A toolkit for genetics providers in follow‐up of patients with non‐diagnostic exome sequencing

Zastrow, Diane B.; Kohler, Jennefer N.; Bonner, Devon; Reuter, Chloe; Fernández, Liliana; Grove, Megan E.; Fisk, Dianna G.; Yang, Yaping; Eng, Christine M.; Ward, Patricia A.; Bick, David; Worthey, Elizabeth A.; Fisher, Paul G.; Ashley, Euan A.; Bernstein, Jonathan A.; Wheeler, Matthew T.

doi:10.1002/jgc4.1119

Cited by 12 publications

(9 citation statements)

References 63 publications

(86 reference statements)

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“…This presents a challenge for parents when making decisions, particularly in Cases 53–56, in which one of the compound heterozygous variations was classified as VUS. Therefore, conducting long‐term postpartum follow‐up, postmortem fetal autopsy and gene functional research can provide valuable information for confirming the clinical diagnosis and tracking phenotypical clues 37 , which are crucial for accurately identifying and interpreting genetic variations.…”

Section: Discussionmentioning

confidence: 99%

Prenatal exome sequencing analysis in fetuses with central nervous system anomalies

Zhi

Liu

Wang

et al. 2023

Ultrasound in Obstet & Gyne

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ObjectiveTo evaluate the utility of prenatal exome sequencing (pES) in fetuses with central nervous system (CNS) abnormalities.MethodsThe parents of fetuses identified with CNS abnormalities were considered as potential participants for this retrospective cohort study. After performing chromosomal microarray (CMA), fetuses with confirmed aneuploidy or causal pathogenic copy number variants (CNVs) were excluded from the pES analyses.ResultsOf the 167 pregnancies included in the study, 42 (25.1%) were identified to have pathogenic or likely pathogenic (P/LP) variants. The diagnostic rate was significantly higher in fetuses with non‐isolated CNS abnormalities than in those with single CNS abnormalities (20/56, 35.7% vs. 8/55, 14.5%, P = 0.010). Moreover, when a fetus combined with three or more brain abnormalities, the positive diagnostic rate increased to 42.9%. Among the 42 positive cases, de novo mutations were the primary factors (25/42, 59.5%), the remaining cases were inherited and carried a significant risk of recurrence. Patients with P/LP mutations in their fetuses were more likely to choose advanced pregnancy termination than those with VUS or negative pES results (83.3% vs. 41.3%, P < 0.001).ConclusionpES significantly improved the identification of genetic disorders in fetuses with CNS anomalies without chromosomal abnormalities or P/LP CNVs, regardless of whether the fetal anomalies are isolated or not, and it can significantly impact parents’ decision‐making.This article is protected by copyright. All rights reserved.

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Section: Discussionmentioning

confidence: 99%

Prenatal exome sequencing analysis in fetuses with central nervous system anomalies

Zhi

Liu

Wang

et al. 2023

Ultrasound in Obstet & Gyne

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“…The uncertainty of the VUSes identified in the fetuses can result in significant anxiety and make decision making challenging for the parents. Effective resolution strategies include family segregation analysis, confirmatory clinical test / tracing phenotypic clues, case matching by genotype, and functional validation [39]. Family segregation analysis is the most convenient to carry out in clinical practice; however, it is not helpful for the de novo VUS, comprising 29.8% (39/131) of inconclusive results in prenatal cases.…”

Section: Discussionmentioning

confidence: 99%

Application of exome sequencing for prenatal diagnosis of fetal structural anomalies: clinical experience and lessons learned from a cohort of 1618 fetuses

