Exome analysis of a family with pleiotropic congenital heart disease.

BACKGROUND: A number of single gene defects have been identified in patients with isolated or nonsyndromic congenital heart defects (CHDs). However, due to significant genetic heterogeneity, candidate gene approaches have had limited success in finding high-risk alleles in most cases. The purpose of this study was to use exome sequencing to identify high-risk gene variants in a family with highly penetrant pleiotropic CHD. METHODS AND RESULTS: DNA samples from 2 members of a family with diverse CHD were analyzed by exome sequencing. Variants were filtered to eliminate common variants and sequencing artifacts and then prioritized based on the predicted effect of the variant and on gene function. The remainder of the family was screened using polymerase chain reaction, high-resolution melting analysis, and DNA sequencing to evaluate variant segregation. After filtering, >2000 rare variants (including single nucleotide substitutions and indels) were shared by the 2 individuals. Of these, 46 were nonsynonymous, 3 were predicted to alter splicing, and 6 resulted in a frameshift. Prioritization reduced the number of variants potentially involved in CHD to 18. None of the variants completely segregated with CHD in the kindred. However, 1 variant, Myh6 Ala290Pro, was identified in all but 1 affected individual. This variant was previously identified in a patient with tricuspid atresia and large secundum atrial septal defect. CONCLUSIONS: It is likely that next-generation sequencing will become the method of choice for unraveling the complex genetics of CHD, but information gained by analysis of transmission through families will be crucial.

Patent foramen ovale in children with migraine headaches.

OBJECTIVE: To determine the prevalence of patent foramen ovale (PFO) in children with migraine. STUDY DESIGN: Children aged 6.0 to 18.0 years with migraine headache were evaluated for PFO and right-to-left shunting with color-flow Doppler scanning, saline solution contrast transthoracic echocardiography, and contrast transcranial Doppler scanning. RESULTS: The population consisted of 109 children with migraine; 38 (35%) with aura and 71 (65%) without aura. The overall PFO prevalence was 35%, similar to the general population (35% vs 25%; P = .13). However, compared with the general population (25%), the PFO prevalence was significantly greater in subjects with aura (50%, P = .0004) but similar in those without aura (27%, P = .73). Atrial shunt size was not associated with the presence or absence of aura. CONCLUSION: Children with migraine with aura have a significantly higher prevalence of PFO compared with those without aura or the general population. These data suggest that PFO may contribute to the pathogenesis of migraine with aura in children and have implications for clinical decision making.