Genetic and Congenital Disorders

• Genetic disorders are diseases or conditions that are caused by abnormalities in the genes or chromosomes. They can be inherited from one or both parents or acquired during development or life. 

• They can affect any aspect of human health and development. Some examples of genetic disorders are:

  • Chromosomal disorders: caused by changes in the number or structure of chromosomes. For example: Down syndrome (trisomy 21), Turner syndrome (monosomy X), Klinefelter syndrome (XXY), Cri du chat syndrome (deletion of 5p), etc.

  • Single-gene disorders: caused by mutations in a single gene. They can be classified into autosomal dominant, autosomal recessive, or X-linked depending on the mode of inheritance. For example: Huntington disease (autosomal dominant), cystic fibrosis (autosomal recessive), hemophilia (X-linked), etc.

  • Multifactorial disorders: caused by the interaction of multiple genes and environmental factors. For example: diabetes mellitus, hypertension, coronary artery disease, etc.

  • Mitochondrial disorders: caused by mutations in the mitochondrial DNA or genes that affect mitochondrial function. For example: Leber hereditary optic neuropathy, mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), etc.

• The pathophysiology of genetic disorders involves the disruption of normal gene expression or function that results in abnormal protein synthesis or metabolism. The main mechanisms involved are:

• Loss-of-function mutations: reduce or eliminate the function of a gene product. For example: cystic fibrosis is caused by a mutation in the CFTR gene that encodes a chloride channel that regulates fluid and electrolyte balance in various tissues. The mutation impairs the function of the channel and causes thick and sticky mucus to accumulate in the lungs, pancreas, and other organs.

• Gain-of-function mutations: increase or alter the function of a gene product. For example: Huntington disease is caused by a mutation in the HTT gene that encodes a protein called huntingtin that is involved in nerve cell function. The mutation expands a repeated sequence of three nucleotides (CAG) in the gene and causes the protein to become toxic and aggregate in the brain cells.

• Haploinsufficiency: occur when one copy of a gene is mutated or deleted and the remaining copy is not enough to maintain normal function. For example: Cri du chat syndrome is caused by a deletion of part of chromosome 5 that includes several genes. The deletion reduces the dosage of these genes and causes various developmental abnormalities, such as microcephaly, intellectual disability, and a distinctive cry.

• Dominant negative mutations: occur when a mutated gene product interferes with the function of the normal gene product. For example: Marfan syndrome is caused by a mutation in the FBN1 gene that encodes a protein called fibrillin-1 that is involved in connective tissue structure and elasticity. The mutation produces an abnormal fibrillin-1 that disrupts the formation of normal fibrillin-1 fibers and causes various skeletal, cardiovascular, and ocular defects.

• The diagnosis of genetic disorders involves various methods, such as family history, physical examination, laboratory tests (blood tests, biochemical tests, etc.), cytogenetic tests (karyotype, fluorescence in situ hybridization, etc.), molecular tests (polymerase chain reaction, molecular tests (polymerase chain reaction, DNA sequencing, microarray, etc.), and prenatal tests (amniocentesis, chorionic villus sampling, etc.). The genetic counseling of genetic disorders involves the provision of information, education, and support to individuals or families who are affected by or at risk of a genetic disorder. It aims to help them understand the nature, inheritance, diagnosis, treatment, and prevention of the disorder; to assess their risk and options; and to cope with the psychological and social implications of the disorder.

• Congenital disorders are diseases or conditions that are present at birth or develop during the prenatal period. They can be caused by genetic or environmental factors or a combination of both. They can affect any aspect of human health and development. Some examples of congenital disorders are:

• Genetic congenital disorders: caused by inherited or acquired genetic abnormalities that affect the development of the embryo or fetus. For example: Down syndrome, Turner syndrome, Klinefelter syndrome, cystic fibrosis, hemophilia, etc.

• Environmental congenital disorders: caused by exposure to teratogens (substances or agents that cause birth defects) during the critical period of embryonic or fetal development. For example: fetal alcohol syndrome (alcohol), thalidomide syndrome (thalidomide), congenital rubella syndrome (rubella virus), etc.

• Multifactorial congenital disorders: caused by the interaction of genetic and environmental factors that affect the development of the embryo or fetus. For example: cleft lip and palate, spina bifida, congenital heart defects, etc.

• The pathophysiology of congenital disorders involves the disruption of normal embryonic or fetal development that results in structural or functional abnormalities. The main mechanisms involved are:

• Malformation: a defect in the formation of an organ or a part of an organ. For example: anencephaly (absence of brain), holoprosencephaly (incomplete separation of brain hemispheres), ectopia cordis (displacement of heart outside the chest), etc.

• Deformation: a distortion of an organ or a part of an organ by mechanical forces. For example: clubfoot (abnormal bending of foot), torticollis (abnormal twisting of neck), plagiocephaly (asymmetrical flattening of skull), etc.

• Disruption: a destruction of an organ or a part of an organ by a vascular accident or an external agent. For example: amniotic band syndrome (entrapment of limbs by fibrous bands), gastroschisis (rupture of abdominal wall), hydrops fetalis (accumulation of fluid in fetal tissues), etc.

• Dysplasia: a disorder in the differentiation or maturation of cells or tissues. For example: achondroplasia (defective growth of cartilage), osteogenesis imperfecta (defective synthesis of collagen), ectodermal dysplasia (defective development of ectodermal structures), etc.

• The diagnosis of congenital disorders involves various methods, such as physical examination, imaging studies (ultrasound, computed tomography, magnetic resonance imaging, etc.), laboratory tests (blood tests, biochemical tests, etc.), cytogenetic tests (karyotype, fluorescence in situ hybridization, etc.), molecular tests (polymerase chain reaction, DNA sequencing, microarray, etc.), and prenatal tests (amniocentesis, chorionic villus sampling, etc.). The treatment and prevention of congenital disorders depend on several factors, such as the type, cause, severity, and prognosis of the disorder; the availability and effectiveness of medical resources; and the ethical and legal issues involved. Some possible interventions are:

• Treatment: aimed at correcting or improving the structural or functional abnormalities caused by the disorder. It may involve surgery, medication, therapy, or supportive care. For example: surgery for cleft lip and palate, medication for phenylketonuria, therapy for cerebral palsy, or supportive care for trisomy 18.

• Prevention: aimed at reducing or eliminating the risk factors that cause or contribute to the disorder. It may involve genetic screening, genetic counseling, prenatal diagnosis, prenatal treatment, or termination of pregnancy. For example: genetic screening for cystic fibrosis, genetic counseling for Down syndrome, prenatal diagnosis for spina bifida, prenatal treatment for congenital adrenal hyperplasia, or termination of pregnancy for anencephaly.