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 1.Single gene mutations,(Mendelian disorders)- 6% 2.Chromosomal disorders. (7.5%) 3.Multifactorially inherited conditions. (20%) 4.Disorders that show an unusual pattern of inheritance. (2-3%) 5.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. hallmark The hallmark of a single-gene disorder is that the phenotype is overwhelmingly determined by changes that affect an individual gene (quantity or function.) variable expressivity 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. tuberous sclerosis 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: non 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. penetrance. where as other such individuals manifest symptoms. This phenomenon is referred to as penetrance. complete 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 SystemDisorders NervousNeurofibromatosis Tuberous sclerosis HematologyHereditary spherocytosis Von Willebrand disease skeletalAchondroplasia Marfan syndrome GITFamilial polyposis coli UrinaryPolycystic kidney disease MetabolicFamilial 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:  Musculoskeletal findings: include o Dolichostenomelia (a tall, thin body habitus). o Arachnodactyly (spider-like fingers and toes). o Abnormalities of the sternum (pectus excavatum or carinatum). o Kyphoscoliosis. o Pes planus. o Joint laxity.

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

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