Mendelian Genetic Disorders Research Articles

Longer time scale for human evolution

During the past few years, the best estimates of the human single nucleotide mutation rate have been cut in half. Until recently, estimates of mutation rate have relied on counting substitutions between primate species and assuming that fossil relatives of living species can accurately pin dates onto phylogenetic branches. This procedure allows very precise estimates, but introduces systematic bias toward higher substitution rates and longer branch lengths because a new lineage can leave a fossil record only after its origin, never beforehand (1). Now, widespread resequencing, initially of de novo Mendelian genetic disorders (2, 3) and later of whole genomes in parent–offspring trios (4), has allowed direct comparisons of parent and offspring genomes. The most commonly used, but now outdated, estimate of the mutation rate was 2.4 × 10−8 changes per nucleotide per generation (5). Current estimates of the same value based on resequencing data are much lower, approximately 1.1 to 1.28 × 10−8 (3, 4).

Next Generation Sequence Analysis and Computational Genomics Using Graphical Pipeline Workflows

Whole-genome and exome sequencing have already proven to be essential and powerful methods to identify genes responsible for simple Mendelian inherited disorders. These methods can be applied to complex disorders as well, and have been adopted as one of the current mainstream approaches in population genetics. These achievements have been made possible by next generation sequencing (NGS) technologies, which require substantial bioinformatics resources to analyze the dense and complex sequence data. The huge analytical burden of data from genome sequencing might be seen as a bottleneck slowing the publication of NGS papers at this time, especially in psychiatric genetics. We review the existing methods for processing NGS data, to place into context the rationale for the design of a computational resource. We describe our method, the Graphical Pipeline for Computational Genomics (GPCG), to perform the computational steps required to analyze NGS data. The GPCG implements flexible workflows for basic sequence alignment, sequence data quality control, single nucleotide polymorphism analysis, copy number variant identification, annotation, and visualization of results. These workflows cover all the analytical steps required for NGS data, from processing the raw reads to variant calling and annotation. The current version of the pipeline is freely available at http://pipeline.loni.ucla.edu. These applications of NGS analysis may gain clinical utility in the near future (e.g., identifying miRNA signatures in diseases) when the bioinformatics approach is made feasible. Taken together, the annotation tools and strategies that have been developed to retrieve information and test hypotheses about the functional role of variants present in the human genome will help to pinpoint the genetic risk factors for psychiatric disorders.

Mendelian Puzzles

Variations that lie outside of the coding region of a mutated gene can give rise to a range of clinical phenotypes for a Mendelian genetic disorder.

Rates and Fitness Consequences of New Mutations in Humans

The human mutation rate per nucleotide site per generation (μ) can be estimated from data on mutation rates at loci causing Mendelian genetic disease, by comparing putatively neutrally evolving nucleotide sequences between humans and chimpanzees and by comparing the genome sequences of relatives. Direct estimates from genome sequencing of relatives suggest that μ is about 1.1 × 10(-8), which is about twofold lower than estimates based on the human-chimp divergence. This implies that an average of ~70 new mutations arise in the human diploid genome per generation. Most of these mutations are paternal in origin, but the male:female mutation rate ratio is currently uncertain and might vary even among individuals within a population. On the basis of a method proposed by Kondrashov and Crow, the genome-wide deleterious mutation rate (U) can be estimated from the product of the number of nucleotide sites in the genome, μ, and the mean selective constraint per site. Although the presence of many weakly selected mutations in human noncoding DNA makes this approach somewhat problematic, estimates are U ≈ 2.2 for the whole diploid genome per generation and 0.35 for mutations that change an amino acid of a protein-coding gene. A genome-wide deleterious mutation rate of 2.2 seems higher than humans could tolerate if natural selection is "hard," but could be tolerated if selection acts on relative fitness differences between individuals or if there is synergistic epistasis. I argue that in the foreseeable future, an accumulation of new deleterious mutations is unlikely to lead to a detectable decline in fitness of human populations.

