ABSTRACT
Ascertaining a diagnosis through exome sequencing can provide potential benefits to patients, insurance companies, and the healthcare system. Yet, as diagnostic sequencing is increasingly ...employed, vast amounts of human genetic data are produced that need careful curation. We discuss methods for accurately assessing the clinical validity of gene–disease relationships to interpret new research findings in a clinical context and increase the diagnostic rate. The specifics of a gene–disease scoring system adapted for use in a clinical laboratory are described. In turn, clinical validity scoring of gene–disease relationships can inform exome reporting for the identification of new or the upgrade of previous, clinically relevant gene findings. Our retrospective analysis of all reclassification reports from the first 4 years of diagnostic exome sequencing showed that 78% were due to new gene–disease discoveries published in the literature. Among all exome positive/likely positive findings in characterized genes, 32% were in genetic etiologies that were discovered after 2010. Our data underscore the importance and benefits of active and up‐to‐date curation of a gene–disease database combined with critical clinical validity scoring and proactive reanalysis in the clinical genomics era.
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As diagnostic sequencing is increasingly employed, vast amounts of human genetic data are produced that need careful curation. We describe a standardized scoring system for accurately assessing the clinical validity of gene–disease relationships to interpret new research findings in a clinical context and increase the diagnostic rate. In turn, clinical validity scoring of gene–disease relationships can inform exome reporting and reanalysis, and gene selection for creation of diagnostic panels.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Access to genetic testing, namely, diagnostic exome sequencing (DES), has significantly improved, subsequently increasing the likelihood of discovering incidental findings, such as misattributed ...relationships and specifically misattributed parentage (MP). Until the recently published ACMG statement, there had been no consensus for laboratories and clinicians to follow when addressing such findings. Family‐based genomic testing is valuable for accurate variant interpretation but has the potential to uncover misattributed familial relationships. Here, we present the first published data on the frequency of MP identified through DES at a clinical laboratory. We also investigated clinicians' decisions on how to proceed with analysis, reporting, and disclosure. A database of 6,752 families who underwent parent‐proband (‘trio’) DES was retrospectively reviewed for molecular identification of MP and clinicians' MP disclosure decisions. Among 6,752 trios, 39 cases of MP were detected (0.58%). Non‐paternity was detected in all cases, and in one instance, non‐maternity was also identified. All clinicians decided to proceed by omitting the MP individual from the analysis. Clinicians chose to proceed with duo analysis (87.2%), modify information on the report (74.4%), and communicate MP results to the mother (71.8%), suggesting a trend toward not disclosing to the putative father or proband. The data show that trio DES involves a chance of detecting MP and that clinician disclosure practices do not appear to routinely include direct disclosure to the putative father. MP identified in our parent‐proband trios sent in for DES is lower than the reported frequency of MP in the general population due in part to ascertainment bias as families with known or suspected MP are presumably less likely to pursue trio testing. These data may inform laboratory policies and clinician practices for addressing incidental findings such as MP.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK, VSZLJ
Most chromosomal deletions and duplications (copy-number variants) that are associated with neurodevelopmental disorders are known to result in a wide variation of clinical phenotypes. This study ...describes a genetic mechanism for such variation.
Genomic rearrangements are an important source of genetic and phenotypic variation. Rare, recurrent copy-number variants of pathogenic significance, termed genomic disorders, were originally identified in persons with a characteristic set of clinically recognizable features, such as the Smith–Magenis syndrome, the Sotos syndrome, and the Williams–Beuren syndrome. Although unexplained phenotypic variation and differences in severity have long been recognized among patients with the same genomic disorder,
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comparatively recent discoveries of potentially pathogenic copy-number variants have broadened the phenotypic range associated with a given variant to include entirely distinct diseases. High-throughput analyses of patient populations have implicated the same copy-number variants . . .
Complex neurologic phenotypes are inherently difficult to diagnose. Whole-exome sequencing (WES) is a new tool in the neurologist's diagnostic armamentarium. Whole-exome sequencing can be applied to ...investigate the "diagnostic odyssey" cases. These cases involve patients with rare diseases that likely have a genetic etiology but have failed to be diagnosed by clinical evaluation and targeted gene testing. We describe such a case, a 22-year-old man who had mild intellectual developmental disability and episodes of jerking ataxic movements that affected his whole body. He underwent numerous multidisciplinary and multicentric evaluations throughout his life that failed to establish a clear diagnosis. Following his visit to Mayo Clinic in Jacksonville, Florida, WES was applied for genetic determination of the unknown disorder in the proband and his biological parents and sister. Additional clinical evaluation, magnetic resonance neuroimaging, electromyography, and electroencephalography of the proband were performed to verify the phenotype after the WES results were available. To our knowledge, this is the first report of the application of WES to facilitate the diagnosis of episodic ataxia type 1. This case illustrates that WES supported by clinical data is a useful and time-saving tool in the evaluation of patients with rare and complex hereditary disorders.
Diagnostic exome sequencing was immediately successful in diagnosing patients in whom traditional technologies were uninformative. Herein, we provide the results from the first 500 probands referred ...to a clinical laboratory for diagnostic exome sequencing.
Family-based exome sequencing included whole-exome sequencing followed by family inheritance-based model filtering, comprehensive medical review, familial cosegregation analysis, and analysis of novel genes.
A positive or likely positive result in a characterized gene was identified in 30% of patients (152/500). A novel gene finding was identified in 7.5% of patients (31/416). The highest diagnostic rates were observed among patients with ataxia, multiple congenital anomalies, and epilepsy (44, 36, and 35%, respectively). Twenty-three percent of positive findings were within genes characterized within the past 2 years. The diagnostic rate was significantly higher among families undergoing a trio (37%) as compared with a singleton (21%) whole-exome testing strategy.
