Inheritance patterns: Monogenic (Mendelian) Inheritance Polygenic and Multifactorial Inheritance Mitochondrial Inheritance

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<ul><li>Slide 1</li></ul> <p>Inheritance patterns: Monogenic (Mendelian) Inheritance Polygenic and Multifactorial Inheritance Mitochondrial Inheritance Slide 2 Inheritance patterns Inheritance patterns trace the transmission of genetically encoded traits, conditions or diseases to the offsprings. There are several modes of inheritance: Single Gene or Mendelian Polygenic and Multifactorial Mitochondrial Slide 3 Single Gene Inheritance Genetic conditions caused by a mutation in a single gene follow predictable patterns of inheritance within families. Single gene inheritance is also referred to as Mendelian inheritance as they follow transmission patterns he observed in his research on peas. There are 3 types of Mendelian inheritance patterns: 1. Autosomal: the gene responsible for the phenotype is located on one of the 22 pairs of autosomes (non-sex determining chromosomes). 2. X-linked: the gene that encodes for the trait is located on the X chromosome. 3. Y-linked (holandric): the gene that encodes for the trait is located on the Y chromosome Dominant: conditions that are manifest in heterozygotes (individuals with just one copy of the mutant allele). Recessive: conditions are only manifest in individuals who have two copies of the mutant allele (are homozygous). Slide 4 Slide 5 Autosomal dominant (AD) Dominant conditions are expressed in individuals who have just one copy of the mutant allele. The pedigree on the right illustrates the transmission of an autosomal dominant trait. Affected males and females have an equal probability of passing on the trait to offspring. Affected individuals have one normal copy of the gene and one mutant copy of the gene, thus each offspring has a 50% chance on inheriting the mutant allele. As shown in this pedigree, approximately half of the children of affected parents inherit the condition and half do not. Slide 6 AD Incomplete penetrance A typical pedigree from a family with a mutation in the BRCA1 gene. Fathers can be carriers and pass the mutation onto offspring. Not all people who inherit the mutation develop the disease, thus patterns of transmission are not always obvious. Slide 7 Autosomal dominant (AD) Huntington Disease Myotonic muscular dystrophy Achondroplasia (short-limbed dwarfism) Polycystic kidney disease (ADPKD) Brachydactyly Polydactily Syndactyly Adactyly Osteogenesis imperfecta Gout Familial hypercholesterolemia Hypercalcemia (familial) Marfan syndrome Familial Polycystic ovary syndrome (PCOS) Neurofibromatosis Slide 8 Huntington Disease Huntington's disease (HD) is a neurodegenerative genetic disorder that affects muscle coordination and leads to cognitive decline and psychiatric problems. It typically becomes noticeable in mid-adult life. HD is the most common genetic cause of abnormal involuntary writhing movements called chorea, which is why the disease used to be called Huntington's chorea. The Huntingtin gene (HTT=HD=IT15) on 4p16.3 provides the genetic information for a protein that is also called "huntingtin". Expansion of a CAG triplet repeat stretch within the Huntingtin gene results in a different (mutant) form of the protein, which gradually damages cells in the brain, through mechanisms that are not fully understood. The genetic basis of HD was discovered in 1993 by an international collaborative effort spearheaded by the Hereditary Disease Foundation. Slide 9 Huntington Disease Increases in the number of repeats (and hence earlier age of onset and severity of disease) in successive generations is known as genetic anticipation. Instability is greater in spermatogenesis than oogenesis; Individuals with more than sixty repeats often develop the disease before age 20, while those with fewer than 40 repeats may not ever develop noticeable symptoms; Life expectancy in HD is generally around 20 years following the onset of visible symptoms; Most life-threatening complications result from muscle coordination and, to a lesser extent, behavioral changes induced by declining cognitive function. The largest risk is pneumonia, which causes death in one third of those with HD. As the ability to synchronize movements deteriorates, difficulty clearing the lungs and an increased risk of aspirating food or drink both increase the risk of contracting pneumonia. The second greatest risk is heart disease, which causes almost a quarter of fatalities of