An incidental finding of a large genomic deletion of BRCA1 on a molecular karyotype for a 5 year old child

Background The use of microarray based molecular karyotyping for diagnostic testing is now common in clinical practice. A feature of this technology is an increased capacity to uncover genetic abnormalities unrelated to the original indication for the test. These incidental findings can involve the unexpected diagnosis of well recognised Mendelian genetic disorders through the rearrangement of a known disease genes. Large scale genomic rearrangements of BRCA1 make a significant contribution to the molecular pathology of familial breast and ovarian cancer and are potentially detectable by the CGH or SNP microarrays in common use.

Sickle Cell Disease

This issue provides a clinical overview of sickle cell disease focusing on prevention, diagnosis, treatment, practice improvement, and patient information. Readers can complete the accompanying CME quiz for 1.5 credits. Only ACP members and individual subscribers can access the electronic features of In the Clinic. Non-subscribers who wish to access this issue of In the Clinic can elect "Pay for View." Subscribers can receive 1.5 category 1 CME credits by completing the CME quiz that accompanies this issue of In the Clinic. The content of In the Clinic is drawn from the clinical information and education resources of the American College of Physicians (ACP), including PIER (Physicians' Information and Education Resource) and MKSAP (Medical Knowledge and Self Assessment Program). Annals of Internal Medicine editors develop In the Clinic from these primary sources in collaboration with the ACP's Medical Education and Publishing division and with assistance of science writers and physician writers. Editorial consultants from PIER and MKSAP provide expert review of the content. Readers who are interested in these primary resources for more detail can consult www.acponline.org, http://pier.acponline.org, and other resources referenced within each issue of In the Clinic.

Women’s health-what’s new worldwide

Women’s health-what’s new worldwide

Towards a unifying theory of late stochastic effects of ionizing radiation

The traditionally accepted biological basis for the late stochastic effects of ionizing radiation (cancer and hereditary disease), i.e. target theory, has so far been unable to accommodate the more recent findings of non-cancer disease and the so-called non-targeted effects, genomic instability and bystander effect, thus creating uncertainty in radiation risk estimation. We propose that ionizing radiation can give rise to these effects through two distinct and independent routes, one essentially genetic, termed here type A, and the other essentially epigenetic, termed type B. Type B processes entail envisaging phenotype as represented by a dynamic attractor and radiation acting as an agent that stresses cellular processes leading to the adoption of a variant attractor/phenotype. Evidence from the literature indicates that type B processes can lead to the inheritance of variant cell attractors and mediate a category of trans-generational effects quite distinct from classical Mendelian inherited disease, which is type A. The causal relationships for radiation-induced somatic human health detriment, i.e., cancer and non-cancer (e.g., cardiovascular) disease, are discussed from the point of view of the proposed classification. This approach unifies at a fundamental level the heritable and late somatic effects of radiation into a single causal framework that has the potential to be extended to the effects of the other environmental agents damaging to health.

Identical but not the same: The value of discordant monozygotic twins in genetic research

Monozygotic (MZ) twins show remarkable resemblance in many aspects of behavior, health, and disease. Until recently, MZ twins were usually called "genetically identical"; however, evidence for genetic and epigenetic differences within rare MZ twin pairs has accumulated. Here, we summarize the literature on MZ twins discordant for Mendelian inherited disorders and chromosomal abnormalities. A systematic literature search for English articles on discordant MZ twin pairs was performed in Web of Science and PubMed. A total number of 2,016 publications were retrieved and reviewed and 439 reports were retained. Discordant MZ twin pairs are informative in respect to variability of phenotypic expression, pathogenetic mechanisms, epigenetics, and post-zygotic mutagenesis and may serve as a model for research on genetic defects. The analysis of single discordant MZ twin pairs may represent an elegant approach to identify genes in inherited disorders.

Has Human Evolution Stopped?

