First large genomic inversion in familial cerebral cavernous malformation identified by whole genome sequencing

• Published in: Neurogenetics Vol. 19; no. 1; pp. 55 - 59
• Main Authors: Spiegler, Stefanie, Rath, Matthias, Hoffjan, Sabine, Dammann, Philipp, Sure, Ulrich, Pagenstecher, Axel, Strom, Tim, Felbor, Ute
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.01.2018; Springer Nature B.V
• Subjects: Biomedical and Life Sciences; Biomedicine; Breakpoints; CCM2 protein; Congenital defects; Genomes; Hemorrhage; Human Genetics; Inversion; Molecular Medicine; Mutation; Neurosciences; Quantitative analysis; Ribonucleic acid; RNA; Seizures; Short Communication; Stroke; Whole genome sequencing; Cerebral cavernous malformation; Genomic inversion; CCM2
• ISSN: 1364-6745; 1364-6753
• DOI: 10.1007/s10048-017-0531-7

Familial cerebral cavernous malformations (CCMs) predispose to seizures and hemorrhagic stroke. Molecular genetic analyses of CCM1 , CCM2 , and CCM3 result in a mutation detection rate of up to 98%. However, only whole genome sequencing (WGS) in combination with the Manta algorithm for analyses of structural variants revealed a heterozygous 24 kB inversion including exon 1 of CCM2 in a 12-year-old boy with familial CCMs. Its breakpoints were fine-mapped, and quantitative analysis on RNA confirmed reduced CCM2 expression. Our data expand the spectrum of CCM mutations and indicate that the existence of a fourth CCM disease gene is rather unlikely.