Clinical utility of 24-h rapid trio-exome sequencing for critically ill infants

Wang, Huijun; Qian, Yanyan; Lu, Yulan; Qin, Qian; Li, Guoping; Cheng, Guoqiang; Zhang, Ping; Yang, Lin; Wu, Bingbing; Zhou, Wenhao

doi:10.1038/s41525-020-0129-0

Cited by 48 publications

(44 citation statements)

References 28 publications

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“…Therefore, FGA makes it possible to effectively test probands even when parents/family members are not available for testing. This is useful in intensive care units or in other settings where rapid diagnosis is vital to clinical care 29,30 . Variant phasing or the cis or trans configuration can be critical in the rapid evaluation for clinical significance.…”

Section: Discussionmentioning

confidence: 99%

Application of Full Genome Analysis to Diagnose Rare Monogenic Disorders

Shieh

Penón-Portmann

Wong

et al. 2020

Preprint

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Current genetic tests for rare diseases provide a diagnosis in only a modest proportion of cases. The Full Genome Analysis method, FGA, combines long-range assembly and whole-genome sequencing to detect small variants, structural variants with breakpoint resolution, and phasing. We built a variant prioritization pipeline and tested FGAs utility for diagnosis of rare diseases in a clinical setting. FGA identified structural variants and small variants with an overall diagnostic yield of 40% (20 of 50 cases) and 35% in exome-negative cases (8 of 23 cases), 4 of these were structural variants. FGA detected and mapped structural variants that are missed by short reads, including non-coding duplication, and phased variants across long distances of more than 180kb. With the prioritization algorithm, longer DNA technologies could replace multiple tests for monogenic disorders and expand the range of variants detected. Our study suggests that genomes produced from technologies like FGA can improve variant detection and provide higher resolution genome maps for future application.

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Section: Discussionmentioning

confidence: 99%

Application of Full Genome Analysis to Diagnose Rare Monogenic Disorders

Shieh

Penón-Portmann

Wong

et al. 2020

Preprint

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“…The diagnostic process of CMA plus ES is time-consuming, with a median TAT of 10 (SD 2) days for CMA and 21 (SD 6) days for ES, and a total amount of ~400 ng DNA would be required from limited prenatal samples. However, the GS approach requires a lower amount of fetal DNA (100 ng) and provides a more rapid median TAT of 18 (SD 6) days (Table S6), which is meaningful for such a time-sensitive analysis [36] since it reduces anxiety and stress for families and allows couples to have adequate time for genetic counseling and decision-making.…”

Section: Discussionmentioning

confidence: 99%

Comprehensive genome sequencing analysis as a promising option in the prenatal diagnosis of fetal structural anomalies: a prospective study

Zhou

Yang

et al. 2020

Preprint

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PurposeGenome sequencing (GS) is a powerful tool for postnatal genetic diagnosis, but relevant clinical studies in the field of prenatal diagnosis are few. We aimed to evaluate the feasibility of GS as a first-line approach in prenatal diagnosis and compare its clinical value with the chromosomal microarray analysis (CMA) plus exome sequencing (ES) sequential testing.MethodsWe applied trio GS (∼40-fold) in parallel with CMA plus ES to investigate the genetic basis for structural or growth anomalies in 111 fetuses and compared their results.ResultsGS covered all genetic variants in 22 diagnosed cases detected by CMA plus ES, yielding a diagnostic rate of 19.8% (22/110). Moreover, GS provided more comprehensive and precise genetic information than CMA plus ES, revealing twin fetuses with an imbalanced translocation arising from a balanced paternal translocation and one fetus with an extra pathogenic variant in the GJA8 gene, and incidentally identified intrauterine CMV infection in a growth-restricted fetus.ConclusionCompared with CMA plus ES, GS offers a more comprehensive view of the genetic etiology of fetal anomalies and provides clues for nongenetic factors such as intrauterine infection. Our study demonstrates the feasibility of GS as a promising first-line test in prenatal diagnosis.

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“…Accepted Article [97][98][99]]. Such analysis presents a powerful tool for the interpretation of heterozygous variants in dominant disease genes but also detection of de novo variants and variant phasing.…”

Section: Limitations Of Current Genetic Analysismentioning

confidence: 99%

“…As VUS compose 47% of all reported variants [38], it is clear that additional functional evidence apart from sequence information predicted consequence on a transcript/ protein level, and frequency is needed to annotate variant´s pathogenicity. Trio sequencing, where the index and parents are sequenced simultaneously, has been shown to be more effective than singleton one despite higher costs and longer data analysis [95], and is thus increasingly applied in diagnostics [86,[95][96][97]. Such analysis presents a powerful tool not only for the interpretation of heterozygous variants in dominant disease genes but also for the detection of de novo variants and variant phasing.…”

Section: Limitations Of Current Genetic Analysismentioning

confidence: 99%

Genetic basis of mitochondrial diseases

Gusic

2021

FEBS Letters

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Mitochondrial disorders are monogenic disorders characterized by a defect in oxidative phosphorylation and caused by pathogenic variants in one of over 340 different genes. The implementation of whole exome sequencing has led to a revolution in their diagnosis, duplicated the number of associated disease genes, and significantly increased the diagnosed fraction. However, the genetic etiology of a substantial fraction of patients exhibiting mitochondrial disorders remains unknown, highlighting limitations in variant detection and interpretation, which calls for improved computational and DNA sequencing methods, as well as the addition of OMICS tools. More intriguingly, this also suggests that some pathogenic variants lie outside of the proteincoding genes and that the mechanisms beyond the Mendelian inheritance and the mtDNA are of relevance. This review covers the current status of the genetic basis of mitochondrial diseases, discusses current challenges and perspectives, and explores the contribution of factors beyond the protein-coding regions and monogenic inheritance in the expansion of the genetic spectrum of disease.

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Clinical utility of 24-h rapid trio-exome sequencing for critically ill infants

Cited by 48 publications

References 28 publications

Application of Full Genome Analysis to Diagnose Rare Monogenic Disorders

Application of Full Genome Analysis to Diagnose Rare Monogenic Disorders

Comprehensive genome sequencing analysis as a promising option in the prenatal diagnosis of fetal structural anomalies: a prospective study

Genetic basis of mitochondrial diseases

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