et al. 2022

Genome Med

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Background Exome sequencing (ES) is becoming more widely available in prenatal diagnosis. However, data on its clinical utility and integration into clinical management remain limited in practice. Herein, we report our experience implementing prenatal ES (pES) in a large cohort of fetuses with anomalies detected by ultrasonography using a hospital-based in-house multidisciplinary team (MDT) facilitated by a three-step genotype-driven followed by phenotype-driven analysis framework. Methods We performed pES in 1618 fetal cases with positive ultrasound findings but negative for karyotyping and chromosome microarray analysis between January 2014 and October 2021, including both retrospective (n=565) and prospective (n=1053) cohorts. The diagnostic efficiency and its correlation to organ systems involved, phenotypic spectrum, and the clinical impacts of pES results on pregnancy outcomes were analyzed. Results A genotype-driven followed by phenotype-driven three-step approach was carried out in all trio pES. Step 1, a genotype-driven analysis resulted in a diagnostic rate of 11.6% (187/1618). Step 2, a phenotype-driven comprehensive analysis yielded additional diagnostic findings for another 28 cases (1.7%; 28/1618). In the final step 3, data reanalyses based on new phenotypes and/or clinical requests found molecular diagnosis in 14 additional cases (0.9%; 14/1618). Altogether, 229 fetal cases (14.2%) received a molecular diagnosis, with a higher positive rate in the retrospective than the prospective cohort (17.3% vs. 12.4%, p<0.01). The diagnostic rates were highest in fetuses with skeletal anomalies (30.4%) and multiple organ involvements (25.9%), and lowest in fetuses with chest anomalies (0%). In addition, incidental and secondary findings with childhood-onset disorders were detected in 11 (0.7%) cases. Furthermore, we described the prenatal phenotypes for the first time for 27 gene-associated conditions (20.0%, 27/135) upon a systematic analysis of the diagnosed cases and expanded the phenotype spectrum for 26 (19.3%) genes where limited fetal phenotypic information was available. In the prospective cohort, the combined prenatal ultrasound and pES results had significantly impacted the clinical decisions (61.5%, 648/1053). Conclusions The genotype-driven approach could identify about 81.7% positive cases (11.6% of the total cohort) with the initial limited fetal phenotype information considered. The following two steps of phenotype-driven analysis and data reanalyses helped us find the causative variants in an additional 2.6% of the entire cohort (18.3% of all positive findings). Our extensive phenotype analysis on a large number of molecularly confirmed prenatal cases had greatly enriched our current knowledge on fetal phenotype-genotype correlation, which may guide more focused prenatal ultrasound in the future. This is by far the largest pES cohort study that combines a robust trio sequence data analysis, systematic phenotype-genotype correlation, and well-established MDT in a single prenatal clinical setting. This work underlines the value of pES as an essential component in prenatal diagnosis in guiding medical management and parental decision making.

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“…Innovative analysis of genomic data and collaborative investigations to advance genomic science : When feasible, pre-existing raw sequence data (FASTQ/BAM) from prior non-diagnostic ESs were reanalyzed through research pipelines at the clinical sites. 28 , 35 A non-diagnostic ES was operationalized as one in which there were no variants, or a single heterozygous variant was found in genes for autosomal recessive conditions, or VUSs in novel candidate or known disease-associated genes that could not be resolved further. For others, new ES or GS was performed at the UDN sequencing core laboratory, with dual analysis of the data by the core and the clinical sites.…”

Section: Methodsmentioning

confidence: 99%

Clinical sites of the Undiagnosed Diseases Network: unique contributions to genomic medicine and science

Schoch

Esteves

Bican

et al. 2021

Genetics in Medicine

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Purpose: The NIH Undiagnosed Diseases Network (UDN) evaluates participants with disorders that have defied diagnosis, applying personalized clinical and genomic evaluations and innovative research. The clinical sites of the UDN are essential to advancing the UDN mission; this study assesses their contributions relative to standard clinical practices. Methods: We analyzed retrospective data from four UDN clinical sites, from July 2015-September 2019, for diagnoses, new disease gene discoveries and the underlying investigative methods. Results: Of 791 evaluated individuals, 231 received 240 diagnoses and 17 new disease-gene associations were recognized. Straightforward diagnoses on UDN exome and genome sequencing occurred in 35% (84/240). We considered these tractable in standard clinical practice, although genome sequencing is not yet widely available clinically. The majority (156/240, 65%) required additional UDN-driven investigations, including 90 diagnoses that occurred after prior non-diagnostic exome sequencing and 45 diagnoses (19%) that were non-genetic. The UDN-driven investigations included complementary/supplementary phenotyping, innovative analyses of genomic variants and collaborative science for functional assays and animal modeling. Conclusion: Investigations driven by the clinical sites identified diagnostic and research paradigms that surpass standard diagnostic processes. The new diagnoses, disease gene discoveries and delineation of novel disorders represent a model for genomic medicine and science.

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A toolkit for genetics providers in follow‐up of patients with non‐diagnostic exome sequencing

Cited by 12 publications

References 63 publications

Prenatal exome sequencing analysis in fetuses with central nervous system anomalies

Prenatal exome sequencing analysis in fetuses with central nervous system anomalies

Application of exome sequencing for prenatal diagnosis of fetal structural anomalies: clinical experience and lessons learned from a cohort of 1618 fetuses

Clinical sites of the Undiagnosed Diseases Network: unique contributions to genomic medicine and science

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