Genetic factors play a major part in intellectual disability (ID), but genetic studies have been complicated for a long time by the extreme clinical and genetic heterogeneity. Recently, progress has ...been made using different next-generation sequencing approaches in combination with new functional readout systems. This approach has provided novel insights into the biological pathways underlying ID, improved the diagnostic process and offered new targets for therapy. In this Review, we highlight the insights obtained from recent studies on the role of genetics in ID and its impact on diagnosis, prognosis and therapy. We also discuss the future directions of genetics research for ID and related neurodevelopmental disorders.
In this study, exome sequencing yielded a genetic diagnosis in 16% of patients who had previously been evaluated to rule out known causes of intellectual disability.
Severe intellectual disability, ...which is also referred to as cognitive impairment or mental retardation, affects approximately 0.5% of the population in Western countries
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and represents an important health burden. A clinical diagnosis of severe intellectual disability is generally based on an IQ of less than 50 and substantial limitations in activities of daily living. In early childhood, the diagnosis is based on substantial developmental delays, including motor, cognitive, and speech delays. Children with different nonsyndromic forms of intellectual disability are clinically indistinguishable.
Intellectual disability can be caused by nongenetic factors, such as infections and perinatal asphyxia. In developed countries, . . .
De novo mutations (DNMs) originating in gametogenesis are an important source of genetic variation. We use a data set of 7,216 autosomal DNMs with resolved parent of origin from whole-genome ...sequencing of 816 parent-offspring trios to investigate differences between maternally and paternally derived DNMs and study the underlying mutational mechanisms. Our results show that the number of DNMs in offspring increases not only with paternal age, but also with maternal age, and that some genome regions show enrichment for maternally derived DNMs. We identify parent-of-origin-specific mutation signatures that become more pronounced with increased parental age, pointing to different mutational mechanisms in spermatogenesis and oogenesis. Moreover, we find DNMs that are spatially clustered to have a unique mutational signature with no significant differences between parental alleles, suggesting a different mutational mechanism. Our findings provide insights into the molecular mechanisms that underlie mutagenesis and are relevant to disease and evolution in humans.
The substantial technological advancements in next-generation sequencing (NGS), combined with dropping costs, have allowed for a swift diffusion of NGS applications in clinical settings. Although ...several commercial parties report to have broken the $1000 barrier for sequencing an entire human genome, a valid cost overview for NGS is currently lacking. This study provides a complete, transparent and up-to-date overview of the total costs of different NGS applications.
Cost calculations for targeted gene panels (TGP), whole exome sequencing (WES) and whole genome sequencing (WGS) were based on the Illumina NextSeq500, HiSeq4000, and HiSeqX5 platforms, respectively. To anticipate future developments, sensitivity analyses are performed.
Per-sample costs were €1669 for WGS, € 792 for WES and €333 for TGP. To reach the coveted $1000 genome, not only is the long-term and efficient use of the sequencing equipment needed, but also large reductions in capital costs and especially consumable costs are also required.
WES and TGP are considerably lower-cost alternatives to WGS. However, this does not imply that these NGS approaches should be preferred in clinical practice, since this should be based on the tradeoff between costs and the expected clinical utility of the approach chosen. The results of the present study contribute to the evaluation of such tradeoffs.
A de novo paradigm for mental retardation Brunner, Han G; Veltman, Joris A; Vissers, Lisenka E L M ...
Nature genetics,
12/2010, Letnik:
42, Številka:
12
Journal Article
Recenzirano
The per-generation mutation rate in humans is high. De novo mutations may compensate for allele loss due to severely reduced fecundity in common neurodevelopmental and psychiatric diseases, ...explaining a major paradox in evolutionary genetic theory. Here we used a family based exome sequencing approach to test this de novo mutation hypothesis in ten individuals with unexplained mental retardation. We identified and validated unique non-synonymous de novo mutations in nine genes. Six of these, identified in six different individuals, are likely to be pathogenic based on gene function, evolutionary conservation and mutation impact. Our findings provide strong experimental support for a de novo paradigm for mental retardation. Together with de novo copy number variation, de novo point mutations of large effect could explain the majority of all mental retardation cases in the population.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Severe intellectual disability (ID) occurs in 0.5% of newborns and is thought to be largely genetic in origin. The extensive genetic heterogeneity of this disorder requires a genome-wide detection of ...all types of genetic variation. Microarray studies and, more recently, exome sequencing have demonstrated the importance of de novo copy number variations (CNVs) and single-nucleotide variations (SNVs) in ID, but the majority of cases remain undiagnosed. Here we applied whole-genome sequencing to 50 patients with severe ID and their unaffected parents. All patients included had not received a molecular diagnosis after extensive genetic prescreening, including microarray-based CNV studies and exome sequencing. Notwithstanding this prescreening, 84 de novo SNVs affecting the coding region were identified, which showed a statistically significant enrichment of loss-of-function mutations as well as an enrichment for genes previously implicated in ID-related disorders. In addition, we identified eight de novo CNVs, including single-exon and intra-exonic deletions, as well as interchromosomal duplications. These CNVs affected known ID genes more frequently than expected. On the basis of diagnostic interpretation of all de novo variants, a conclusive genetic diagnosis was reached in 20 patients. Together with one compound heterozygous CNV causing disease in a recessive mode, this results in a diagnostic yield of 42% in this extensively studied cohort, and 62% as a cumulative estimate in an unselected cohort. These results suggest that de novo SNVs and CNVs affecting the coding region are a major cause of severe ID. Genome sequencing can be applied as a single genetic test to reliably identify and characterize the comprehensive spectrum of genetic variation, providing a genetic diagnosis in the majority of patients with severe ID.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Implementation of novel genetic diagnostic tests is generally driven by technological advances because they promise shorter turnaround times and/or higher diagnostic yields. Other aspects, including ...impact on clinical management or cost-effectiveness, are often not assessed in detail prior to implementation.
