIRED INTERFERONOPATHIES: DIFFERENTIATED APPROACHES TO THE INTERFERON-CORRECTIVE THERAPY

Various disturbances in the interferon system (IFN) — interferonopathy are considered. The classification of developed by the author is given. The clinical features of Type I interferonopathy associated with the overexpression of type I interferons in the rare Mendelian genetic diseases, some autoimmune diseases, the immune dysregulation syndrome, are characterized. The developed methods of targeted therapy of type I interferonopathies aimed at blocking overexpression of type I interferons as hyperproduction IFNa are described. Interferonopathies most often occur as IFN deficiency: congenital or acquired IFNa/b and IFNg deficiencies in children and adults who are associated with atypical viral or mycobacterial infections. Patients with congenital IFNa deficiency are shown to have replacement interferon therapy. With the acquired deficiency of IFNa, differentiated interferon-corrective therapy is performed. For replacement and interferon-corrective therapy, it is used with good clinical efficacy, safe, no side effects, recombinant human IFNa2b in combination with antioxidants — VIFERONR.

De novo mtDNA point mutations are common and have a low recurrence risk

BackgroundSevere, disease-causing germline mitochondrial (mt)DNA mutations are maternally inherited or arise de novo. Strategies to prevent transmission are generally available, but depend on recurrence risks, ranging from high/unpredictable for many...

Epigenetic RELN Dysfunction in Schizophrenia and Related Neuropsychiatric Disorders.

REELIN (RELN) is a large (420 kDa) glycoprotein that in adulthood is mostly synthesized in GABAergic neurons of corticolimbic structures. Upon secretion in the extracellular matrix (ECM), RELN binds to VLDL, APOE2, and α3β2 Integrin receptors located on dendritic shafts and spines of postsynaptic pyramidal neurons. Reduced levels of RELN expression in the adult brain induce cognitive impairment and dendritic spine density deficits. RELN supplementation recovers these deficits suggesting a trophic action for RELN in synaptic plasticity. We and others have shown that altered RELN expression in schizophrenia (SZ) and bipolar (BP) disorder patients is difficult to reconcile with classical Mendelian genetic disorders and it is instead plausible to associate these disorders with altered epigenetic homeostasis. Support for the contribution of altered epigenetic mechanisms in the down-regulation of RELN expression in corticolimbic structures of psychotic patients includes the concomitant increase of DNA-methyltransferases and the increased levels of the methyl donor S-adenosylmethionine (SAM). It is hypothesized that these conditions lead to RELN promoter hypermethylation and a reduction in RELN protein amounts in psychotic patients. The decreased synthesis and release of RELN from GABAergic corticolimbic neurons could serve as a model to elucidate the epigenetic pathophysiological mechanisms acting at pyramidal neuron dendrites that regulate synaptic plasticity and cognition in psychotic and non-psychotic subjects.

Thiamine Metabolites and Dementia?

