The cause of<unk><unk>  disease may be genetic, environmental, or a combination of both. Genetic Genetic mutations, often sporadic, represent the largest known cause of<unk> s. 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 syndrome) Karyotyping Copy number variants 10-12% 22q11.2 deletion/duplication (velocardiofacial/DiGeorge syndrome), 1q21.1 deletion/duplication, 8p23.1 deletion/duplication, 15q11.2 deletion (Burnside-Butler syndrome) 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 syndrome, Noonan syndrome, Alagille syndrome Gene panel De novo protein-coding SNV or indel ~10% Mutations in genes highly expressed during<unk>  development Whole exome sequencing Molecular pathways The genes regulating the complex developmental sequence have only been partly elucidated. Some genes are associated with specific<unk> s. A number of genes have been associated with cardiac manifestations. Mutations of a<unk>  muscle protein, α-myosin heavy chain (MYH6) are associated with atrial septal<unk> s. Several proteins that interact with MYH6 are also associated with cardiac<unk> s. 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<unk> s; In addition, NKX2-5 is associated with<unk> s in the electrical conduction of the<unk>  and TBX5 is related to the Holt-Oram syndrome which includes electrical conduction<unk> s 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 syndrome. Another T-box gene, TBX1, is involved in velo-cardio-facial syndrome DiGeorge syndrome, the most common deletion which has extensive symptoms including<unk> s 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 Syndrome Holt-Oram DiGeorge Atrial septal<unk> s ✔ ✔ ✔ ✔ Ventricular septal<unk> s ✔ ✔ ✔ 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<unk>  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 syndrome), characterized by<unk> s of the great vessels (pulmonary artery stenosis),<unk>  (tetralogy of Fallot in 13% of cases), liver, eyes, face, and bones. Though less than 1% of all cases, where no<unk> s are found in the Jagged1 gene,<unk> s 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<unk>  disease in adults. Mutations of a cell regulatory mechanism, the RasMAPK pathway are responsible for a variety of syndromes, including Noonan syndrome, LEOPARD syndrome, Costello syndrome and cardiofaciocutaneous syndrome 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<unk> s 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<unk> s. Being overweight or obese increases the risk of<unk><unk>  disease. Additionally, as maternal obesity increases, the risk of<unk><unk> s also increases. A distinct physiological mechanism has not been identified to explain the link between maternal obesity and<unk> , but both pre-pregnancy folate deficiency and diabetes have been implicated in some studies.
Congenital heart defect
Musculoskeletal abnormality
Neuromuscular disease
Vascular anomaly
Genetic disorder
Brain damage
Neuromuscular junction disease
Musculoskeletal injury