Severe hemophilia A caused by an unbalanced chromosomal rearrangement identified using nanopore sequencing

Chatron, Nicolas; Schluth-Bolard, Caroline; Frétigny, Mathilde; Labalme, Audrey; Vilchez, Gaelle; Castet, Sabine-Marie; Négrier, Claude; Sanlaville, Damien; Vinciguerra, Christine; Jourdy, Yohann

doi:10.1111/jth.14460

Cited by 11 publications

(10 citation statements)

References 19 publications

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“…A similar molecular mechanism occurs for inv1 6,9 . The remaining cases of F8 structural variants result from non‐recurrent molecular mechanisms 10–13 …”

Section: Introductionmentioning

confidence: 69%

Complete characterisation of two new large Xq28 duplications involving F8 using whole genome sequencing in patients without haemophilia A

et al. 2021

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Introduction Depending on the location of insertion of the gained region, F8 duplications can have variable clinical impacts from benign impact to severe haemophilia A phenotype. Aim To characterize two large Xq28 duplications involving F8 incidentally detected by chromosome microarray analysis (CMA) in two patients presenting severe intellectual disability but no history of bleeding disorder. Methods Whole genome sequencing (WGS) was performed in order to characterize the two large Xq28 duplications at nucleotide level. Results In patient 1, a 60–73 kb gained region encompassing the exons 23–26 of F8 and SMIM9 was inserted at the int22h‐2 locus following a non‐homologous recombination between int22h‐1 and int22h‐2. We hypothesized that two independent events, micro‐homology‐mediated break‐induced replication (MMBIR) and break‐induced replication (BIR), could be involved in this rearrangement. In patient 2, the CMA found duplication from 101 to 116‐kb long encompassing the exons 16–26 of F8 and SMIM9. The WGS analysis identified a more complex rearrangement with the presence of three genomic junctions. Due to the multiple micro‐homologies observed at breakpoints, a replication‐based mechanism such as fork stalling and template switching (FoSTeS) was greatly suspected. In both cases, these complex rearrangements preserved an intact copy of the F8. Conclusion This study highlights the value of WGS to characterize the genomic junction at the nucleotide level and ultimately better describe the molecular mechanisms involved in Xq28 structural variations. It also emphasizes the importance of specifying the structure of the genomic gain in order to improve genotype‐phenotype correlation and genetic counselling.

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“…A similar molecular mechanism occurs for inv1 6,9 . The remaining cases of F8 structural variants result from non‐recurrent molecular mechanisms 10–13 …”

Section: Introductionmentioning

confidence: 69%

Complete characterisation of two new large Xq28 duplications involving F8 using whole genome sequencing in patients without haemophilia A

et al. 2021

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“…For example, ONT sequencing of human genomes revealed that an expansion of tandem repeats in the ABCA7 gene was associated with an increased risk of Alzheimer's disease 207 . ONT sequencing was also used to discover a new 3.8-Mb duplication in the intronic region of the F8 gene in an individual with hemophilia A 208 . Other examples cover a large range of diseases and conditions, including autism spectrum disorder 209 , Temple syndrome 210 , congenital abnormalities 112 , glycogen storage disease type Ia (ref.…”

Section: Identifying Large Svsmentioning

confidence: 99%

Nanopore sequencing technology, bioinformatics and applications

et al. 2021

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“…Long-read sequencing is becoming increasingly used in clinical research 58 . Advantages over short-read methods have been noted for applications such as identifying SVs 28,59 , resolving complex SVs 29 , phasing alleles 60 , sequencing repetitive or highly homologous regions 61 and inferring methylation state 30 . The fast turn-around time of Nanopore sequencing in particular has already led to the development of rapid diagnostic assays for specific cancers 30,31 .…”

Section: Discussionmentioning

confidence: 99%

Short and long-read genome sequencing methodologies for somatic variant detection; genomic analysis of a patient with diffuse large B-cell lymphoma

Roberts

Lopopolo

Pagnamenta

et al. 2020

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Recent advances in throughput and accuracy mean that the Oxford Nanopore Technologies (ONT) PromethION platform is a now a viable solution for genome sequencing. Much of the validation of bioinformatic tools for this long-read data has focussed on calling germline variants (including structural variants). Somatic variants are outnumbered many-fold by germline variants and their detection is further complicated by the effects of tumour purity/subclonality. Here, we evaluate the extent to which Nanopore sequencing enables genome-wide detection and analysis of somatic variation. We do this through sequencing tumour and germline genomes for a patient with diffuse B-cell lymphoma and comparing results with 150bp short-read sequencing of the same samples. Calling germline single nucleotide variants (SNVs) from the long-read data achieved good specificity and sensitivity.However, results of somatic SNV calling highlight the need for the development of specialized joint calling algorithms. We find the comparative performance of different tools varies significantly between structural variant types, and suggest long reads are especially advantageous for calling large somatic deletions and duplications. Finally, we highlight the utility of long reads for phasing clinically relevant variants, confirming that a somatic 1.6Mb deletion and a p.(Arg249Met) mutation involving TP53 are oriented in trans.

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Severe hemophilia A caused by an unbalanced chromosomal rearrangement identified using nanopore sequencing

Cited by 11 publications

References 19 publications

Complete characterisation of two new large Xq28 duplications involving F8 using whole genome sequencing in patients without haemophilia A

Complete characterisation of two new large Xq28 duplications involving F8 using whole genome sequencing in patients without haemophilia A

Nanopore sequencing technology, bioinformatics and applications

Short and long-read genome sequencing methodologies for somatic variant detection; genomic analysis of a patient with diffuse large B-cell lymphoma

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