The determinants of amyloid deposition in the brain, increased intracerebral phosphorylated tau, hippocampal atrophy, and loss of synapses in areas of brain (the pathogenic determinants of most dementia) remain undetermined except for Mendelian genetic disorders and higher risk of both amyloid deposition and dementia among individuals who carry the apolipoprotein e4 (APOE e4) genotype, especially homozygous e4 (Kuller et al., 2015, Vardarajan et al., 2014, Leduc et al., 2010). The incidence of dementia doubles every 5 years after the age of 65 and probably 2/3 or more of incident dementia cases occur over the age of 80 (Prince et al., 2013). The increasing longevity of the population is a major determinant of the ‘epidemic of dementia’ in many countries. There is little evidence that Alzheimer's disease (AD) pathology or incidence of dementia varies substantially among countries or within countries. Better-educated individuals and those with higher IQ have lower age-specific incidence of dementia attributed to ‘brain reserve.’ An excess or restriction of an exposure in the environment, lifestyle, such as consumption of a nutrient like thiamine, could be a determinant of increased or decreased risk of an age-associated disease like dementia, specifically AD. The brain requirement of a specific nutrient, e.g. thiamine, could increase with aging, either due to loss of a cellular receptor or changes in intracellular metabolism, greater degradation of the metabolite or increase in interfering agents, e.g. drugs. A vitamin deficiency in the past, e.g. pellagra, was a ‘cause of dementia’ that was successfully treated by diet change well before the specific vitamin was identified (nicotinic acid) (Terris, 1964). There is no evidence at present that deficiency of thiamine or any other B vitamin decreases risk of dementia. However, it could be necessary to consume a specific metabolite of the vitamin to have a beneficial effect in the brain. An alternative hypothesis is that lower thiamine metabolites in patients with AD identified in the paper by Xiaoli Pan and colleagues in EBioMedicine (Pan et al., 2015) is due to changes in patients' diet after diagnosis of dementia or secondary to comorbidity after diagnosis of dementia, e.g. reverse causality. The next steps would be to compare blood levels of thiamine metabolites in longitudinal studies with available stored blood samples prior to diagnosis of dementia. If the relative risk of AD or dementia is increased in relation to thiamine metabolites independent of age and education, then small feeding experiments in humans could evaluate whether thiamine metabolites have any effect on cognition in cognitively normal, mild cognitive impairment (MCI), and dementia patients and finally test the hypothesis by feeding metabolites in larger clinical trials of both risk of dementia among those who are cognitively normal and effects on changes in cognition in MCI and possibly dementia patients. The search for a nutrient that could prevent or delay onset or even reverse pathology of AD or other pathologies associated with dementia should have high priority given the worldwide magnitude of dementia, growing incidence and prevalence, and lack of effective therapies for prevention and treatment. It is very possible that a deficiency of a nutrient could be a cause of dementia among older individuals, possibly the nutrient is important only in susceptible individuals based on unique genotype, older ages, or comorbidities.

Abstract 16554: Rapid Identification of Familial Hypercholesterolemia From Electronic Health Records

Background: Familial hypercholesterolemia (FH) is an important public health burden as it is a relatively common Mendelian genetic disorder which is associated with dramatically increased lifetime risk for premature atherosclerotic cardiovascular disease (ASCVD) due to elevated plasma low-density lipoprotein cholesterol (LDL-C) levels. Little is known about prevalence and control of FH in the US. Objective: To develop an electronic phenotyping algorithm for rapid identification of FH in electronic health records (EHRs) and thereby address knowledge gaps in prevalence and control of FH. Methods: We identified patients in the Mayo Employee and Community Health (ECH) system who met the following inclusion criteria: 1) gave research authorization, 2) any LDL-C in EHR ≥190 mg/dL; 2) triglycerides <400 mg/dL; 3) absence of secondary causes of hyperlipidemia (hypothyroidism, cholestatic liver diseases, nephrotic syndrome, renal failure, and pregnancy). Next we applied the Dutch Lipid Clinic Network (DLCN) criteria to ascertain FH cases. ASCVD-related diagnosis codes, laboratory data, and medications were obtained from structured EHR datasets. We used the Mayo natural language processing (NLP) system to ascertain presence of family and personal history of premature ASCVD, xanthomas and corneal arcus from clinical text notes. Results: Of a total of 131,000 patients seen in ECH clinics between July 1993 and December 2014, 6018 met the inclusion criteria. Implementing the electronic phenotyping algorithm for FH in these patients identified 178 definite and 369 probable cases (DLCN score >8 and 6-8 points, respectively) with an overall FH prevalence of 0.4% (1:240). Blinded expert review of 160 randomly chosen patients showed positive and negative predictive values for electronic phenotyping algorithm at 85% and 90%, respectively. Only 40% of these patients achieved LDL-C ≤100 mg/dL on treatment. Conclusions: 1) An EHR-based phenotyping algorithm that included NLP had reasonable accuracy in ascertaining FH cases. 2) Implementing this algorithm revealed the prevalence of FH in the study cohort to be nearly twice the current estimate of 1:500 in the general population. 3) Less than half of the FH patients had optimal LDL-C levels on treatment.