It has been argued that human evolution has stopped because humans now adapt to their environment via cultural evolution and not biological evolution. However, all organisms adapt to their environment, and humans are no exception. Culture defines much of the human environment, so cultural evolution has actually led to adaptive evolution in humans. Examples are given to illustrate the rapid pace of adaptive evolution in response to cultural innovations. These adaptive responses have important implications for infectious diseases, Mendelian genetic diseases, and systemic diseases in current human populations. Moreover, evolution proceeds by mechanisms other than natural selection. The recent growth in human population size has greatly increased the reservoir of mutational variants in the human gene pool, thereby enhancing the potential for human evolution. The increase in human population size coupled with our increased capacity to move across the globe has induced a rapid and ongoing evolutionary shift in how genetic variation is distributed within and among local human populations. In particular, genetic differences between human populations are rapidly diminishing and individual heterozygosity is increasing, with beneficial health effects. Finally, even when cultural evolution eliminates selection on a trait, the trait can still evolve due to natural selection on other traits. Our traits are not isolated, independent units, but rather are integrated into a functional whole, so selection on one trait can cause evolution to occur on another trait, sometimes with mildly maladaptive consequences.

Autoinflammatory conditions: when to suspect? How to treat?

The term 'autoinflammatory disease' encompasses an enlarging group of inflammatory disorders defined as Mendelian genetic diseases of the innate immune system. This group is growing considering the fact that diseases sharing strong similarities with this core group can be defined as autoinflammatory. The core group consists now of six disorders also known as hereditary recurrent fever syndromes. Thez most common is familial Mediterranean fever, an autosomal recessive disease affecting mainly populations of Mediterranean ancestry. All these six diseases are characterised by inflammatory attacks both at the clinical and at the biological level. The diagnosis of each of these diseases relies first on clinical features and second on genetic testing, which is guided by the clinical results. Deciphering the role of interleukin-1 in the regulation of the inflammatory response through the inflammasome represents a major advance in the knowledge of the mechanisms of these diseases with, as a main consequence, treatment with interleukin-1 inhibitors.

Abstract CN04-04: Cancer predisposition: I say genetics, you say genomics, but are we there yet?

Abstract In the United States, major contributors to premature mortality are behavior (40%) and genetics (35%). Amongst all diseases, scientific knowledge regarding genetic predisposition to cancer is one of the most advanced. Based on multidisciplinary research spanning the last 2 deacdes, the practice of clinical cancer genetics has empowered patients, their family members and healthcare providers with genetics-informed cancer risk assessment and management. On average, 10% of all cancers are caused by a strong (high penetrance) genetic predisposition, with a range between 5% and 30%. Yet, are those at genetic risk for cancer reaching proper care for prevention? An interactive-electronic family cancer history survey performed in a cancer hospital serving the population of central Ohio revealed that only 7% of all those assessed by cancer genetics professionals to be at high risk for cancer predisposition were recognized either by the patients' healthcare providers or the patients themselves, and referred to cancer genetics professionals. A recent national survey of >35,000 women without personal breast or ovarian cancer histories revealed that ∼1% (∼350) were at high risk for breast and/or ovarian cancer based on family history alone (i.e., at risk for carrying BRCA1/2 mutation). Yet, of these ∼350, only 10% (∼35) discussed this genetic risk with any healthcare provider, and only ∼1.5% (∼4) had BRCA1/2 gene testing. BRCA1/2 are “the most popular”” breast cancer predisposition genes and yet this population is under-serviced. There are at least 6 other high penetrance breast cancer-predisposition genes, including PTEN. Because of the lack of a systematic manner of identifying and managing all individuals at genetic risk for cancer, the great majority of individuals at high risk for cancer predisposition are never identified (in this BRCA1/2 national survey, 90%) nor reach appropriate medical care (99%). Therefore, we believe that individuals and their families at genetic risk for cancer are an under-served population. Paradoxically or perhaps due to the lack of knowledge of the availability and the power of validated genetics services, direct-to-consumer (DTC) personal genome scanning or screening has begun to gain popularity or at least peak public interest. In contrast to validated genetic testing, that is always focused on one or very few genes guided by medical and family histories, personal genomic scanning is currently based on multiple statistical comparisons called genome-wide association. Validated genetic testing is offered by healthcare providers to individuals at high risk of Mendelian genetic disease. This model of validated Mendelian genetic testing focuses only on one or a few genes that are known to be strongly associated with disease. If a gene mutation is identified, the individual is at high risk (sometime ∼100% likelihood) of developing the associated disease, and this type of genetic knowledge is clinically utile and actionable for prevention or very early detection. A few examples include Lynch syndrome, hereditary breast-ovarian cancer syndrome and Cowden syndrome. Personal genomic screening, or personal genome testing or profiling, uses data derived from genome-wide association studies to predict an individual's probability of developing many different disorders and traits in a lifetime. The majority of such genome-wide association studies are case-control studies which study hundreds to thousands of individuals to search for genetic markers shown to be statistically more common in individuals with disease compared with controls. These genetic markers are most commonly Single Nucleotide Polymorphisms (SNPs). They are common in the general population and may or may not have a known functional consequence. These types of data usually provide an odds ratio or relative risk of the likelihood that an individual with a particular genotype will have disease. As a result, most such DTC scanning currently has no to little analytic validity (because SNP choice and algorithms may differ), no clinical validity, no clinical utility and no actionability. Thus, interdisciplinary research directed at clinical outcomes or subsets of individuals or clinical situations where they can be used in a valid and actionable way should be performed. Citation Information: Cancer Prev Res 2010;3(1 Suppl):CN04-04.

