L35 Mendelian Inheritance AD vs AR PDF

35 Mendelian Inheritance Autosomal Dominant vs Recessive Disorders ILOs By the end of this lecture, students will be able to 1. Determine patterns of Mendelian inheritance. 2. Identify characteristics of autosomal inheritance. 3. Calculate the recurrence risk of monogenic au...

35 Mendelian Inheritance Autosomal Dominant vs Recessive Disorders ILOs By the end of this lecture, students will be able to 1. Determine patterns of Mendelian inheritance. 2. Identify characteristics of autosomal inheritance. 3. Calculate the recurrence risk of monogenic autosomal disorders using Punnett square. 4. Interpret pedigrees for autosomal dominant and recessive modes of inheritance. 5. Correlate hereditary disorders with autosomal dominant and recessive modes of inheritance. Mendelian inheritance Simple Mendelian inheritance refers to the inheritance of traits controlled by a single gene with two alleles, one of which may be completely dominant to the other. The pattern of inheritance of simple traits depends on whether the traits are controlled by genes on autosomes (autosomal inheritance) or by genes on sex chromosomes (sex-linked inheritance). Mendelian inheritance follows the laws of segregation and independent assortment in which a gene inherited from either parent segregates into gametes at an equal frequency. More than 16000 traits or disorders in humans exhibit single gene or simple mendelian inheritance. However, characteristics such as height, and many common familial disorders, such as diabetes or hypertension, usually follow a non-mendelian inheritance. Studying Inheritance Patterns There are two very useful tools for studying how traits are passed from one generation to the next: 1. Pedigree: A pedigree is a chart representation of an individual ancestry and relatedness of family member constructed from detailed family history with use of standard symbols (Figure 1). It shows relationships and identifies individuals with a given trait. It shows how a trait is passed from generation to generation within a family. It determines the mode of inheritance of a trait; whether a trait is an autosomal dominant, autosomal recessive or X-linked trait. It allows accurate risk calculation for family members. Page 1 of 4  Figure 1. Symbols commonly used in pedigree charts. 2. Punnett Square (Figure 3 & 5) A Punnett square is a chart that allows determination of the expected ratios of possible genotypes in the offspring of two parents. CHARACTERSTICS OF DIFFERENT MODES OF MENDELIAN INHERITANCE: Autosomal dominant (AD) inheritance: An autosomal dominant trait is one that manifests in the heterozygous state, that is, in a person possessing both an abnormal or mutant allele and the normal allele. It is often possible to trace a dominantly inherited trait or disorder through many generations of a family. Each gamete from an individual with a dominant trait or disorder will contain either the normal allele or the mutant allele. Characteristics of AD inheritance: Affect both males and females in equal proportions. All forms of transmission between the sexes are observed Affected people are usually born to at least one affected parent (unless new mutation). The pedigree usually shows vertical transmission of the trait through generations (Figure 2). Usually involves genes encoding regulatory proteins of complex metabolic pathways or key structural proteins (fibrillin in Marfan syndrome). Affected children are usually heterozygous. Homozygous genotype is rare and when it occurs usually shows a more severe phenotype than heterozygous. Page 2 of 4  NB. The phenotype in AD inheritance usually appears in every generation, each affected person having an affected parent. Exceptions or apparent exceptions to this rule in clinical genetics are: (1) Cases originating from fresh mutations in a gamete of a phenotypically normal parent. (2) Cases in which the disorder is not expressed (non-penetrant). (3) Cases in which the disorder shows variation in the clinical phenotype among generations of the same family (Variable expressivity) as polycystic kidney. Genetic risk of AD inheritance: A child of an affected heterozygous parent has a 50% risk of being affected independent of sex. Usually, unaffected members of the family do not carry the mutant allele; thus they cannot transmit a disease allele to the next generation (Figure 3). Figure 2. Pedigree of AD trait. Figure 3. Punnett square of AD trait. Examples of AD inheritance: Nervous system: Neurofibromatosis. Hematology: Hereditary spherocytosis. Autosomal Recessive (AR) inheritance: In autosomal recessive inheritance, both alleles must be abnormal for the disease trait to be expressed. The unaffected parents of an affected child are obligate heterozygote carriers for the recessive mutant allele. Characteristics of AR inheritance: Males and females are equally likely to be affected. Transmitted by either sex Page 3 of 4  Affected people are usually born to un affected parents (asymptomatic healthy carriers) More commonly observed with consanguineous matings. The pedigree usually shows horizontal transmission of trait with multiple members of one generation affected (Figure 4). Usually involve genes of enzymes and proteins. Affected children may be homozygous for a specific recessive mutant allele, or they may be compound heterozygotes for two different mutations. Genetic risk of AR inheritance: Couples who are heterozygous carriers of a recessive mutant allele have a 25% risk of having an affected child with each pregnancy. The unaffected siblings have a 67% (two-thirds) chance of being a carrier for the mutant allele (Figure 5). Figure 5. Punnett square of AR trait. FIGURE 5. A Punnett square of AR trait. Examples of AR inheritance: The OMIM (Online Mendelian Inheritance in Man) database contains nearly 4,000 traits inherited as autosomal recessives. Metabolic disorders: cystic fibrosis, phenylketonuria, lysosomal storage disorders Haematology: sickle cell anemia, thalassemia. Page 4 of 4