those with HD. [ [ Slide 10 Huntington Disease Recommended (highly) to see what Huntington is all about An excellent French documentary (subtitled in English) about a family carrying such a genetic burden, including aspects of their life and expectancies As a reminder, the disease has a complete penetrance (100%) make the disease, usually after 35-40 years of age, and transmit it to their progenitors (it takes 1 hour and a half) Slide 11 Other AD conditions Myotonic muscular dystrophy (dystrophia myotonica, myotonia atrophica) is a chronic, slowly progressing, highly variable, inherited multisystemic disease. It is characterized by wasting of the muscles (muscular dystrophy), cataracts, heart conduction defects, endocrine changes, and myotonia. Achondroplasia is a common cause of dwarfism. It occurs as a sporadic mutation in approximately 75% of cases (associated with advanced paternal age) or may be inherited as an autosomal dominant genetic disorder. People with achondroplasia have short stature, with an average adult height of 131 centimeters for males and 123 centimeters for females. Achondroplastic adults are known to be as short as 62.8 cm. Polycystic kidney disease (PKD or PCKD, also known as polycystic kidney syndrome) is a cystic genetic disorder of the kidneys. There are two types of PKD: autosomal dominant polycystic kidney disease (ADPKD) and the less-common autosomal recessive polycystic kidney disease (ARPKD). Polycystic kidney disease is one of the most common life-threatening genetic diseases, affecting an estimated 12.5 million people worldwide. Slide 12 Other AD conditions Brachydactyly (short fingers/toes) Polydactily (extra fingers/toes) Syndactyly (two or more digits are fused together) Adactyly (congenital absence of fingers and/or toes) Osteogenesis imperfecta types I-V (OI and sometimes known as brittle bone disease, or "Lobstein syndrome") is a congenital bone disorder. People with OI are born with defective connective tissue, or without the ability to make it, usually because of a deficiency of Type-I collagen. As a genetic disorder, OI has historically been viewed as an autosomal dominant disorder of type I collagen. In the past several years, there has been the identification of autosomal recessive forms. Most people with OI receive it from a parent but in 35% of cases it is an individual (de novo or "sporadic") mutation. There are eight different types of OI, Type I being the most common, though the symptoms vary from person to person. Slide 13 Osteogenesis imperfecta Slide 14 Other AD conditions Gout (also known as podagra when it involves the big toe). is a medical condition usually characterized by recurrent attacks of acute inflammatory arthritisa red, tender, hot, swollen joint. The metatarsal-phalangeal joint at the base of the big toe is the most commonly affected (approximately 50% of cases). However, it may also present as tophi, kidney stones, or urate nephropathy. It is caused by elevated levels of uric acid in the blood. The uric acid crystallizes, and the crystals deposit in joints, tendons, and surrounding tissues. The occurrence of gout is partly genetic, contributing to about 60% of variability in uric acid level. Familial hypercholesterolemia (abbreviated FH) is a genetic disorder characterized by high cholesterol levels, specifically very high levels of low-density lipoprotein (LDL, "bad cholesterol"), in the blood and early cardiovascular disease. Many patients have mutations in the LDLR gene that encodes the LDL receptor protein, which normally removes LDL from the circulation, or apolipoprotein B (ApoB), which is the part of LDL that binds with the receptor; mutations in other genes are rare. Patients who have one abnormal copy (are heterozygous) of the LDLR gene may have premature cardiovascular disease at the age of 30 to 40. Having two abnormal copies (being homozygous) may cause severe cardiovascular disease in childhood. Heterozygous FH is a common genetic disorder, inherited in an autosomal dominant pattern, occurring in 1:500 people in most countries; homozygous FH is much rarer, occurring in 1 in a million births. Slide 15 Other AD conditions Hypercalcemia - Familial hypocalciuric hypercalcemia is a condition that can cause hypercalcemia, a serum calcium level typically above 10.2 mg/dL. It is also known as familial benign hypocalciuric hypercalcemia (FBHH) where there is usually a family history of hypercalcemia which is mild, a urine calcium to creatinine ratio</p>


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