Article Type: Short Communication
Title: First large genomic inversion in familial cerebral cavernous malformation identified by whole genome sequencing
Authors: Stefanie Spiegler1, Matthias Rath1, Sabine Hoffjan2, Philipp Dammann3, Ulrich Sure3, Axel Pagenstecher4, Tim Strom5,6, Ute Felbor1
Author Affiliations:
1Department of Human Genetics, University Medicine Greifswald, and Interfaculty Institute of Genetics and Functional Genomics, University of Greifswald, 17475 Greifswald, Germany
2Department of Human Genetics, Ruhr-University, 44801 Bochum, Germany
3Department of Neurosurgery, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany
4Department of Neuropathology, University Hospital Giessen and Marburg, 35043 Marburg, Germany
5Institute of Human Genetics, TechnischeUniversitätMünchen, 81675 Munich, Germany
6Institute of Human Genetics, Helmholtz ZentrumMünchen, 85764 Neuherberg, Germany
Corresponding Author:
Prof. Dr. Ute Felbor, MD
E-mail:
Phone: +49-3834-86-5371
Fax: +49-3834-86-5369
Online Resource
Supplementary Fig.S17 Tesla Susceptibility weighted imaging (SWI) of I:2. Axial slices (a-c) and mIP reconstruction (d) showing multiple spot-like CCM lesions distributed all over the brain involving supra- and infratentorial regions. Acute hemorrhage was found in one pontine lesion showing a large blooming artefact (narrow arrow c). Normal underlying venous angioarchitecture(d) without associated developmental venous anomaly
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Supplementary Tab.S1: Updated evaluation of the CCM1 missense change c.313G>C; p.(Gly105Arg) [LRG_650t1] according to the consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology [1].Despite its absence from controls and computational evidence for probable deleteriousness, it was classified as variant of uncertain significance
SIFT / PolyPhen-2HumVar / Mutation Taster / CADD / PhyloP / GnomAD / Segregation / ACMG-AMP 2015 classification
damaging
(0.01) / probably damaging
(0.998) / disease causing
(0.999) / score= 26.7 / score= 2.59 / not detected / lack of segregation in II:2; II:4 and I:2 / uncertain significance (contradictory criteria for benign and pathogenic*)
*PM2 + PP3 + PP4 and BS4 + BP1 + BP5.
Supplementary Tab. S2: Variants located in or near to CCM2 exon 1 [LRG_664t2] that are listed in the Human Gene Mutation Database as disease-causing (HGMD 2017.2).
n.d. = not detected; n.s. = not specified; § = reported in two or more CCM families; *additional clinical information from the cohort of Spiegler et al. 2014 that has not been published yet; #classification according to the consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology [1]; the PVS1 criterion was not assigned for all variants as the function of alternative CCM2 transcripts is yet unknown. Since information on functional studies are not available for the first three variants, PS3 criterion was not assigned for these variants and they were classified as likely pathogenic (two moderate and more than two supporting criteria according to the ACMG-AMP 2015 classification)
Nucleotide change(LRG_664t2) / Molecularmechanism / GnomAD / Reference / Presentation as described in the literature / Ethnicity / Symptoms / ACMG-AMP classification#
c.1-36_4 / mutation of the initiation codon / n.d. / [2] / isolated / Caucasian* / CCM-hemorrhage with hemiparesis and aphasia* / likely pathogenic
c.1A>G / mutation of the initiation codon / n.d. / [3] / familial / n.s. / n.s. / likely pathogenic
c.23delG / frameshift mutation / n.d. / [4] / familial / n.s. / strokeandseizures / likelypathogenic
c.30G>A / splicemutation / n.d. / [4]
[5]
[2]§ / isolated
n.s.
familial; isolated / n.s.
n.s.
Caucasian* / n.s.
n.s.
CCM-hemorrhage and unsteady gait* / pathogenic
c.30+1G>A / splicemutation / n.d. / [6]
[7,8] / familial
familial / n.s.
Spanish* / n.s.
CCM-hemorrhage with an acute obstructive hydrocephalus* / pathogenic
c.30+5G>A / splicemutation / n.d. / [5]§ / n.s. / n.s. / n.s. / pathogenic
c.30+5_30+6delinsTT / splicemutation / n.d. / [9]§
[5] / familial
n.s. / AshkenaziJewish
n.s. / n.s.
n.s. / pathogenic
Deletionofexon 1 / deletion / - / [3]§
[4] / familial
familial / n.s.
Non-Hispanic American / n.s.
n.s. / pathogenic
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