Novel Pathogenic Variants in a Cassette Exon of CCM2 in Patients With Cerebral Cavernous Malformations.

Christiane D Much,Matthias Rath,Loay Shoubash,Dariush Skowronek,Ingo Kurth,Henry W S Schroeder,Stefanie Spiegler,Ute Felbor,Agnes Flöel,Felix Von Podewils,Konrad Schwefel,Miriam Elbracht

doi:10.3389/fneur.2019.01219

Christiane D Much, Matthias Rath + Show 10 more

Open Access

https://doi.org/10.3389/fneur.2019.01219

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Abstract

Autosomal dominant cerebral cavernous malformation (CCM) represents a genetic disorder with a high mutation detection rate given that stringent inclusion criteria are used and copy number variation analyses are part of the diagnostic workflow. Pathogenic variants in either CCM1 (KRIT1), CCM2 or CCM3 (PDCD10) can be identified in 87–98% of CCM families with at least two affected individuals. However, the interpretation of novel sequence variants in the 5′-region of CCM2 remains challenging as there are various alternatively spliced transcripts and different transcription start sites. Comprehensive genetic and clinical data of CCM2 patients with variants in cassette exons that are either skipped or included into alternative CCM2 transcripts in the splicing process can significantly facilitate clinical variant interpretation. We here report novel pathogenic CCM2 variants in exon 3 and the adjacent donor splice site, describe the natural history of CCM disease in mutation carriers and provide further evidence for the classification of the amino acids encoded by the nucleotides of this cassette exon as a critical region within CCM2. Finally, we illustrate the advantage of a combined single nucleotide and copy number variation detection approach in NGS-based CCM1/CCM2/CCM3 gene panel analyses which can significantly reduce diagnostic turnaround time.

Highlights

Cerebral cavernous malformations (CCMs; MIM: 116860, 603284, 603285) are mulberry-like vascular lesions that are formed by thin-walled and densely packed endothelial channels [1, 2]
We describe the natural history of CCM disease in mutation carriers and illustrate the advantages of a combined NGS-based single nucleotide variants (SNVs)/copy-number variants (CNVs) detection workflow in CCM1/CCM2/CCM3 gene panel analyses
Thirty-one probands were analyzed for pathogenic CCM1, CCM2, or CCM3 variants by hybridization capture-based target enrichment and generation sequencing and another 2 patients were analyzed by Sanger sequencing as described previously [6]

Summary

Introduction

Cerebral cavernous malformations (CCMs; MIM: 116860, 603284, 603285) are mulberry-like vascular lesions that are formed by thin-walled and densely packed endothelial channels [1, 2]. These low-flow sinusoidal convolutes are characterized by an impaired blood-brain-barrier due to a complex dysfunction of the lining endothelial cells. Surgical resection can be an option for accessible symptomatic CCMs, cavernous lesions that cause epilepsy or for deep CCMs that are either symptomatic or have already led to intracerebral hemorrhage. Treatment of CCM patients with brainstem CCMs is often difficult and the risk of post-operative morbidity and mortality always needs to be critically discussed before the indication for surgical resection is made [4]

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