We studied the clinical utility of whole-exome sequencing (WES) in complex pediatric neurology in terms of diagnostic yield and costs. We analyzed 150 patients (and their parents) presenting with complex neurological disorders of suspected genetic origin. In a parallel study, all patients received both the standard diagnostic workup (e.g., cerebral imaging, muscle biopsies or lumbar punctures, and sequential gene-by-gene-based testing) and WES simultaneously.
Our unique study design allowed direct comparison of diagnostic yield of both trajectories and provided insight into the economic implications of implementing WES in this diagnostic trajectory. We showed that WES identified significantly more conclusive diagnoses (29.3%) than the standard care pathway (7.3%) without incurring higher costs. Exploratory analysis of WES as a first-tier diagnostic test indicates that WES may even be cost-saving, depending on the extent of other tests being omitted.
Our data support such a use of WES in pediatric neurology for disorders of presumed genetic origin.Genet Med advance online publication 23 March 2017.
De novo mutations are recognized both as an important source of genetic variation and as a prominent cause of sporadic disease in humans. Mutations identified as de novo are generally assumed to have ...occurred during gametogenesis and, consequently, to be present as germline events in an individual. Because Sanger sequencing does not provide the sensitivity to reliably distinguish somatic from germline mutations, the proportion of de novo mutations that occur somatically rather than in the germline remains largely unknown. To determine the contribution of post-zygotic events to de novo mutations, we analyzed a set of 107 de novo mutations in 50 parent-offspring trios. Using four different sequencing techniques, we found that 7 (6.5%) of these presumed germline de novo mutations were in fact present as mosaic mutations in the blood of the offspring and were therefore likely to have occurred post-zygotically. Furthermore, genome-wide analysis of “de novo” variants in the proband led to the identification of 4/4,081 variants that were also detectable in the blood of one of the parents, implying parental mosaicism as the origin of these variants. Thus, our results show that an important fraction of de novo mutations presumed to be germline in fact occurred either post-zygotically in the offspring or were inherited as a consequence of low-level mosaicism in one of the parents.
Certain human traits such as neurodevelopmental disorders (NDs) and congenital anomalies (CAs) are believed to be primarily genetic in origin. However, even after whole-genome sequencing (WGS), a ...substantial fraction of such disorders remain unexplained. We hypothesize that some cases of ND-CA are caused by aberrant DNA methylation leading to dysregulated genome function. Comparing DNA methylation profiles from 489 individuals with ND-CAs against 1534 controls, we identify epivariations as a frequent occurrence in the human genome. De novo epivariations are significantly enriched in cases, while RNAseq analysis shows that epivariations often have an impact on gene expression comparable to loss-of-function mutations. Additionally, we detect and replicate an enrichment of rare sequence mutations overlapping CTCF binding sites close to epivariations, providing a rationale for interpreting non-coding variation. We propose that epivariations contribute to the pathogenesis of some patients with unexplained ND-CAs, and as such likely have diagnostic relevance.
Abstract
STUDY QUESTION
Which genes are confidently linked to human monogenic male infertility?
SUMMARY ANSWER
Our systematic literature search and clinical validity assessment reveals that a total ...of 78 genes are currently confidently linked to 92 human male infertility phenotypes.
WHAT IS KNOWN ALREADY
The discovery of novel male infertility genes is rapidly accelerating with the availability of next-generating sequencing methods, but the quality of evidence for gene-disease relationships varies greatly. In order to improve genetic research, diagnostics and counseling, there is a need for an evidence-based overview of the currently known genes.
STUDY DESIGN, SIZE, DURATION
We performed a systematic literature search and evidence assessment for all publications in Pubmed until December 2018 covering genetic causes of male infertility and/or defective male genitourinary development.
PARTICIPANTS/MATERIALS, SETTING, METHODS
Two independent reviewers conducted the literature search and included papers on the monogenic causes of human male infertility and excluded papers on genetic association or risk factors, karyotype anomalies and/or copy number variations affecting multiple genes. Next, the quality and the extent of all evidence supporting selected genes was weighed by a standardized scoring method and used to determine the clinical validity of each gene-disease relationship as expressed by the following six categories: no evidence, limited, moderate, strong, definitive or unable to classify.
MAIN RESULTS AND THE ROLE OF CHANCE
From a total of 23 526 records, we included 1337 publications about monogenic causes of male infertility leading to a list of 521 gene-disease relationships. The clinical validity of these gene-disease relationships varied widely and ranged from definitive (n = 38) to strong (n = 22), moderate (n = 32), limited (n = 93) or no evidence (n = 160). A total of 176 gene-disease relationships could not be classified because our scoring method was not suitable.
LARGE SCALE DATA
Not applicable.
LIMITATIONS, REASONS FOR CAUTION
Our literature search was limited to Pubmed.
WIDER IMPLICATIONS OF THE FINDINGS
The comprehensive overview will aid researchers and clinicians in the field to establish gene lists for diagnostic screening using validated gene-disease criteria and help to identify gaps in our knowledge of male infertility. For future studies, the authors discuss the relevant and important international guidelines regarding research related to gene discovery and provide specific recommendations for the field of male infertility.
STUDY FUNDING/COMPETING INTEREST(S)
This work was supported by a VICI grant from The Netherlands Organization for Scientific Research (918-15-667 to J.A.V.), the Royal Society, and Wolfson Foundation (WM160091 to J.A.V.) as well as an investigator award in science from the Wellcome Trust (209451 to J.A.V.).
PROSPERO REGISTRATION NUMBER
None.
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