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| A specific segment of DNA on a chromosome which contains information for production of a functional product |
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| Alternate forms of a gene occupying the same locus on homologous chromosomes |
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| Two members of a pair of chromosomes |
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| Different alleles at each of the two homologous loci. Dominant manifestation |
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| Both alleles are the same. Can be recessive manifestation |
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| Male only. Genes on X chromosome |
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| The genetic constitution of an individual at allelic level or whole genome. |
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| The observed characteristics arising from interaction of genes with environment or other genes. |
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| An alteration in DNA sequence. |
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| Multiple effects of a single gene. Ex: When a gene mutation manifests in several regions of a body. |
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| Similar phenotypes due to different genetic abnormalities. |
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| Can indicate the mode of inheritance, diagnosis, and risk to other family members. |
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| Autosomal dominant Conditions |
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| Incomplete penetrance, variable expressivity, higher rate of new mutations, especially in cases with reduced reproductive fitness. Ex: Neurofibromatosis - from large gene, which makes it more susceptible to mutation. Complete penetrance, (if you inherit the gene, you will get the disease). Variable expressivity, (many different phenotypes from mild to severe, few to many, including cafe au lait spots, speech delay, stunted growth, neurofibromas, pseudoarthrosis (false joint seen at mid calf), and lisch nodule in eye. |
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| An autosomal dominant disorder coming from a mutation of a large gene, which makes it more susceptible to mutation. Complete penetrance, (if you inherit the gene, you will get the disease). Variable expressivity, (many different phenotypes from mild to severe, few to many, including cafe au lait spots, speech delay, stunted growth, neurofibromas, pseudoarthrosis (false joint seen at mid calf), and lisch nodule in eye. |
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| Low penetrance = a condition that manifests in less than 1005 of individuals who have the mutant genotype. May appear to skip generations and may be age/sex dependent. Ex: (1) Baldness gene is 100% penetrant in men and 0% penetrant in women because the gene relies on male hormone for expression. (2) Myotonic Dystrophy - adult muscular dystrophy, myotonia (muscle weakness and waning), cardiac condution defects due to neuromuscular deficit, cataracts, diabetes, hypogonadism, congenital form is usualy exacerbated in next generation due to CTG trinucleotide repeat expansion. (3) Achondroplasia - shorter limbs, same amount of skin. 90% of the time, results from new mutation (not from mom/dad gene or previous generations). However, these mutations ccur in meiosis so it is not possible that other gametes are formed with same mutation. |
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| Baldness gene is 100% penetrant in men and 0% penetrant in women because the gene relies on male hormone for expression. |
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| Adult muscular dystrophy, myotonia (muscle weakness and waning), cardiac condution defects due to neuromuscular deficit, cataracts, diabetes, hypogonadism, congenital form is usualy exacerbated in next generation due to CTG trinucleotide repeat expansion. |
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| Complete penetrance disorder of shorter limbs, same amount of skin. 90% of the time, results from new mutation (not from mom/dad gene or previous generations). However, these mutations occur in meiosis so it is not possible that other gametes are formed with same mutation. |
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| Males and females affected. Single generations affected. 1/4 of offspring at risk, parents are often consanguineous (blood relatives). Of normal children, there is 66% chance that they are carriers. Ex: Hurler's syndrome - Inability to degrae gylocosaminoglycans (GAGs) in lysosome. Drawfism, progressive retardation, death by age 10 due to cardiac/respiratory insufficiency. |
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| Autosomal dominant condition characterized by the inability to degrade gylocosaminoglycans (GAGs) in lysosome. Drawfism, progressive retardation, death by age 10 due to cardiac/respiratory insufficiency. |
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| Males only affectd. Sporadic generations affected in pedigree, 1/2 of sons affected, daughters of affected males are carriers. Ex: (1) Hunter's syndrome - presents like Hurler's but x-linked. (2) Duchenne Muscular Dystrophy - Most common, severe, mutation in dystrophin gene (very big), 1/3 are new mutations, 65% are deletions leading to frame shift. (3) Fragile X syndrome - most common form of mental retardation in males. X-linked semi-dominant (1/3 of females who have mutant gene have some disability or psychosocial issues due to lyonization--random inactivation of 1 X chromosome in female somatic cell, occurs randomly at 200 cell stage, leading to mosaicism and variable expression patterns like muscle weakness in mothers with boys with DMD). Transmitting males may be clinically unaffected (depends on number of CGG repeats, which often get expanded with each generation during maternal meiosis, NOT paternal. Once # o repeats exceeds 200, the gene is methylated and inactive. Clinical features = mild to severe retardation, large ears, elongated face, connective tissue dysfunction, hyperactivity, autism, speech issues. |
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| Presents like Hurler's but x-linked. |
