Whole-genome sequencing as a first-tier diagnostic framework for rare genetic diseases

Nisar, Haseeb; Wajid, Bilal; Shahid, Salman; Anwar, Faria; Wajid, Imran; Khatoon, Asia; Sattar, Mian Usman; Sadaf, Saima

doi:10.1177/15353702211040046

Cited by 21 publications

(13 citation statements)

References 69 publications

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“…The yield of WGS in an unscreened population is likely to be higher compared with that demonstrated by this review, and inclusion of diagnoses secondary to aneuploidy, unbalanced structural variants, loss of heterozygosity and CNV > 100 kb, all of which are detectable on WGS, would likely increase the yield over ES 11 . This and the fact that WGS requires less DNA and potentially shorter TAT justify its laboratory use and potential cost-effectiveness over and above stepwise testing 15,51,52 . In addition, the wet laboratory process of WGS is more rapid and comprehensive than that of ES.…”

Section: Discussionmentioning

confidence: 99%

“…Whole-genome sequencing (WGS) allows assessment of the entire genome and theoretically should offer additional diagnostic capability due to its ability to capture information such as pathogenic copy number variants (CNV) with greater resolution compared with that of CMA, as well as intronic variants, repeat expansions, structural DNA alterations and mitochondrial disorders [9][10][11] . Additionally, it is potentially less affected by GC-rich regions and offers more uniform coverage, requiring an overall lower quantity of DNA compared with the sequential QF-PCR/CMA and ES approach [12][13][14][15] . However, despite its increasingly competitive costs, there remain concerns related to the cost-effectiveness of WGS and postsequencing interpretation of findings 16,17 .…”

Section: Introductionmentioning

confidence: 99%

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Incremental yield of whole‐genome sequencing over chromosomal microarray analysis and exome sequencing for congenital anomalies in prenatal period and infancy: systematic review and meta‐analysis

Shreeve,

Sproule,

Choy

et al. 2024

Ultrasound in Obstet & Gyne

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ObjectivePrimarily to determine the incremental yield of Whole Genome Sequencing (WGS) over Chromosome Microarray Assessment (CMA) and/or Exome Sequencing (ES) in fetuses and infants with a congenital anomaly that was or could have been detectable on ultrasound prenatally. Secondly, to evaluate the turnaround time (TAT) and quantity of DNA required for testing using these pathways.MethodsOVID MEDLINE(R), EMBASE, Medline (Web of Science), Cochrane Library, and ClinicalTrials.gov databases were searched electronically (January 2010 to December 2022). Inclusion criteria were cohort studies including fetuses/infants with ≥n=3 cases of: (i) one or more congenital anomalies; (ii) an anomaly which was or would have been detectable on prenatal ultrasound and; (iii) exclusion of aneuploidy and pathogenic Copy Number Variants >50kb. Pooled incremental yield was determined using a random‐effects model and heterogeneity was assessed statistically using Higgins’ I2. Sub‐analyses were performed based on pre‐ or postnatal presentation, multi‐system anomalies and classification based upon NHS England prenatal (R21) ES inclusion criteria. PROSPERO 2022 CRD42022380483ResultsEighteen studies incorporating n=1284 cases were included, of which n=8 (44.4%) incorporating n=754 (58.7%) cases were prenatal cohorts and the remainder representing postmortem (postnatal evaluation), neonatal or infants with congenital structural anomalies. The incremental yield of WGS over QF‐PCR/CMA was 26% (95% CI 18‐36%, I2=86%), 16% (9‐24%, I2=85%) and 39% (95%CI 27‐51%, I2=53%) for all, prenatal and postnatal cases. The incremental yields were optimal where sequencing was performed in line with NHS England prenatal ES criteria; 32% (22%‐42%, I2=70%). The incremental yield of Variants of Uncertain Significance (VUS) was 18% (95% CI 7‐33%, I2=74%). The yield of WGS over ES was non‐significant at 1% (95% CI 0%‐4%, I2=47%). The pooled median TAT for WGS was 18 days (range: 1‐912 days) and the quantity of DNA required for WGS versus CMA and ES was 100ng (±0) and 350ng (±50) p=0.03 respectively.ConclusionWhilst WGS investigation for congenital anomaly holds great promise, for the future, its’ incremental yield over ES is yet to be demonstrated. However, the laboratory pathway for WGS (compared to sequential QF‐PCR/CMA/ES) requires less DNA with a potentially faster TAT. There was a relatively high rate of VUS.This article is protected by copyright. All rights reserved.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Incremental yield of whole‐genome sequencing over chromosomal microarray analysis and exome sequencing for congenital anomalies in prenatal period and infancy: systematic review and meta‐analysis