Overall, we present results from the largest clinical cohort of diagnostic exome sequencing cases to date. These data demonstrate the utility of family-based exome sequencing and analysis to obtain the highest reported detection rate in an unselected clinical cohort, illustrating the utility of diagnostic exome sequencing as a transformative technology for the molecular diagnosis of genetic disease.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract Background Exome Sequencing has recently proven to be a successful diagnostic method for complex neurodevelopmental disorders. However, the diagnostic yield of exome sequencing for autism ...spectrum disorders has not been extensively evaluated in large cohorts to date. Materials and Methods We performed diagnostic exome sequencing in a cohort of 163 individuals with autism spectrum disorder (ASD; 66.3%) or autistic features (33.7%). Results The diagnostic yield observed in patients in our cohort was 25.8% (42/163) for positive/likely positive findings in characterized disease genes, while a candidate genetic etiology was reported for an additional 3.3% (4/120) of patients. Among the positive findings in the patients with ASD or autistic features, 61.9% were the result of de novo mutations. Patients presenting with psychiatric conditions or ataxia and/or paraplegia in addition to ASD or autistic features were significantly more likely to receive positive results compared to patients without these clinical features (95.6% vs. 27.1%, p <0.0001 83.3% vs. 21.2%, p <0.0001respectively). The majority of the positive findings were in recently identified ASD genes, supporting the importance of diagnostic exome sequencing for patients with ASD or autistic features as the causative genes might evade traditional sequential or panel testing. Conclusions These results suggest that diagnostic exome sequencing would be an efficient primary diagnostic method for patients with ASDs or autistic features. Moreover, our data may aid clinicians to better determine which subset of patients with ASD with additional clinical features would benefit the most from diagnostic exome sequencing.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Abstract Microdeletions of 1q41q42 have recently been classified as a syndrome. Features include significant developmental delay and characteristic dysmorphic features as well as cleft palate, ...clubfeet, seizures, and short stature in some individuals, with a clinical diagnosis of Fryns syndrome in two individuals with congenital diaphragmatic hernia at the severe end of the spectrum. The gene DISP1 , which is involved in sonic hedgehog signaling, has been proposed as a candidate for the midline defects in this syndrome. We undertook a genotype–phenotype analysis of seven previously unreported individuals with deletions of 1q41q42 that range from 777 kb to 6.87 Mb. Three of the individuals in our cohort do not display the major features of the syndrome and have more proximal deletions that only overlap with the previously described 1q41q42 smallest region of overlap (SRO) at DISP1 . One individual with several features of the syndrome has a more distal deletion that excludes DISP1 . The three remaining individuals have larger deletions that include the entire SRO and demonstrate features of the microdeletion syndrome. Confounding genotype–phenotype correlations, one of the small deletions involving DISP1 was inherited from a phenotypically normal parent. DISP1 haploinsufficiency may not be solely responsible for the major features of 1q41q42 microdeletion syndrome, and other genes in the SRO likely play a role in the phenotype. Additionally, some features present in a minority of individuals, such as Pelger–Huët anomaly, may be attributed to deletions of genes outside of the SRO.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
We report the identification of a recurrent, 520-kb 16p12.1 microdeletion associated with childhood developmental delay. The microdeletion was detected in 20 of 11,873 cases compared with 2 of 8,540 ...controls (P = 0.0009, OR = 7.2) and replicated in a second series of 22 of 9,254 cases compared with 6 of 6,299 controls (P = 0.028, OR = 2.5). Most deletions were inherited, with carrier parents likely to manifest neuropsychiatric phenotypes compared to non-carrier parents (P = 0.037, OR = 6). Probands were more likely to carry an additional large copy-number variant when compared to matched controls (10 of 42 cases, P = 5.7 x 10(-5), OR = 6.6). The clinical features of individuals with two mutations were distinct from and/or more severe than those of individuals carrying only the co-occurring mutation. Our data support a two-hit model in which the 16p12.1 microdeletion both predisposes to neuropsychiatric phenotypes as a single event and exacerbates neurodevelopmental phenotypes in association with other large deletions or duplications. Analysis of other microdeletions with variable expressivity indicates that this two-hit model might be more generally applicable to neuropsychiatric disease.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Diagnostic exome sequencing (DES) is now a commonly ordered test for individuals with undiagnosed genetic disorders. In addition to providing a diagnosis for characterized diseases, exome sequencing ...has the capacity to uncover novel candidate genes for disease.
Family-based DES included analysis of both characterized and novel genetic etiologies. To evaluate candidate genes for disease in the clinical setting, we developed a systematic, rule-based classification schema.
Testing identified a candidate gene among 7.7% (72/934) of patients referred for DES; 37 (4.0%) and 35 (3.7%) of the genes received evidence scores of “candidate” and “suspected candidate,” respectively. A total of 71 independent candidate genes were reported among the 72 patients, and 38% (27/71) were subsequently corroborated in the peer-reviewed literature. This rate of corroboration increased to 51.9% (27/52) among patients whose gene was reported at least 12 months previously.
Herein, we provide transparent, comprehensive, and standardized scoring criteria for the clinical reporting of candidate genes. These results demonstrate that DES is an integral tool for genetic diagnosis, especially for elucidating the molecular basis for both characterized and novel candidate genetic etiologies. Gene discoveries also advance the understanding of normal human biology and more common diseases.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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