Rare and private variations in neural crest, apoptosis and sarcomere genes define the polygenic background of isolated Tetralogy of Fallot.
Tetralogy of Fallot (TOF) is the most common cyanotic congenital heart disease. Its genetic basis is demonstrated by an increased recurrence risk in siblings and familial cases. However, the majority of TOF are sporadic, isolated cases of undefined origin and it had been postulated that rare and private autosomal variations in concert define its genetic basis. To elucidate this hypothesis, we performed a multilevel study using targeted re-sequencing and whole-transcriptome profiling. We developed a novel concept based on a gene's mutation frequency to unravel the polygenic origin of TOF. We show that isolated TOF is caused by a combination of deleterious private and rare mutations in genes essential for apoptosis and cell growth, the assembly of the sarcomere as well as for the neural crest and secondary heart field, the cellular basis of the right ventricle and its outflow tract. Affected genes coincide in an interaction network with significant disturbances in expression shared by cases with a mutually affected TOF gene. The majority of genes show continuous expression during adulthood, which opens a new route to understand the diversity in the long-term clinical outcome of TOF cases. Our findings demonstrate that TOF has a polygenic origin and that understanding the genetic basis can lead to novel diagnostic and therapeutic routes. Moreover, the novel concept of the gene mutation frequency is a versatile measure and can be applied to other open genetic disorders.
Group of Cardiovascular Genetics, Department of Vertebrate Genomics and Cardiovascular Genetics, Experimental and Clinical Research Center, Charité-Universitätsmedizin Berlin and Max Delbrück Center (MDC) for Molecular Medicine, Berlin 13125, Germany.
Marcel
M
Grunert
Group of Cardiovascular Genetics, Department of Vertebrate Genomics and Cardiovascular Genetics, Experimental and Clinical Research Center, Charité-Universitätsmedizin Berlin and Max Delbrück Center (MDC) for Molecular Medicine, Berlin 13125, Germany Department of Biology, Chemistry and Pharmacy, Free University of Berlin, Berlin 14195, Germany.
Cornelia
C
Dorn
Group of Cardiovascular Genetics, Department of Vertebrate Genomics and Cardiovascular Genetics, Experimental and Clinical Research Center, Charité-Universitätsmedizin Berlin and Max Delbrück Center (MDC) for Molecular Medicine, Berlin 13125, Germany.
Markus
M
Schueler
Group of Cardiovascular Genetics, Department of Vertebrate Genomics and.
Ilona
I
Dunkel
Group of Cardiovascular Genetics, Department of Vertebrate Genomics and Cardiovascular Genetics, Experimental and Clinical Research Center, Charité-Universitätsmedizin Berlin and Max Delbrück Center (MDC) for Molecular Medicine, Berlin 13125, Germany.
Jenny
J
Schlesinger
Department of Pediatric Cardiology, German Heart Institute Berlin and Department of Pediatric Cardiology, Charité-Universitätsmedizin Berlin, Berlin 13353, Germany.
Siegrun
S
Mebus
Department of Cardiac Surgery and.
Vladimir
V
Alexi-Meskishvili
Cardiovascular Genetics, Experimental and Clinical Research Center, Charité-Universitätsmedizin Berlin and Max Delbrück Center (MDC) for Molecular Medicine, Berlin 13125, Germany.
Andreas
A
Perrot
Department of Pathology, German Heart Institute Berlin, Berlin, Germany.
Katharina
K
Wassilew
Next Generation Service Group, Max Planck Institute for Molecular Genetics, Berlin 14195, Germany.
Bernd
B
Timmermann
Department of Cardiac Surgery and.
Roland
R
Hetzer
Department of Pediatric Cardiology, German Heart Institute Berlin and Department of Pediatric Cardiology, Charité-Universitätsmedizin Berlin, Berlin 13353, Germany.
Felix
F
Berger
Group of Cardiovascular Genetics, Department of Vertebrate Genomics and Cardiovascular Genetics, Experimental and Clinical Research Center, Charité-Universitätsmedizin Berlin and Max Delbrück Center (MDC) for Molecular Medicine, Berlin 13125, Germany Department of Biology, Chemistry and Pharmacy, Free University of Berlin, Berlin 14195, Germany silke.sperling@charite.de.
Silke R
SR
Sperling
D017209:Apoptosis; D001483:Base Sequence; D049109:Cell Proliferation; D015331:Cohort Studies; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D055106:Genome-Wide Association Study / Q000379:methods*; D006801:Humans; D008969:Molecular Sequence Data; D020412:Multifactorial Inheritance; D009154:Mutation; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D017422:Sequence Analysis, DNA; D013771:Tetralogy of Fallot / Q000097:blood / Q000235:genetics* / Q000473:pathology*