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Data on the clinical prevalence and spectrum of uniparental disomy (UPD) remain limited. Trio exome sequencing (ES) presents a comprehensive method for detection of UPD alongside sequence and copy-number variant analysis. We analyzed 32,067 ES trios referred for diagnostic testing to create a profile of UPD events and their disease associations. ES single-nucleotide polymorphism (SNP) and copy-number data were used to identify both whole-chromosome and segmental UPD and to categorize whole-chromosome results as isodisomy, heterodisomy, or mixed. Ninety-nine whole-chromosome and 13 segmental UPD events were identified. Of these, 29 were associated with an imprinting disorder, and 16 were associated with a positive test result through homozygous sequence variants. Isodisomy was more commonly observed in large chromosomes along with a higher rate of homozygous pathogenic variants, while heterodisomy was more frequent in chromosomes associated with imprinting or trisomy mosaicism (14, 15, 16, 20, 22). Whole-chromosome UPD was observed in 0.31% of cases, resulting in a diagnostic finding in 0.14%. Only three UPD-positive cases had a diagnostic finding unrelated to the UPD. Thirteen UPD events were identified in cases with prior normal SNP chromosomal microarray results, demonstrating the additional diagnostic value of UPD detection by trio ES.

We report the diagnostic yield of whole-exome sequencing (WES) in 3,040 consecutive cases at a single clinical laboratory. WES was performed for many different clinical indications and included the proband plus two or more family members in 76% of cases. The overall diagnostic yield of WES was 28.8%. The diagnostic yield was 23.6% in proband-only cases and 31.0% when three family members were analyzed. The highest yield was for patients who had disorders involving hearing (55%, N = 11), vision (47%, N = 60), the skeletal muscle system (40%, N = 43), the skeletal system (39%, N = 54), multiple congenital anomalies (36%, N = 729), skin (32%, N = 31), the central nervous system (31%, N = 1,082), and the cardiovascular system (28%, N = 54). Of 2,091 cases in which secondary findings were analyzed for 56 American College of Medical Genetics and Genomics–recommended genes, 6.2% (N = 129) had reportable pathogenic variants. In addition to cases with a definitive diagnosis, in 24.2% of cases a candidate gene was reported that may later be reclassified as being associated with a definitive diagnosis. Our experience with our first 3,040 WES cases suggests that analysis of trios significantly improves the diagnostic yield compared with proband-only testing for genetically heterogeneous disorders and facilitates identification of novel candidate genes.

Purpose Mosaicism probably represents an underreported cause of genetic disorders due to detection challenges during routine molecular diagnostics. The purpose of this study was to evaluate the frequency of mosaicism detected by next-generation sequencing in genes associated with epilepsy-related neurodevelopmental disorders. Methods We conducted a retrospective analysis of 893 probands with epilepsy who had a multigene epilepsy panel or whole-exome sequencing performed in a clinical diagnostic laboratory and were positive for a pathogenic or likely pathogenic variant in one of nine genes ( CDKL5 , GABRA1 , GABRG2 , GRIN2B , KCNQ2 , MECP2 , PCDH19 , SCN1A , or SCN2A ). Parental results were available for 395 of these probands. Results Mosaicism was most common in the CDKL5 , PCDH19 , SCN2A , and SCN1A genes. Mosaicism was observed in GABRA1 , GABRG2 , and GRIN2B , which previously have not been reported to have mosaicism, and also in KCNQ2 and MECP2 . Parental mosaicism was observed for pathogenic variants in multiple genes including KCNQ2 , MECP2 , SCN1A , and SCN2A. Conclusion Mosaic pathogenic variants were identified frequently in nine genes associated with various neurological conditions. Given the potential clinical ramifications, our findings suggest that next-generation sequencing diagnostic methods may be utilized when testing these genes in a diagnostic laboratory.

Purpose Exome sequencing (ES) is increasingly used for the diagnosis of rare genetic disease. However, some pathogenic sequence variants within the exome go undetected due to the technical difficulty of identifying them. Mobile element insertions (MEIs) are a known cause of genetic disease in humans but have been historically difficult to detect via ES and similar targeted sequencing methods. Methods We developed and applied a novel MEI detection method prospectively to samples received for clinical ES beginning in November 2017. Positive MEI findings were confirmed by an orthogonal method and reported back to the ordering provider. In this study, we examined 89,874 samples from 38,871 cases. Results Diagnostic MEIs were present in 0.03% (95% binomial test confidence interval: 0.02–0.06%) of all cases and account for 0.15% (95% binomial test confidence interval: 0.08–0.25%) of cases with a molecular diagnosis. One diagnostic MEI was a novel founder event. Most patients with pathogenic MEIs had prior genetic testing, three of whom had previous negative DNA sequencing analysis of the diagnostic gene. Conclusion MEI detection from ES is a valuable diagnostic tool, reveals molecular findings that may be undetected by other sequencing assays, and increases diagnostic yield by 0.15%.

