CELSR2 is a candidate susceptibility gene in idiopathic scoliosis

A Swedish pedigree with an autosomal dominant inheritance of idiopathic scoliosis was initially studied by genetic linkage analysis, prioritising genomic regions for further analysis. This revealed a locus on chromosome 1 with a putative risk haplotype shared by all affected individuals. Two affected individuals were subsequently exome-sequenced, identifying a rare, non-synonymous variant in the CELSR2 gene. This variant is rs141489111, a c. G6859A change in exon 21 (NM_001408), leading to a predicted p. V2287I (NP_001399.1) change. This variant was found in all affected members of the pedigree, but showed reduced penetrance. Analysis of tagging variants in CELSR1-3 in a set of 1739 Swedish-Danish scoliosis cases and 1812 controls revealed significant association (p = 0.0001) to rs2281894, a common synonymous variant in CELSR2. This association was not replicated in case-control cohorts from Japan and the US. No association was found to variants in CELSR1 or CELSR3. Our findings suggest a rare variant in CELSR2 as causative for idiopathic scoliosis in a family with dominant segregation and further highlight common variation in CELSR2 in general susceptibility to idiopathic scoliosis in the Swedish-Danish population. Both variants are located in the highly conserved GAIN protein domain, which is necessary for the auto-proteolysis of CELSR2, suggesting its functional importance.Peer reviewe

Survival After Out-of-Hospital Cardiac Arrest in Relation to Age and Early Identification of Patients With Minimal Chance of Long-Term Survival

Background— Survival after out-of-hospital cardiac arrest has increased during the last decade in Denmark. We aimed to study the impact of age on changes in survival and whether it was possible to identify patients with minimal chance of 30-day survival. Methods and Results— Using data from the nationwide Danish Cardiac Arrest Registry (2001─2011), we identified 21 480 patients ≥18 years old with a presumed cardiac-caused out-of-hospital cardiac arrest for which resuscitation was attempted. Patients were divided into 3 preselected age-groups: working-age patients 18 to 65 years of age (33.7%), early senior patients 66 to 80 years of age (41.5%), and late senior patients &gt;80 years of age (24.8%). Characteristics in working-age patients, early senior patients, and late senior patients were as follows: witnessed arrest in 53.8%, 51.1%, and 52.1%; bystander cardiopulmonary resuscitation in 44.7%, 30.3%, and 23.4%; and prehospital shock from a defibrillator in 54.7%, 45.0%, and 33.8% (all P &lt;0.05). Between 2001 and 2011, return of spontaneous circulation on hospital arrival increased: working-age patients, from 12.1% to 34.6%; early senior patients, from 6.4% to 21.5%; and late senior patients, from 4.0% to 15.0% (all P &lt;0.001). Furthermore, 30-day survival increased: working-age patients, 5.8% to 22.0% ( P &lt;0.001); and early senior patients, 2.7% to 8.4% ( P &lt;0.001), whereas late senior patients experienced only a minor increase (1.5% to 2.0%; P =0.01). Overall, 3 of 9499 patients achieved 30-day survival if they met 2 criteria: had not achieved return of spontaneous circulation on hospital arrival and had not received a prehospital shock from a defibrillator. Conclusions— All age groups experienced a large temporal increase in survival on hospital arrival, but the increase in 30-day survival was most prominent in the young. With the use of only 2 criteria, it was possible to identify patients with a minimal chance of 30-day survival. </jats:sec

The pedigree included in the current study.

<p>Affected individuals are indicated in black, unaffected in white. An obligate carrier of the chromosome 1 putative scoliosis risk haplotype (denoted by blue bars) is marked with a black dot. All numbered individuals have been genotyped and included in the linkage analysis. All putative non-risk haplotypes are denoted by white bars. The two exome-sequenced individuals are marked with asterisks. Carriers of the rare <i>CELSR2</i> variant identified by exome sequencing are marked by a green box.</p

Schematic of the structure of the <i>CELSR2</i> protein.

<p>Shown are the cadherin, EGF-like, and laminin-G-like domains. Also the transmembrane (TM) 7-pass domain and the evolutionarily conserved GAIN domain. The GAIN domain contains within it a GPS domain and is the site of autoproteolytic cleavage of <i>CELSR2</i>. The rare V2287I variant and more common R2060R tagging variant are both located within the GAIN domain.</p

Genetic linkage peak on chromosome 1, indicating sharing in all affected individuals.

<p>The maximum K&C non-parametric LOD (NPL) score was attained through the exponential model. The x-axis shows the position on the chromosome (in cM), the y-axis shows the NPL score.</p