Expanding the phenome and variome of the ROBO-SLIT pathway in congenital heart defects: toward improving the genetic testing yield of CHD

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Abstract

Background

Recent studies have shown the implication of the ROBO-SLIT pathway in heart development. Within this study, we aimed to further assess the implication of the ROBO and SLIT genes mainly in bicuspid aortic valve (BAV) and other human congenital heart defects (CHD).

Methods

We have analyzed a cohort of singleton exome sequencing data comprising 40 adult BAV patients, 20 pediatric BAV patients generated by the Pediatric Cardiac Genomics Consortium, 10 pediatric cases with tetralogy of Fallot (ToF), and one case with coarctation of the aorta. A gene-centered analysis of data was performed. To further advance the interpretation of the variants, we intended to combine more than 5 prediction tools comprising the assessment of protein structure and stability.

Results

A total of 24 variants were identified. Only 4 adult BAV patients (10%) had missense variants in the ROBO and SLIT genes. In contrast, 19 pediatric cases carried variants in ROBO or SLIT genes (61%). Three BAV patients with a severe phenotype were digenic. Segregation analysis was possible for two BAV patients. For the homozygous ROBO4: p.(Arg776Cys) variant, family segregation was consistent with an autosomal recessive pattern of inheritance. The ROBO4: c.3001 + 3G > A variant segregates with the affected family members. Interestingly, these variants were also found in two unrelated patients with ToF highlighting that the same variant in the ROBO4 gene may underlie different cardiac phenotypes affecting the outflow tract development.

Conclusion

Our results further reinforce the implication of the ROBO4 gene not only in BAV but also in ToF hence the importance of its inclusion in clinical genetic testing. The remaining ROBO and SLIT genes may be screened in patients with negative or inconclusive genetic tests.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12967-023-03994-y.

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ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data

Kai Wang, Mingyao Li, Hakon Hakonarson (2010)

High-throughput sequencing platforms are generating massive amounts of genetic variation data for diverse genomes, but it remains a challenge to pinpoint a small subset of functionally important variants. To fill these unmet needs, we developed the ANNOVAR tool to annotate single nucleotide variants (SNVs) and insertions/deletions, such as examining their functional consequence on genes, inferring cytogenetic bands, reporting functional importance scores, finding variants in conserved regions, or identifying variants reported in the 1000 Genomes Project and dbSNP. ANNOVAR can utilize annotation databases from the UCSC Genome Browser or any annotation data set conforming to Generic Feature Format version 3 (GFF3). We also illustrate a ‘variants reduction’ protocol on 4.7 million SNVs and indels from a human genome, including two causal mutations for Miller syndrome, a rare recessive disease. Through a stepwise procedure, we excluded variants that are unlikely to be causal, and identified 20 candidate genes including the causal gene. Using a desktop computer, ANNOVAR requires ∼4 min to perform gene-based annotation and ∼15 min to perform variants reduction on 4.7 million variants, making it practical to handle hundreds of human genomes in a day. ANNOVAR is freely available at http://www.openbioinformatics.org/annovar/ .

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Fast and accurate long-read alignment with Burrows–Wheeler transform

Heng Li, Richard Durbin (2010)

Motivation: Many programs for aligning short sequencing reads to a reference genome have been developed in the last 2 years. Most of them are very efficient for short reads but inefficient or not applicable for reads >200 bp because the algorithms are heavily and specifically tuned for short queries with low sequencing error rate. However, some sequencing platforms already produce longer reads and others are expected to become available soon. For longer reads, hashing-based software such as BLAT and SSAHA2 remain the only choices. Nonetheless, these methods are substantially slower than short-read aligners in terms of aligned bases per unit time. Results: We designed and implemented a new algorithm, Burrows-Wheeler Aligner's Smith-Waterman Alignment (BWA-SW), to align long sequences up to 1 Mb against a large sequence database (e.g. the human genome) with a few gigabytes of memory. The algorithm is as accurate as SSAHA2, more accurate than BLAT, and is several to tens of times faster than both. Availability: http://bio-bwa.sourceforge.net Contact: rd@sanger.ac.uk

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From FastQ data to high confidence variant calls: the Genome Analysis Toolkit best practices pipeline.

Geraldine Auwera, Mauricio Carneiro, Christopher Hartl … (2013)

This unit describes how to use BWA and the Genome Analysis Toolkit (GATK) to map genome sequencing data to a reference and produce high-quality variant calls that can be used in downstream analyses. The complete workflow includes the core NGS data processing steps that are necessary to make the raw data suitable for analysis by the GATK, as well as the key methods involved in variant discovery using the GATK.

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Author and article information

Contributors

Stéphane Zaffran:

ORCID: http://orcid.org/0000-0002-0811-418X

stephane.zaffran@univ-amu.fr

Journal

Journal ID (nlm-ta): J Transl Med

Journal ID (iso-abbrev): J Transl Med

Title: Journal of Translational Medicine

Publisher: BioMed Central (London )

ISSN (Electronic): 1479-5876

Publication date (Electronic): 28 February 2023

Publication date PMC-release: 28 February 2023

Publication date Collection: 2023

Volume: 21

Electronic Location Identifier: 160

Affiliations

[1 ]GRID grid.5399.6, ISNI 0000 0001 2176 4817, Marseille Medical Genetics (MMG) U1251, , Aix Marseille Université, INSERM, ; 13005 Marseille, France

[2 ]GRID grid.121334.6, ISNI 0000 0001 2097 0141, Institute of Functional Genomics (IGF), , University of Montpellier, CNRS, INSERM, LabEx ICST, ; Montpellier, France

[3 ]GRID grid.412134.1, ISNI 0000 0004 0593 9113, Service de Cardiologie Congénitale Et Pédiatrique, Centre de Référence Malformations Cardiaques Congénitales Complexes - M3C, , Hôpital Necker-Enfants Malades, APHP and Université Paris Cité, ; Paris, France

[4 ]GRID grid.411266.6, ISNI 0000 0001 0404 1115, Department of Cardiac Surgery, , La Timone Hospital, AP-HM, ; Marseille, France

[5 ]GRID grid.411266.6, ISNI 0000 0001 0404 1115, Department of Cardiology, , La Timone Hospital, AP-HM, ; Marseille, France

[6 ]GRID grid.414336.7, ISNI 0000 0001 0407 1584, Department of Pediatric Cardiology, , Timone Enfant Hospital, AP-HM, ; Marseille, France

Author information

Stéphane Zaffran http://orcid.org/0000-0002-0811-418X

Article

Publisher ID: 3994

DOI: 10.1186/s12967-023-03994-y

PMC ID: 9976407

PubMed ID: 36855159

SO-VID: a6cb6f45-2505-4a07-96eb-d9b0ccc46916

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 15 December 2022

Date accepted : 15 February 2023

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ScienceOpen disciplines: Medicine

Keywords: congenital heart defects,robo-slit pathway,genetics,exome sequencing

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ScienceOpen disciplines: Medicine

Keywords: congenital heart defects, robo-slit pathway, genetics, exome sequencing

Expanding the phenome and variome of the ROBO-SLIT pathway in congenital heart defects: toward improving the genetic testing yield of CHD

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Supplementary Information

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Network Medicine

Most cited references 44

ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data

Fast and accurate long-read alignment with Burrows–Wheeler transform

From FastQ data to high confidence variant calls: the Genome Analysis Toolkit best practices pipeline.

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