Genetics, Genetic Testing, and Biomarkers of Digestive Diseases

Genetics, Genetic Testing, and Biomarkers of Digestive Diseases

Somatic NOD2 mosaicism in Blau syndrome

Somatic NOD2 mosaicism in Blau syndrome

CHIPS to Disseminate the Genetic Testing of Rare Diseases

With the advance of molecular genetics, causative genes of about half of the estimated 7,000 Mendelian inherited diseases were identified. It becomes more important than ever before to confirm the diagnosis by genetic testing for appropriate medical care of the patient and genetic counseling to the family.

Splicing mutation analysis reveals previously unrecognized pathways in lymph node-invasive breast cancer.

Somatic mutations reported in large-scale breast cancer (BC) sequencing studies primarily consist of protein coding mutations. mRNA splicing mutation analyses have been limited in scope, despite their prevalence in Mendelian genetic disorders. We predicted splicing mutations in 442 BC tumour and matched normal exomes from The Cancer Genome Atlas Consortium (TCGA). These splicing defects were validated by abnormal expression changes in these tumours. Of the 5,206 putative mutations identified, exon skipping, leaky or cryptic splicing was confirmed for 988 variants. Pathway enrichment analysis of the mutated genes revealed mutations in 9 NCAM1-related pathways, which were significantly increased in samples with evidence of lymph node metastasis, but not in lymph node-negative tumours. We suggest that comprehensive reporting of DNA sequencing data should include non-trivial splicing analyses to avoid missing clinically-significant deleterious splicing mutations, which may reveal novel mutated pathways present in genetic disorders.

Exploration of molecular genetic etiology for Korean cochlear implantees with severe to profound hearing loss and its implication.

BackgroundSevere to profound sensorineural hearing loss (SNHL) requires cochlear implantation (CI) for auditory rehabilitation. Etiologic diagnoses can contribute to candidacy selection and decision-making regarding the timing of successful CI. However, few studies have been performed to address the etiologic spectrum of severe SNHL in the population where there is no consanguineous marriage and the majority of SNHL cases are sporadic in small sized families. The authors sought to comprehensively understand the etiologies of Korean cochlear implantees by incorporating the targeted resequencing of 204 candidate deafness genes (TRS-204) and a phenotype-driven candidate gene approach.MethodsNinety-three that consented to molecular genetic testing and underwent at least one molecular genetic test were included. Patients with a characteristic Phenotypic marker were subject to Sanger sequencing to detect variants in corresponding candidate genes. The rest of patients without any prominent phenotype were tested on GJB2. Next, TRS-204 was applied in GJB2-negative cases without any phenotypic marker. In addition, the sibling recurrence-risk of SNHL among families with non-diagnostic genotypes after TRS-204 was performed to gain insight of etiologies in non-diagnostic cases.ResultsOverall, we could find causative variants in 51 (54.8%) of the 93 cochlear implantees. Thirty (32.3%) probands could be diagnosed by direct Sanger sequencing of candidate genes selected by their phenotypes. GJB2 sequencing added 10 subjects to the group with a diagnostic genotype. TRS-204 could detect a causative variant from additional 11 cases (11.8%). We could not detect any pathogenic deletion or duplication on 204 target genes. The sibling recurrence-risk of SNHL among 42 genetically undiagnosed families with 0.03 (1/38) was significantly lower than among genetically diagnosed recessive families with 0.19 (7/37).ConclusionDespite that the majority of severe or more degree of SNHL occurs sporadically in Koreans, at least 54.8% of such cases that were willing to join the genetic study in the Korean population are monogenic Mendelian disorders with convincing causative variants. This study also indicates that a substantial portion of unsolved cases after applying our current protocol are predicted to have non-genetic or complex etiology rather than a Mendelian genetic disorder involving new genes beyond the 204 target genes.Electronic supplementary materialThe online version of this article (doi:10.1186/s13023-014-0167-8) contains supplementary material, which is available to authorized users.

