Rare copy number variations in adults with tetralogy of Fallot implicate novel risk gene pathways.
Structural genetic changes, especially copy number variants (CNVs), represent a major source of genetic variation contributing to human disease. Tetralogy of Fallot (TOF) is the most common form of cyanotic congenital heart disease, but to date little is known about the role of CNVs in the etiology of TOF. Using high-resolution genome-wide microarrays and stringent calling methods, we investigated rare CNVs in a prospectively recruited cohort of 433 unrelated adults with TOF and/or pulmonary atresia at a single centre. We excluded those with recognized syndromes, including 22q11.2 deletion syndrome. We identified candidate genes for TOF based on converging evidence between rare CNVs that overlapped the same gene in unrelated individuals and from pathway analyses comparing rare CNVs in TOF cases to those in epidemiologic controls. Even after excluding the 53 (10.7%) subjects with 22q11.2 deletions, we found that adults with TOF had a greater burden of large rare genic CNVs compared to controls (8.82% vs. 4.33%, p = 0.0117). Six loci showed evidence for recurrence in TOF or related congenital heart disease, including typical 1q21.1 duplications in four (1.18%) of 340 Caucasian probands. The rare CNVs implicated novel candidate genes of interest for TOF, including PLXNA2, a gene involved in semaphorin signaling. Independent pathway analyses highlighted developmental processes as potential contributors to the pathogenesis of TOF. These results indicate that individually rare CNVs are collectively significant contributors to the genetic burden of TOF. Further, the data provide new evidence for dosage sensitive genes in PLXNA2-semaphorin signaling and related developmental processes in human cardiovascular development, consistent with previous animal models.
Toronto Congenital Cardiac Centre for Adults, Peter Munk Cardiac Centre, University Health Network, Toronto, Ontario, Canada.
Candice K
CK
Silversides
Anath C
AC
Lionel
Gregory
G
Costain
Daniele
D
Merico
Ohsuke
O
Migita
Ben
B
Liu
Tracy
T
Yuen
Jessica
J
Rickaby
Bhooma
B
Thiruvahindrapuram
Christian R
CR
Marshall
Stephen W
SW
Scherer
Anne S
AS
Bassett
D000328:Adult; D016022:Case-Control Studies; D015331:Cohort Studies; D005260:Female; D018628:Gene Dosage; D018507:Gene Expression Regulation, Developmental; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008875:Middle Aged; D005810:Multigene Family; D009419:Nerve Tissue Proteins / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D018579:Patient Selection; D020641:Polymorphism, Single Nucleotide; D018633:Pulmonary Atresia / Q000150:complications / Q000235:genetics*; D011956:Receptors, Cell Surface / Q000235:genetics*; D012306:Risk; D015398:Signal Transduction / Q000235:genetics; D013771:Tetralogy of Fallot / Q000150:complications / Q000235:genetics*
D009419:Nerve Tissue Proteins; C515995:PLXNA2 protein, human; D011956:Receptors, Cell Surface