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| Duchenne Muscular Dystrophy |
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| Most common, severe, mutation in dystrophin gene (very big) on X chromosome. 1/3 are new mutations, 65% are deletions leading to frame shift. |
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| Most common form of mental retardation in males. X-linked semi-dominant (1/3 of females who have mutant gene have some disability or psychosocial issues due to lyonization--random inactivation of 1 X chromosome in female somatic cell, occurs randomly at 200 cell stage, leading to mosaicism and variable expression patterns like muscle weakness in mothers with boys with DMD). Transmitting males may be clinically unaffected (depends on number of CGG repeats, which often get expanded with each generation during maternal meiosis, NOT paternal. Once # o repeats exceeds 200, the gene is methylated and inactive. Clinical features = mild to severe retardation, large ears, elongated face, connective tissue dysfunction, hyperactivity, autism, speech issues. |
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| lyonization--random inactivation of 1 X chromosome in female somatic cell, occurs randomly at 200 cell stage, leading to mosaicism and variable expression patterns like muscle weakness in mothers with boys with Duchenne Muscular Dystrophy). |
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| Females are affected more often than males. Successive generations affected. 1/2 of children of affective females will be affected. All daughters, but no sons of an affected male are affected. Can be lethal in hemizygous affected male. Ex: (1) incontinentia pigmentosi - affects skin, hair, nais, teeth, CNS. (2) X-linked hypophosphatemia - Vitamin D resistant rickets. |
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| X-linked dominant disorder affecting skin, hair, nais, teeth, CNS. |
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| X-linked hypophosphatemia |
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| X-linked dominant Vitamin D resistant rickets. |
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| many proteins, 22 tRNAs and 2rRNAs are involved in oxidative phosphorulation. Transmitted by females only. Hundreds of copies per cell. Cells may contain a mixture of normal and abnormal DNA and phenotypic expression varies, since mitochondria are partitioned randomly to daughter cells. Ex of disorders: (1) MELAS - mitochondrial encephalomyopathy lactic acidosis. Leads to stroke-like episodes. (2)MERRF - Mycolonus epilepsy with ragged red fibers. Accumuated clumps of diseased mitochondria, particularly in muscle. (3) Kearns-Sayre syndrome - opthalmoplegia (no use of eye muscles), retinal generations, heart block. (4) Leber's hereditary optic atrophy (blindness in early adulthood. |
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| mitochondrial encephalomyopathy lactic acidosis. Leads to stroke-like episodes. |
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| Mitochondrial - Mycolonus epilepsy with ragged red fibers. Accumuated clumps of diseased mitochondria, particularly in muscle. |
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| Mitochondrial - opthalmoplegia (no use of eye muscles), retinal generations, heart block. |
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| Leber's hereditary optic atrophy |
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| Mitochondrial - Blindness in early adulthood. |
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| Multi-factoral complex inheritance |
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| Due to gene-gene and gene-environment interactions. Inclues diabetes, 25-50% of peds hospitalizations, 25-35% of peds mortality, and greater % for adults. |
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| Describe distribution of liability of multifactoral complex inheritance in the population |
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| Shifts once a family member has a trait. Ex: if family incidence is 5% in general population, risk increased to 10% if family member has a disease. Still lower risk than mendelian trait. Higher concordance in monozygotic twins with same genomic information. Low concordance in monozygotic twins, even in strong environmental component. Higher concordance in dizygotic twins than in regular siblings. Adoption studies indicate a high level of disorder in adopted offspring with affected parent indicates strong genetic effect. |
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| What does individual risk of multifactorial complex inherited disease depend on? |
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| Severity of disease in relative, relationship with family member, # of affected family members, sex of proband, age of onset, and sonsanguinity. |
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| Example of multifactoral inherited condition - 90% come from negative family history. However, once a child is observed with the defect, incidence is slightly higher. Daily folic acid in 1st trimester helps to prevent this. |
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| What do adoption studies tell us about the genetic component of multi-factorial inherited diseases? |
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| Adoption studies indicate a high level of disorder in adopted offspring with affected parent indicates strong genetic effect. |
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| Examples of Multifactorial inherited disease |
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| (1) Type I diabetes - risk of 1st deg relative much higher than in general population. (2) Type II diabetes - risk higher with relatives and associated with obeisity and insulin resistance. (3) MODY (maturity onsety diabetes in young) - multi-gene autosomal dominant. (4) Breast cancer - BRCA1/2 mutations responsible for 5-10% of cases in US, still strong familiar aggregation. (5) Alcoholism - 10% of adult males, 3-5% in females, 60% monozyg. twin concodance, 30% in diazyg. twins, increased risk even if adopted. (6) Schizophrenia (7) Alzheimers - genes involved in presinilin 1/2 and amyloid beta A4. (8)Affective disorders |
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