Non-Native Interactions Are Critical for Mechanical Strength in PKD Domains

SummaryExperimental observation has led to the commonly held view that native state protein topology is the principle determinant of mechanical strength. However, the PKD domains of polycystin-1 challenge this assumption: they are stronger than predicted from their native structure. Molecular dynamics simulations suggest that force induces rearrangement to an intermediate structure, with nonnative hydrogen bonds, that resists unfolding. Here we test this hypothesis directly by introducing mutations designed to prevent formation of these nonnative interactions. We find that these mutations, which only moderately destabilize the native state, reduce the mechanical stability dramatically. The results demonstrate that nonnative interactions impart significant mechanical stability, necessary for the mechanosensor function of polycystin-1. Remarkably, such nonnative interactions result from force-induced conformational change: the PKD domain is strengthened by the application of force.

“10 001 Dalmatians:” Croatia Launches Its National Biobank

“10 001 Dalmatians:” Croatia Launches Its National Biobank

Genomic analysis of the TRIM family reveals two groups of genes with distinct evolutionary properties

BackgroundThe TRIM family is composed of multi-domain proteins that display the Tripartite Motif (RING, B-box and Coiled-coil) that can be associated with a C-terminal domain. TRIM genes are involved in ubiquitylation and are implicated in a variety of human pathologies, from Mendelian inherited disorders to cancer, and are also involved in cellular response to viral infection.ResultsHere we defined the entire human TRIM family and also identified the TRIM sets of other vertebrate (mouse, rat, dog, cow, chicken, tetraodon, and zebrafish) and invertebrate species (fruitfly, worm, and ciona). By means of comparative analyses we found that, after assembly of the tripartite motif in an early metazoan ancestor, few types of C-terminal domains have been associated with this module during evolution and that an important increase in TRIM number occurred in vertebrate species concomitantly with the addition of the SPRY domain. We showed that the human TRIM family is split into two groups that differ in domain structure, genomic organization and evolutionary properties. Group 1 members present a variety of C-terminal domains, are highly conserved among vertebrate species, and are represented in invertebrates. Conversely, group 2 is absent in invertebrates, is characterized by the presence of a C-terminal SPRY domain and presents unique sets of genes in each mammal examined. The generation of independent sets of group 2 genes is also evident in the other vertebrate species. Comparing the murine and human TRIM sets, we found that group 1 and 2 genes evolve at different speeds and are subject to different selective pressures.ConclusionWe found that the TRIM family is composed of two groups of genes with distinct evolutionary properties. Group 2 is younger, highly dynamic, and might act as a reservoir to develop novel TRIM functions. Since some group 2 genes are implicated in innate immune response, their evolutionary features may account for species-specific battles against viral infection.

