A custom-designed panel sequencing study in 201 Chinese patients with craniosynostosis revealed novel variants and distinct mutation spectra

Wu, Yi; Ma, Peng; Chen, Jieyi; Suo, Jinlong; Zou, Sihai; Xu, Yunfeng; Wilkie, Andrew; Zou, Weiguo; Mu, Xin; Wang, Sijia

doi:10.1016/j.jgg.2020.11.004

Cited by 3 publications

(7 citation statements)

References 19 publications

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“…CRS patients visiting or being referred to Huashan Hospital Fudan University during 2017-2021 were recruited. We initially enrolled 264 patients and their available parents into the study, including the 201 patients enrolled in the previous study (Wu et al, 2021) (Supplementary Figure S1). Doctors collected their clinical information and a mouth swab sample for genetic analysis for all the enrolled subjects.…”

Section: Patient Cohort and Sample Collectionmentioning

confidence: 99%

“…DNA extraction and 17-gene-panel sequencing were the same as the previous study (Wu et al, 2021). For WES, the sequencing library was constructed and subjected to the exome sequence capture using an AIExome V1-CNV kit (iGeneTech, Beijing, China).…”

Section: Dna Extraction and Sequencingmentioning

confidence: 99%

“…Monogenic, polygenic, chromosomal disorders, and environmental factors might cause CRS in children (Twigg and Wilkie, 2015;Flaherty et al, 2016;Poot, 2019). Previous studies performed different sequencing strategies and focused on genetic diagnosis for CRS patient cohorts (Wilkie et al, 2010;Roscioli et al, 2013;Paumard-Hernandez et al, 2015;Ye et al, 2016;Wilkie et al, 2017;Lee et al, 2018;Topa et al, 2020;Yoon et al, 2020;Tonne et al, 2021;Wu et al, 2021). With the development of the next-generation sequencing (NGS), specific sequencing panels were designed for CRS genetic diagnosis.…”

Section: Introductionmentioning

confidence: 99%

“…With the development of the next-generation sequencing (NGS), specific sequencing panels were designed for CRS genetic diagnosis. These panels could achieve 28%-52% diagnostic yield for CRS patients, but the good performance was limited in core CRS genes, such as FGFR2, FGFR3, ERF, TWIST1, TCF12, and EFBN1 (Wilkie et al, 2010;Roscioli et al, 2013;Paumard-Hernandez et al, 2015;Wilkie et al, 2017;Lee et al, 2018;Yoon et al, 2020;Wu et al, 2021). The diagnosis is still complex and ambiguous for a minority of cases.…”

Section: Introductionmentioning

confidence: 99%

“…Therefore, WES is recommended for CRS patients who are difficult to be diagnosed by core genes. Recently, we performed the first genetic research in the Chinese CRS cohort, which sequenced 17 genes known to be associated with CRS, including FGFR2, FGFR3, TWIST1, EFNB1, TCF12, SKI, RAB23, FGFR1, TGFBR2, POR, SMAD3, ERF, TGFBR1, MSX2, RECQL4, TGFB2, IFT43 (Wu et al, 2021). About half of these patients were identified with pathogenic/likely pathogenic (P/LP) variants, including single nucleotide variants (SNVs) and small insertions and deletions (InDels).…”

Section: Introductionmentioning

confidence: 99%

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An additional whole-exome sequencing study in 102 panel-undiagnosed patients: A retrospective study in a Chinese craniosynostosis cohort

Chen

Zhang

et al. 2022

Front. Genet.

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Craniosynostosis (CRS) is a disease with prematurely fused cranial sutures. In the last decade, the whole-exome sequencing (WES) was widely used in Caucasian populations. The WES largely contributed in genetic diagnosis and exploration on new genetic mechanisms of CRS. In this study, we enrolled 264 CRS patients in China. After a 17-gene-panel sequencing designed in the previous study, 139 patients were identified with pathogenic/likely pathogenic (P/LP) variants according to the ACMG guideline as positive genetic diagnosis. WES was then performed on 102 patients with negative genetic diagnosis by panel. Ten P/LP variants were additionally identified in ten patients, increasing the genetic diagnostic yield by 3.8% (10/264). The novel variants in ANKH, H1-4, EIF5A, SOX6, and ARID1B expanded the mutation spectra of CRS. Then we designed a compatible research pipeline (RP) for further exploration. The RP could detect all seven P/LP SNVs and InDels identified above, in addition to 15 candidate variants found in 13 patients with worthy of further study. In sum, the 17-gene panel and WES identified positive genetic diagnosis for 56.4% patients (149/264) in 16 genes. At last, in our estimation, the genetic testing strategy of “Panel-first” saves 24.3% of the cost compared with “WES only”, suggesting the “Panel-first” is an economical strategy.

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Section: Patient Cohort and Sample Collectionmentioning

confidence: 99%

Section: Dna Extraction and Sequencingmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

An additional whole-exome sequencing study in 102 panel-undiagnosed patients: A retrospective study in a Chinese craniosynostosis cohort

Chen

Zhang

et al. 2022

Front. Genet.

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The current understanding of germline predisposition in non-syndromic sagittal craniosynostosis: a systematic review

2022

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Review of Recurrently Mutated Genes in Craniosynostosis Supports Expansion of Diagnostic Gene Panels

Tooze

Calpena

Weber

et al. 2023

Genes

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Craniosynostosis, the premature fusion of the cranial sutures, affects ~1 in 2000 children. Although many patients with a genetically determined cause harbor a variant in one of just seven genes or have a chromosomal abnormality, over 60 genes are known to be recurrently mutated, thus comprising a long tail of rarer diagnoses. Genome sequencing for the diagnosis of rare diseases is increasingly used in clinical settings, but analysis of the data is labor intensive and involves a trade-off between achieving high sensitivity or high precision. PanelApp, a crowd-sourced disease-focused set of gene panels, was designed to enable prioritization of variants in known disease genes for a given pathology, allowing enhanced identification of true-positives. For heterogeneous disorders like craniosynostosis, these panels must be regularly updated to ensure that diagnoses are not being missed. We provide a systematic review of genetic literature on craniosynostosis over the last 5 years, including additional results from resequencing a 42-gene panel in 617 affected individuals. We identify 16 genes (representing a 25% uplift) that should be added to the list of bona fide craniosynostosis disease genes and discuss the insights that these new genes provide into pathophysiological mechanisms of craniosynostosis.

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A custom-designed panel sequencing study in 201 Chinese patients with craniosynostosis revealed novel variants and distinct mutation spectra

Cited by 3 publications

References 19 publications

An additional whole-exome sequencing study in 102 panel-undiagnosed patients: A retrospective study in a Chinese craniosynostosis cohort

An additional whole-exome sequencing study in 102 panel-undiagnosed patients: A retrospective study in a Chinese craniosynostosis cohort

The current understanding of germline predisposition in non-syndromic sagittal craniosynostosis: a systematic review

Review of Recurrently Mutated Genes in Craniosynostosis Supports Expansion of Diagnostic Gene Panels

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