Clinical utility of whole-exome sequencing in rare diseases: Galactosialidosis

Rare genetic disorders can go undiagnosed for years as the entire spectrum of phenotypic variation is not well characterized given the reduced number of patients reported in the literature and the low frequency at which these occur. Moreover, the current paradigm for clinical diagnostics defines disease diagnosis by a specified spectrum of phenotypic findings; when such parameters are either missing, or other findings not usually observed are seen, the phenotype driven approach to diagnosis may result in a specific etiological diagnosis not even being considered within the differential diagnosis. The novel implementation of genomic sequencing approaches to investigate rare genetic disorders is allowing not only the discovery of new genes, but also the phenotypic expansion of known Mendelian genetic disorders. Here we report the detailed clinical assessment of a patient with a rare genetic disorder with undefined molecular diagnosis. We applied whole-exome sequencing to this patient and unaffected parents in order to identify the molecular cause of her disorder. We identified compound heterozygous mutations in the CTSA gene, responsible for causing galactosialidosis; the molecular diagnosis was further confirmed by biochemical studies. This report expands on the clinical spectrum of this rare lysosomal disorder and exemplifies how genomic approaches are further elucidating the characterization and understanding of genetic diseases.

Simultaneous identification and prioritization of variants in familial, de novo, and somatic genetic disorders with VariantMaster

There is increasing interest in clinical genetics pertaining to the utilization of high-throughput sequencing data for accurate diagnoses of monogenic diseases. Moreover, massive whole-exome sequencing of tumors has provided significant advances in the understanding of cancer development through the recognition of somatic driver variants. To improve the identification of the variants from HTS, we developed VariantMaster, an original program that accurately and efficiently extracts causative variants in familial and sporadic genetic diseases. The algorithm takes into account predicted variants (SNPs and indels) in affected individuals or tumor samples and utilizes the row (BAM) data to robustly estimate the conditional probability of segregation in a family, as well as the probability of it being de novo or somatic. In familial cases, various modes of inheritance are considered: X-linked, autosomal dominant, and recessive (homozygosity or compound heterozygosity). Moreover, VariantMaster integrates phenotypes and genotypes, and employs Annovar to produce additional information such as allelic frequencies in the general population and damaging scores to further reduce the number of putative variants. As a proof of concept, we successfully applied VariantMaster to identify (1) de novo mutations in a previously described data set, (2) causative variants in a rare Mendelian genetic disease, and (3) known and new “driver” mutations in previously reported cancer data sets. Our results demonstrate that VariantMaster is considerably more accurate in terms of precision and sensitivity compared with previously published algorithms.

Research progress in heritable dyslipidemia

Dyslipidemia is defined as high levels of serum cholesterol and/or triglycerides. Dyslipidemia often leads to severe cardiovascular diseases including coronary heart disease and stroke as the first clinical manifestation, thus threatening the health of human beings. Dyslipidemia diseases can be caused by the genetic factors, including the Mandelian or polygenic inheritance. Traditional methods of identifying genes associated with dyslipidemia are mainly DNA sequencing and linkage analysis, suitable for Mendelian genetic dyslipidemia disease. The rise of next-generation sequencing technology applies to not only Mandelian inheritance, but also complex forms of dyslipidemia diseases. Since 2006, genome-wide association studies (GWAS) screened out many causative genes associated with dyslipidemia, and most of these genes were the previously identified ones by the pedigree-based classic approaches. Furthermore, GWAS revealed that there were the different frequencies of gene variations related to complex forms of dyslipidemia diseases. Most of the identified single nucleotide polymorphisms (SNPs) associated with dyslipidemia are located in non-coding regions and thus people gradually focus on the gene variations of these loci. The identification of the causative genes will provide new insights into the pathophysiology of dyslipidemia diseases and a step toward therapeutic intervention. This review summarized recent pro-gress in heritable dyslipidemia.