Purpose: Detection of copy-number variation (CNV) is important for investigating many genetic disorders. Testing a large clinical cohort by array comparative genomic hybridization provides a deep perspective on the spectrum of pathogenic CNV. In this context, we describe a bioinformatics approach to extract CNV information from whole-exome sequencing and demonstrate its utility in clinical testing. Methods: Exon-focused arrays and whole-genome chromosomal microarray analysis were used to test 14,228 and 14,000 individuals, respectively. Based on these results, we developed an algorithm to detect deletions/duplications in whole-exome sequencing data and a novel whole-exome array. Results: In the exon array cohort, we observed a positive detection rate of 2.4% (25 duplications, 318 deletions), of which 39% involved one or two exons. Chromosomal microarray analysis identified 3,345 CNVs affecting single genes (18%). We demonstrate that our whole-exome sequencing algorithm resolves CNVs of three or more exons. Conclusion: These results demonstrate the clinical utility of single-exon resolution in CNV assays. Our whole-exome sequencing algorithm approaches this resolution but is complemented by a whole-exome array to unambiguously identify intragenic CNVs and single-exon changes. These data illustrate the next advancements in CNV analysis through whole-exome sequencing and whole-exome array. Genet Med 17 8, 623–629.

Hexokinase 1 (HK1) phosphorylates glucose to glucose-6-phosphate, the first rate-limiting step in glycolysis. Homozygous and heterozygous variants in HK1 have been shown to cause autosomal recessive non-spherocytic hemolytic anemia, autosomal recessive Russe type hereditary motor and sensory neuropathy, and autosomal dominant retinitis pigmentosa (adRP). We report seven patients from six unrelated families with a neurodevelopmental disorder associated with developmental delay, intellectual disability, structural brain abnormality, and visual impairments in whom we identified four novel, de novo missense variants in the N-terminal half of HK1. Hexokinase activity in red blood cells of two patients was normal, suggesting that the disease mechanism is not due to loss of hexokinase enzymatic activity.

Background Genes in the homologous recombination pathway have shown varying results in the literature regarding ovarian cancer (OC) association. Recent case-control studies have used allele counts alone to quantify genetic associations with cancer. Methods A retrospective case-control study was performed on 6,182 women with OC referred for hereditary cancer multi-gene panel testing (cases) and 4,690 mothers from trios who were referred for whole-exome sequencing (controls). We present age-adjusted odds ratios (OR Adj ) to determine association of OC with pathogenic variants (PVs) in homologous recombination genes. Results Significant associations with OC were observed in BRCA1, BRCA2, RAD51C and RAD51D. Other homologous recombination genes, BARD1, NBN, and PALB2, were not significantly associated with OC. ATM and CHEK2 were only significantly associated with OC by crude odds ratio (OR Crude ) or by OR Adj , respectively. However, there was no significant difference between OR Crude and OR Adj for these two genes. The significant association of PVs in BRIP1 by OR Crude (2.05, CI = 1.11 to 3.94, P  = 0.03) was not observed by OR Adj (0.87, CI = 0.41 to 1.93, P  = 0.73). Interestingly, the confidence intervals of the two effect sizes were significantly different ( P  = 0.04). Conclusion The lack of association of PVs in BRIP1 with OC by OR Adj is inconsistent with some previous literature and current management recommendations, highlighted by the significantly older age of OC onset for BRIP1 PV carriers compared to non-carriers. By reporting OR Adj , this study presents associations that reflect more informed genetic contributions to OC when compared to traditional count-based methods.

The magnetospheric O^sup +^ population in the 52-180 keV range during storms is investigated through the analysis of energetic neutral atom (ENA) images. The images are obtained from the high energy neutral atom (HENA) imager onboard the IMAGE satellite. At each substorm onset following the commencement of a geomagnetic storm the oxygen ENA display 30 min intense bursts. Only very weak corresponding features in the 60-119 keV hydrogen ENA can be occasionally seen. The dominating fraction of the oxygen ENA emissions are produced when O^sup +^ ions mirror/precipitate at low altitudes, where the number density of the neutral atmosphere is high. During the storm we observed several bursts of oxygen ENA, but it is still not clear how much the O^sup +^ content of the ring current increases during the storm main phase. Our observations suggest that the responsible injection mechanism is mass-dependent and scatters the pitch angles. This leads us to favor a non-adiabatic mechanism proposed by (Delcourt, 2002).[PUBLICATION ABSTRACT]

The discovery of the genetic cause of an inflammatory disorder shows that, in winnowing down candidate variants obtained by DNA sequencing screens, geneticists have been (so to speak) throwing the baby out with the bath water.

De novo mutations in protein-coding genes are a well-established cause of developmental disorders 1 . However, genes known to be associated with developmental disorders account for only a minority of the observed excess of such de novo mutations 1 , 2 . Here, to identify previously undescribed genes associated with developmental disorders, we integrate healthcare and research exome-sequence data from 31,058 parent–offspring trios of individuals with developmental disorders, and develop a simulation-based statistical test to identify gene-specific enrichment of de novo mutations. We identified 285 genes that were significantly associated with developmental disorders, including 28 that had not previously been robustly associated with developmental disorders. Although we detected more genes associated with developmental disorders, much of the excess of de novo mutations in protein-coding genes remains unaccounted for. Modelling suggests that more than 1,000 genes associated with developmental disorders have not yet been described, many of which are likely to be less penetrant than the currently known genes. Research access to clinical diagnostic datasets will be critical for completing the map of genes associated with developmental disorders. By integrating healthcare and exome-sequencing data from parent–offspring trios of patients with developmental disorders, 28 genes that had not previously been associated with developmental disorders were identified.