genetic

Genetic Disorders

Common, with 2-4% of live-born babies having a significant congenital malformation and about 5% a genetic disorder. 30-50% of hospitalized children have congenital anomalies or genetic disorders.

Categories of Genetic Disorders

Single gene mutations,(Mendelian disorders)- 6% Chromosomal disorders. (7.5%) Multifactorially inherited conditions. (20%) Disorders that show an unusual pattern of inheritance. (2-3%) Teratogenically caused conditions. (6%)

Single Gene Disorders

Disorders with these patterns of inheritance, described by Mendel in 1865, are rare individually, but collectively they represent an important contribution to childhood disease. The hallmark of a single-gene disorder is that the phenotype is overwhelmingly determined by changes that affect an individual gene (quantity or function.) The phenotypes associated with single-gene disorders can vary from one patient to another based on the severity of the change affecting the gene and additional modifications caused by genetic, environmental, and/or stochastic factors. This feature of genetic disease is termed variable expressivity.

Variable Expressivity: AD disorders show variability in symptoms expressed in different individuals carrying the same mutated gene. Some individuals have only mild clinical symptoms, whereas others have more severe disease. For example, a parent with tuberous sclerosis may have mild skin abnormalities only, but his or her affected child may have, in addition, epilepsy and learning difficulties.

Patterns Of Inheritance:

Autosomal Dominant. Autosomal Recessive. X-Linked Recessive. X-Linked Dominant.

Autosomal Dominant Inheritance

This is the most common mode of Mendelian inheritance.Single copy of a gene bearing mutation (one of the autosomes; chromosomes 1–22) is sufficient to cause disease, that is usually manifest in heterozygous state.

PENETRANCE:

Some people who are obligate carriers of a mutation known to cause an AD disorder may not show clinical signs of disorders, this is referred as non penetrance, e.g. otosclerosis, in which only about 40% of gene carriers develop deafness. where as other such individuals manifest symptoms. This phenomenon is referred to as penetrance. If all individuals who carry a mutation for an AD disorder show signs of that disorder, the gene is said to have complete penetrance.

Example of non-penetrance

Spontaneous Mutation:
AD disorders sometimes appear in a child of unaffected parents because of a spontaneous mutation ”a new mutation in one of the gametes leading to the conception of the affected person”. This is the most common reason for absence of a family history in dominant disorders, e.g. >80% of individuals with achondroplasia have normal parents.

E.g. of some AD inheritance

System
Disorders
Nervous
Neurofibromatosis Tuberous sclerosis
Hematology
Hereditary spherocytosis Von Willebrand disease
skeletal
Achondroplasia Marfan syndrome
GIT
Familial polyposis coli
Urinary
Polycystic kidney disease
Metabolic
Familial hypercholesterolemia

Achondroplasia

Achondroplasia is the most common skeletal dysplasia in humans. The bony abnormalities in achondroplasia lead to short stature, macrocephaly, a flat midface with a prominent forehead, and rhizomelic shortening of the limbs.

Marfan Syndrome

Clinical symptoms mostly involve three systems: cardiac, musculoskeletal, and ophthalmologic. Musculoskeletal findings: include Dolichostenomelia (a tall, thin body habitus). Arachnodactyly (spider-like fingers and toes). Abnormalities of the sternum (pectus excavatum or carinatum). Kyphoscoliosis. Pes planus. Joint laxity.


Eye findings: include High myopia, which eventually can lead to vitreoretinal degeneration. Abnormal suspensory ligament of the lens, which can lead to ectopia lentis (dislocation of the lens usually upward and outward). Cataracts. Cardiac findings: include Weakened aortic wall, which leads to progressive dilation of the aortic root. Aortic insufficiency followed by aortic dissection.

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