A balanced translocation truncates Neurotrimin in a family with intracranial and thoracic aortic aneurysm.
BACKGROUND
Balanced chromosomal rearrangements occasionally have strong phenotypic effects, which may be useful in understanding pathobiology. However, conventional strategies for characterising breakpoints are laborious and inaccurate. We present here a proband with a thoracic aortic aneurysm (TAA) and a balanced translocation t(10;11) (q23.2;q24.2). Our purpose was to sequence the chromosomal breaks in this family to reveal a novel candidate gene for aneurysm.


RESULTS
Intracranial aneurysm (IA) and TAAs appear to run in the family in an autosomal dominant manner: After exploring the family history, we observed that the proband's two siblings both died from cerebral haemorrhage, and the proband's parent and parent's sibling died from aortic rupture. After application of a genome-wide paired-end DNA sequencing method for breakpoint mapping, we demonstrate that this translocation breaks intron 1 of a splicing isoform of Neurotrimin at 11q25 in a previously implicated candidate region for IAs and AAs (OMIM 612161).


CONCLUSIONS
Our results demonstrate the feasibility of genome-wide paired-end sequencing for the characterisation of balanced rearrangements and identification of candidate genes in patients with potentially disease-associated chromosome rearrangements. The family samples were gathered as a part of our recently launched National Registry of Reciprocal Balanced Translocations and Inversions in Finland (n=2575), and we believe that such a registry will be a powerful resource for the localisation of chromosomal aberrations, which can bring insight into the aetiology of related phenotypes.
Institute for Molecular Medicine Finland FIMM, Helsinki, Finland.
Tiia M
TM
Luukkonen
Minna
M
Pöyhönen
Aarno
A
Palotie
Pekka
P
Ellonen
Sonja
S
Lagström
Joseph H
JH
Lee
Joseph D
JD
Terwilliger
Riitta
R
Salonen
Teppo
T
Varilo
D000199:Actins / Q000235:genetics; D017545:Aortic Aneurysm, Thoracic / Q000150:complications / Q000235:genetics*; D019457:Chromosome Breakage; D002874:Chromosome Mapping; D002879:Chromosomes, Human, Pair 10; D002880:Chromosomes, Human, Pair 11; D056915:DNA Copy Number Variations; D005190:Family; D005387:Finland; D058851:GPI-Linked Proteins / Q000235:genetics; D005787:Gene Frequency; D005799:Genes, Dominant; D005838:Genotype; D006801:Humans; D002532:Intracranial Aneurysm / Q000150:complications / Q000235:genetics*; D007621:Karyotyping; D019006:Neural Cell Adhesion Molecules / Q000235:genetics*; D010375:Pedigree; D010865:Pilot Projects; D012042:Registries; D014178:Translocation, Genetic
C541116:ACTA2 protein, human; D000199:Actins; D058851:GPI-Linked Proteins; D019006:Neural Cell Adhesion Molecules; C092530:neurotrimin