Pedigree Nomenclature Autosomal Dominant (AD) Genders affected male and female at equal frequency Generations affected does not skip generations if two parents without the AD disease have child with an AD disease possibility is reduced penetrance have mutant gene but phenotypically normal de novo germline mutation an affected child must receive disease from an affected parent a homozygote dominant parent has a 100% of having an affected child two heterotyzgote parents with the AD disease condition have a 75% chance of having a child with the disease phenotype Pathology defects in structural genes Presentation timing usually after puberty Other notes often pleiotropic several organ systems affected by single genetic defect only one copy of the defective gene is required to express the disease phenotype Examples von Willebrand disease (most common) Huntington's disease osteogenesis imperfecta achondroplasia Marfan syndrome neurofibromatosis type I acute intermittent porphyria Autosomal Recessive (AR) Genders affected male and female Generations affected 1/4 of offspring affected when both parents are carriers 1/2 of offspring are carriers when both parents are carriers 2/3 of nonaffected children are carriers usually 1 generation Pathology defects in enzymes Presentation timing infancy to childhood Other notes most often more severe than AD must have 2 defective copies of the gene chances greatly increased with consanguinity Examples cystic fibrosis - deficiency in the chloride channel CFTR inborn errors of metabolism PKU, von Gierke's, Pompe's, glycogen storage diseases, sphingolipidoses (except Fabry's), and mucopolysaccharidoses (except Hunter's) sickle cell anemia thalassemias albinism ARPKD hemochromatosis X-linked Recessive (XR) Genders affected males must receive defective gene from carrier mother carrier mother's sons have 50% of having disease affected males give copy to all of their daughters Generations affected skips generations male-to-male transmission not allowed diseases passes through carrier daughters Pathology defects in enzymatic genes similar to AR diseases Presentation timing usually after puberty Other notes only one defective copy necessary for disease in males because males are hemizygous for X chromosome two defective copies necessary for disease in females can be affected with just one defective copy if normal X chromosome is inactivated to Barr body called manifesting heterozygotes phenotype usually milder than affected males Examples hemophilia A and B Menke's disease Duchenne muscular dystrophy Lesch-Nyhan syndrome Ornithine transcarbamoylase deficiency red-green color blindness X-linked Dominant (XD) Genders affected male and female at equal frequency Generations affected does not skip generations only possibility is reduced penetrance females of affected fathers are always affected male-to-male transmission not seen male or females of affected mothers can be affected Pathology defects in structural genes Presentation timing usually after puberty Examples hypophosphatemic rickets Fragile X syndrome Alport syndrome Mitochondrial Inheritance Genders affected male and females at equal frequency Generations affected does not skip generations only transmitted from affected female gives to all offspring due to the fact that the sperm do not contribute mitochondria to the zygote Pathology defects in electron transport/oxidative phosphorylation process presents as neuropathies/myopathies neurons and muscle cells require high amounts of energy and depend on mitochondria Presentation timing usually after puberty Other notes variable expression due to heteroplasmy a small percentage of mitochondria within a cell are affected leading to variable severity Examples myoclonic epilepsy with ragged red muscle fibers Leber hereditary optic neuropathy MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) Inheritance Algorithm Does offspring with disease have a parent with disease? (Y/N) if YES dominant (does not skip generations) is there male-to-male transmission of disease? (Y/N) if YES autosomal dominant if NO do daughters of affected male have disease? (Y/N) if YES X-linked dominant if NO mitochondrial if NO recessive (can skip generations) predominantly males with disease? (Y/N) if YES X-linked recessive if NO autosomal recessive