Exome Sequencing in Today's Lab: Shifting the Paradigm in Translational and Clinical Research

Next generation sequencing technologies have enabled a rapid expansion toward the understanding of inherited disorders, cancer biology, drug development, and treatment resistance. Exome sequencing has been increasingly and successfully applied in the clinical research setting for identifying common single nucleotide variants, copy number variations, and small insertions or deletions as well as rare de novo mutations that may explain Mendelian, complex, and rare genetic disorders. Recent advancement in rapid and low-cost exome sequencing make it an attractive alternative to traditional targeted gene panel sequencing for clinical research, while maintaining the possibility of discovering mutations in genes previously not associated with a disorder. Furthermore, the exome encompasses approximately 1% of the genome, yet contains approximately 85% of disease-causing mutations, making exome sequencing easier and cheaper than whole genome sequencing for identifying disease-causing variants in research. Researchers are now applying proband-father-mother (trio) exome sequencing to uncover variants that potentially either cause or modify the condition under study. In this webinar, the audience will learn about the current applications of exome sequencing in clinical research and its impact on the future of health care.

Age-Dependent Germline Mosaicism of the Most Common Noonan Syndrome Mutation Shows the Signature of Germline Selection

Noonan syndrome (NS) is among the most common Mendelian genetic diseases (∼1/2,000 live births). Most cases (50%-84%) are sporadic, and new mutations are virtually always paternally derived. More than 47 different sites of NS de novo missense mutations are known in the PTPN11 gene that codes for the protein tyrosine phosphatase SHP-2. Surprisingly, many of these mutations are recurrent with nucleotide substitution rates substantially greater than the genome average; the most common mutation, c.922A>G, is at least 2,400 times greater. We examined the spatial distribution of the c.922A>G mutation in testes from 15 unaffected men and found that the mutations were not uniformly distributed across each testis as would be expected for a mutation hot spot but were highly clustered and showed an age-dependent germline mosaicism. Computational modeling that used different stem cell division schemes confirmed that the data were inconsistent with hypermutation, but consistent with germline selection: mutated spermatogonial stem cells gained an advantage that allowed them to increase in frequency. SHP-2 interacts with the transcriptional activator STAT3. Given STAT3's function in mouse spermatogonial stem cells, we suggest that this interaction might explain the mutant's selective advantage by means of repression of stem cell differentiation signals. Repression of STAT3 activity by cyclin D1 might also play a previously unrecognized role in providing a germline-selective advantage to spermatogonia for the recurrent mutations in the receptor tyrosine kinases that cause Apert syndrome and MEN2B. Looking at recurrent mutations driven by germline selection in different gene families can help highlight common causal signaling pathways.

Ocular Genetics: A Sub-specialty Service for Genetic Eye Diseases.