Molecular Diagnosis and Genetic Counseling in Ophthalmology

The science of genetics is impacting medicine at a rapid pace. Through efforts such as the Human Genome Project and the HapMap Project, our knowledge of the human genetic landscape is rapidly evolving. 1,2 The number of genes known to cause mendelian genetic disease in ophthalmology has greatly increased over the past decade (Figure 1). 3 With the identification of mutations in complement factor H as a major risk factor for age-related macular degeneration, vision science is also at the forefront of tackling the problems of more common, complex diseases.

Advances in the molecular genetics of ocular coloboma

Ocular coloboma is a developmental anomaly of the eye that results from incomplete closure of the optic fissure, occurring 5–7 weeks post conception. Congenital colobomata are important causes of childhood visual impairment and blindness. This defect typically affects the iris, cornea, ciliary body, zonules, retina, choroid and optic nerve. Colobomata can be seen in isolation and in combination with an impressive number of multisystem disorders. As yet, no effective treatment is available for this condition and management is only supportive. Based upon animal studies of coloboma, mendelian genetic disorders and chromosomal abnormalities, the molecular and genetic mechanisms that regulate optic fissure morphogenesis are now being discovered. Defining the genes and environmental factors involved in coloboma formation will aid in the development of potential therapies for patients with this malformation. This review explores the progress in understanding the clinical and molecular aspects of ocular coloboma.

Mapping the new frontier: complex genetic disorders

The remarkable achievements in human genetics over the years have been due to technological advances in gene mapping and in statistical methods that relate genetic variants to disease. Nearly every Mendelian genetic disorder has now been mapped to a specific gene or set of genes, but these discoveries have been limited to high-risk, variant alleles that segregate in rare families. With a working draft of the human genome now in hand, the availability of high-throughput genotyping, a plethora of genetic markers, and the development of new analytical methods, scientists are now turning their attention to common complex disorders such as diabetes, obesity, hypertension, and Alzheimer disease. In this issue, the JCI provides readers with a series dedicated to complex genetic disorders, offering a view of genetic medicine in the 21st century.

Suggestive linkage of schizophrenia to 5p13 in Costa Rica

Schizophrenia afflicts roughly 1% of all people worldwide. Remarkably, despite differing cultures and environments, the expression of illness is essentially the same. Family, twin, and adoption studies identify schizophrenia as a genetically influenced disease. Linkage studies suggest many positive regions of interest, but as a complex genetic disorder most of the pathogenic loci have not yet been found. Isolated populations are commonly used to study rare Mendelian inherited diseases due to the more homogenous genetic background of the subjects and are thought to be useful for detecting linkage in complex genetic disorders such as schizophrenia. This study aims to define areas of the genome that exhibit co-inheritance with schizophrenia in one large, Mendelian-like family from the central valley of Costa Rica. The whole genome scan analysis of this pedigree, which included 11 cases of schizophrenia and schizoaffective disorder, identified a number of markers on chromosome 5p that appear to co-segregate with the disease with a maximum lod score of 2.70 at marker D5S426. Current studies include investigating additional Costa Rican pedigrees to replicate these findings and identify additional loci linked to the disease.

Cancer genetics services

Although genetic mechanisms have long been recognized as central in the causation of cancer, the practical importance of genetic and familial aspects is only now widely appreciated. In the past, clinical genetic services were involved only in the rare Mendelian cancer genetic disorders, in which the risks were clear and intervention or surveillance was possible, but it has recently become apparent that in some of the more common cancers (notably colon and breast), there is a Mendelian subset in which the genetic risks are also extremely high. This subset is considerably more common than the combined incidence of the rarer, single-gene familial cancer syndromes. Specific genes underlying most of the rarer familial cancer syndromes and some of the Mendelian subsets of the common cancers have now been identified, and this will increase the extent and accuracy of possible genetic services.