The cause of congenital heart disease may be genetic, environmental, or a combination of both. Genetic Genetic mutations, often sporadic, represent the largest known cause of congenital heart defects. They are described in the table below. + Genetic lesions Attributable percent Examples Primary genetic testing method Aneuploidies 5-8% Survivable autosomal trisomies (chromosomes 13, 18, 21), chromosome X monosomy (Turner<unk>  Karyotyping Copy number variants 10-12% 22q11.2 deletion/duplication (velocardiofacial/DiGeorge<unk> , 1q21.1 deletion/duplication, 8p23.1 deletion/duplication, 15q11.2 deletion (Burnside-Butler<unk>  Array comparative genomic hybridization (also known as chromosomal microarray analysis) Inherited protein-coding single nucleotide variant (SNV) or small insertion/deletion (indel) 3-5% Holt-Oram<unk> , Noonan<unk> , Alagille<unk>  Gene panel De novo protein-coding SNV or indel ~10% Mutations in genes highly expressed during heart development Whole exome sequencing Molecular pathways The genes regulating the complex developmental sequence have only been partly elucidated. Some genes are associated with specific defects. A number of genes have been associated with cardiac manifestations. Mutations of a heart muscle protein, α-myosin heavy chain (MYH6) are associated with atrial septal defects. Several proteins that interact with MYH6 are also associated with cardiac defects. The transcription factor GATA4 forms a complex with the TBX5 which interacts with MYH6. Another factor, the homeobox (developmental) gene, NKX2-5 also interacts with MYH6. Mutations of all these proteins are associated with both atrial and ventricular septal defects; In addition, NKX2-5 is associated with defects in the electrical conduction of the heart and TBX5 is related to the Holt-Oram<unk>  which includes electrical conduction defects and abnormalities of the upper limb. The Wnt signaling co-factors BCL9, BCL9L and PYGO might be part of this molecular pathways, as when their genes are mutated, this causes phenotypes similar to the features present in Holt-Oram<unk> . Another T-box gene, TBX1, is involved in velo-cardio-facial<unk>  DiGeorge<unk> , the most common deletion which has extensive symptoms including defects of the cardiac outflow tract including tetralogy of Fallot. +Examples of gene products and associated features MYH6 GATA4 NKX2-5 TBX5 TBX1 Locus 14q11.2-q13 8p23.1-p22 5q34 12q24.1 22q11.2<unk>  Holt-Oram DiGeorge Atrial septal defects ✔ ✔ ✔ ✔ Ventricular septal defects ✔ ✔ ✔ Electrical conduction abnormalities ✔ ✔ Outflow tract abnormalities ✔ Non-cardiac manifestations Upper limb abnormalities Small or absent thymus Small or absent parathyroids Facial abnormalities The notch signaling pathway, a regulatory mechanism for cell growth and differentiation, plays broad roles in several aspects of cardiac development. Notch elements are involved in determination of the right and left sides of the body plan, so the directional folding of the heart tube can be impacted. Notch signaling is involved early in the formation of the endocardial cushions and continues to be active as the develop into the septa and valves. It is also involved in the development of the ventricular wall and the connection of the outflow tract to the great vessels. Mutations in the gene for one of the notch ligands, Jagged1, are identified in the majority of examined cases of arteriohepatic dysplasia (Alagille<unk> , characterized by defects of the great vessels (pulmonary artery stenosis), heart (tetralogy of Fallot in 13% of cases), liver, eyes, face, and bones. Though less than 1% of all cases, where no defects are found in the Jagged1 gene, defects are found in Notch2 gene. In 10% of cases, no mutation is found in either gene. For another member of the gene family, mutations in the Notch1 gene are associated with bicuspid aortic valve, a valve with two leaflets instead of three. Notch1 is also associated with calcification of the aortic valve, the third most common cause of heart disease in adults. Mutations of a cell regulatory mechanism, the RasMAPK pathway are responsible for a variety of<unk> s, including Noonan<unk> , LEOPARD<unk> , Costello<unk>  and cardiofaciocutaneous<unk>  in which there is cardiac involvement. While the conditions listed are known genetic causes, there are likely many other genes which are more subtle. It is known that the risk for congenital heart defects is higher when there is a close relative with one. Environmental Known environmental factors include certain infections during pregnancy such as rubella, drugs (alcohol, hydantoin, lithium and thalidomide) and maternal illness (diabetes mellitus, phenylketonuria, and systemic lupus erythematosus). Alcohol exposure in the father also appears to increase the risk of congenital heart defects. Being overweight or obese increases the risk of congenital heart disease. Additionally, as maternal obesity increases, the risk of heart defects also increases. A distinct physiological mechanism has not been identified to explain the link between maternal obesity and CHD, but both pre-pregnancy folate deficiency and diabetes have been implicated in some studies.
symptom of Klippel–Feil syndrome
symptom of Hirschsprung's disease
symptom of Scheuermann's disease
symptom of Prader–Willi syndrome
symptom of Rotor syndrome
symptom of Coeliac disease
symptom of Stomach cancer
medical cause of Dysphagia