Only 60-70 years ago in 1943, Oswald Avery proved that deoxyribonucleic acid (DNA) carries genetic information, and in 1953, Watson and Crick discovered the structure of DNA. Since then, the field of genetics has been transformed. The Human Genome Project with the complete sequencing of the human genome, 5 and the Hap Map Project with its unprecedented view of single nucleotide polymorphism (SNP) variation, 6 have induced enormous changes in the human genetic landscape, changing the way in which we view diseases and receive medical care. Now, with the aid of powerful new technologies for the manipulation and analysis of DNA, scientists are able to locate and identify genes responsible for synthesizing proteins, characterize their mutations and gain a deeper understanding of many poorly understood or previously unknown causes of disease. In ophthalmology, the number of genes known to cause Mendelian genetic disease has greatly increased over the past decade. Researchers have discovered numerous mutations that lead to disease. This new knowledge has been shown to be crucial in the management of GED and has resulted in a paradigm shift in diagnosis and therapy. 7,8 Although some of these advancements may be well-known, it may not be possible for the general ophthalmologist to keep abreast with all the developments in the field of ocular genetics. Individually, GEDs are rare and general ophthalmologists are likely to have little experience of diagnosis and counseling. Increasing understanding of the importance of comprehensive care encompassing diagnosis, therapy, rehabilitation, and counseling for such patients, and for advancements in genetics to positively impact the way ophthalmology is clinically practiced, ocular genetics has emerged as a subspecialty in Ophthalmology. A validated approach to genetic diagnosis in an ocular genetics service commences with elaborate history-taking (of the patient and family) and creation of a family pedigree, followed by careful clinical examination (affected people as well as those apparently unaffected); and lastly, clinical and genetic testing. 9 By their nature, genetic disorders may affect other family members. The ocular genetics service is able to encompass the whole family rather than solely the index individual referred. Clear communication is a defining issue of good service. Patients want information on their diagnosis delivered in a manner that they can understand. Genetic counseling which combines the provision of risk information with a support function is an integral part of any ocular genetics service. Patients and their families highlight the value of genetic counseling but report that it is often not offered in eye clinics. 10 Patients note that only when the person has psychologically adjusted to the condition can he or she move forward and start to deal with the implications. Many patients comment on the shock they experience on being given a diagnosis and that no support is offered to help them adjust to the information and its implications. Ocular genetics enhances mutual understanding and communication between ophthalmologists, clinical and molecular geneticists, as well as genetic counselors. Many patients with GED have complex needs and their sight problems may be one of a range of symptoms they experience as a result of their genetic condition. Comprehensive ocular genetics services where ophthalmologists work alongside clinical geneticists in joint clinics or liaise closely with the genetics services ensure that families receive a high quality and comprehensive package of care. Ophthalmology is an area of mainstream medicine where molecular genetic testing is becoming an important aspect of the service. Genetic testing in ophthalmology has been demonstrated

BBGRE: brain and body genetic resource exchange.

Studies of copy number variation (genomic imbalance) are providing insight into both complex and Mendelian genetic disorders. Array comparative genomic hybridization (array CGH), a tool for detecting copy number variants at a resolution previously unattainable in clinical diagnostics, is increasingly used as a first-line test at clinical genetics laboratories. Many copy number variants are of unknown significance; correlation and comparison with other patients will therefore be essential for interpretation. We present a resource for clinicians and researchers to identify specific copy number variants and associated phenotypes in patients from a single catchment area, tested using array CGH at the SE Thames Regional Genetics Centre, London. User-friendly searching is available, with links to external resources, providing a powerful tool for the elucidation of gene function. We hope to promote research by facilitating interactions between researchers and patients. The BBGRE (Brain and Body Genetic Resource Exchange) resource can be accessed at the following website: http://bbgre.orgDatabase URL: http://bbgre.org

Diagnostic Applications of High-Throughput DNA Sequencing

Advances in DNA sequencing technology have allowed comprehensive investigation of the genetics of human beings and human diseases. Insights from sequencing the genomes, exomes, or transcriptomes of healthy and diseased cells in patients are already enabling improved diagnostic classification, prognostication, and therapy selection for many diseases. Understanding the data obtained using new high-throughput DNA sequencing methods, choices made in sequencing strategies, and common challenges in data analysis and genotype-phenotype correlation is essential if pathologists, geneticists, and clinicians are to interpret the growing scientific literature in this area. This review highlights some of the major results and discoveries stemming from high-throughput DNA sequencing research in our understanding of Mendelian genetic disorders, hematologic cancer biology, infectious diseases, the immune system, transplant biology, and prenatal diagnostics. Transition of new DNA sequencing methodologies to the clinical laboratory is under way and is likely to have a major impact on all areas of medicine.