Copy number variants implicate cardiac function and development pathways in earthquake-induced stress cardiomyopathy.

The pathophysiology of stress cardiomyopathy (SCM), also known as takotsubo syndrome, is poorly understood. SCM usually occurs sporadically, often in association with a stressful event, but clusters of cases are reported after major natural disasters. There is some evidence that this is a familial condition. We have examined three possible models for an underlying genetic predisposition to SCM. Our primary study cohort consists of 28 women who suffered SCM as a result of two devastating earthquakes that struck the city of Christchurch, New Zealand, in 2010 and 2011. To seek possible underlying genetic factors we carried out exome analysis, genotyping array analysis, and array comparative genomic hybridization on these subjects. The most striking finding was the observation of a markedly elevated rate of rare, heterogeneous copy number variants (CNV) of uncertain clinical significance (in 12/28 subjects). Several of these CNVs impacted on genes of cardiac relevance including RBFOX1, GPC5, KCNRG, CHODL, and GPBP1L1. There is no physical overlap between the CNVs, and the genes they impact do not appear to be functionally related. The recognition that SCM predisposition may be associated with a high rate of rare CNVs offers a novel perspective on this enigmatic condition.

Mutations in the zinc finger protein gene, ZNF469, contribute to the pathogenesis of keratoconus.

PURPOSE: Mutations in the zinc finger protein gene ZNF469 cause recessive brittle cornea syndrome, characterized by spontaneous corneal perforations. Genome-wide association studies (GWAS) have implicated common variants in this gene as a determinant for central corneal thickness (CCT). We investigated the contribution of ZNF469 in a sample set of keratoconus patients. METHODS: Forty-three patients with keratoconus (49% Maori or Pacific [Polynesian]) were recruited. If a family history was present, family members were recruited. Participants underwent comprehensive examination, and a DNA sample was collected. Mutational analysis of ZNF469 was undertaken using Sanger sequencing, including an ancestrally matched Polynesian control population. Bioinformatic databases of exome variation and protein prediction software were used to determine presence and frequency and the pathogenicity for each observed change. RESULTS: Fourteen nonsynonymous missense single nucleotide polymorphisms (SNPs) were observed in ZNF469. Of the 43 probands, at least one probable disease-causing variant was detected in 20 (46%) (16/32 sporadic, 4/11 familial) and two variants in 5 (11.6%) (3/32 sporadic, 2/11 familial). Only heterozygous changes segregated with disease. Three "deleterious" changes observed in the Polynesian controls were removed from analysis; therefore pathogenic variants occurred in 10/43 (23.3%). CONCLUSIONS: Rare missense mutations in ZNF469, predicted to be pathogenic, occurred heterozygously, at a frequency of 23% in a keratoconus population. ZNF469 is associated with CCT in GWAS and is therefore likely to play a role in the synthesis and/or organization of corneal collagen fibers. The pathogenic changes observed either genetically predispose toward a "thin" cornea, which then becomes keratoconic, or are directly pathogenic.