Shreeve,

Sproule,

Choy

et al. 2024

Ultrasound in Obstet & Gyne

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“…In addition to the Whole Exome Sequencing (WES) there is the possibility of Whole Genome Sequencing (WGS) ( Belkadi et al, 2015 ; Lappalainen et al, 2019 ; Wise et al, 2019 ; Prokop et al, 2018 ; Hou et al ., 2020; Amarasinghe et al, 2020 ; Nisar et al, 2021 ).…”

Section: Next Generation Sequencingmentioning

confidence: 99%

Clinical genomics and precision medicine

Pena

Tarazona‐Santos

2022

Genet. Mol. Biol.

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Precision Medicine emerges from the genomic paradigm of health and disease. For precise molecular diagnoses of genetic diseases, we must analyze the Whole Exome (WES) or the Whole Genome (WGS). By not needing exon capture, WGS is more powerful to detect single nucleotide variants and copy number variants. In healthy individuals, we can observe monogenic highly penetrant variants, which may be causally responsible for diseases, and also susceptibility variants, associated with common polygenic diseases. But there is the major problem of penetrance. Thus, there is the question of whether it is worthwhile to perform WGS in all healthy individuals as a step towards Precision Medicine. The genetic architecture of disease is consistent with the fact that they are all polygenic. Moreover, ancestry adds another layer of complexity. We are now capable of obtaining Polygenic Risk Scores for all complex diseases using only data from new generation sequencing. Yet, review of available evidence does not at present favor the idea that WGS analyses are sufficiently developed to allow reliable predictions of the risk components for monogenic and polygenic hereditary diseases in healthy individuals. Probably, it is still better for WGS to remain reserved for the diagnosis of pathogenic variants of Mendelian diseases.

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“…There are about 7000 rare diseases with genetic causes, leading to nearly 80% of all cases usually with misrepresented symptoms leading to incorrect diagnosis [13]. Whole-exome sequencing (WES) contains an estimated 85% of heritable Mendelian disease-causing mutations [14], yielding a diagnosis of the underlying genetic cause in 25-35% of children with an unexplained presumed genetic disorder or fetal structural anomalies [15].…”

Section: Genetic Manifestationsmentioning

confidence: 99%

Genetic manifestations and phenotype spectrum of feeding difficulty of unknown etiology: a hospital-based cohort study

Han

Shi

Yuan

et al. 2022

Preprint

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Background Feeding difficulties of unknown etiology are often combined with multiple system disorders caused by rare genetic diseases that are difficult to diagnose only based on clinical manifestations. In this study, we aimed to investigate the genetic causes of feeding difficulty of unknown etiology. Methods Patients during 2018-10 to 2022-5 diagnosed with feeding difficulty at our institution were enrolled in this cohort study. WES was performed for patients included with feeding difficulty of unknown etiology. Clinical phenotype and genetic results of those infants were analyzed. Results Of a total of 28 infants included in this study, 12(42.9%) cases were complicated with multiple malformations. 25(89.3%) patients had positive findings in WES, 14(50%) patients were genetically diagnosed and 8(28.6%) patients were suspected diagnosed. Conclusions Feeding difficulty might be part of the phenotype spectrum of rare genetic diseases. We recommend WES for patients with feeding difficulty of unknown etiology.

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Whole-genome sequencing as a first-tier diagnostic framework for rare genetic diseases

Cited by 21 publications

References 69 publications

Incremental yield of whole‐genome sequencing over chromosomal microarray analysis and exome sequencing for congenital anomalies in prenatal period and infancy: systematic review and meta‐analysis

Incremental yield of whole‐genome sequencing over chromosomal microarray analysis and exome sequencing for congenital anomalies in prenatal period and infancy: systematic review and meta‐analysis

Clinical genomics and precision medicine

Genetic manifestations and phenotype spectrum of feeding difficulty of unknown etiology: a hospital-based cohort study

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