Patterns of Single-Gene Inheritance PDF

Patterns of Single-Gene Inheritance Chapter 7 Overview and Concepts Genotype and Phenotype Genotype is the alleles occupying a locus on the two homologous chromosomes, determining an individual's genetic makeup. Haplotype is the set of alleles at neighboring loci on one of the homologous chromosomes...

Patterns of Single-Gene Inheritance Chapter 7 Overview and Concepts Genotype and Phenotype Genotype is the alleles occupying a locus on the two homologous chromosomes, determining an individual's genetic makeup. Haplotype is the set of alleles at neighboring loci on one of the homologous chromosomes, distinct from genotype. Phenotype is the expression of genotype as observable traits, whether morphological, clinical, cellular, or biochemical. Phenotypes can be qualitative (e.g., presence or absence of a disease) or quantitative (e.g., body mass index, blood glucose levels). Overview and Concepts Genotype and Phenotype Homozygosity and heterozygosity refer to having identical or different alleles at a locus, respectively. Compound heterozygotes are individuals who inherit two different mutant alleles of a gene, one from each parent. Hemizygosity is a genetic condition in which an individual has only one copy of a particular gene or DNA sequence in a diploid organism. In human it occurs when an XY male has a variant allele for a gene located on the X chromosome. Overview and Concepts Genotype and Phenotype Mitochondrial DNA genotypes are not described using terms like homozygous or heterozygous due to their unique characteristics. Single-gene disorders are determined by alleles at a single locus and follow mendelian inheritance patterns. Mendelian disorders are important for individual patients due to their impact on family health and the availability of genetic testing and management options. Penetrance and Expressivity - Penetrance is the probability that an allele or alleles will have any phenotypic expression at all. - Penetrance is all or nothing. - Expressivity refers to the severity of expression of that phenotype among individuals with the same diseasecausing genotype. Pedigree A graphical representation of the family tree – with use of standard symbols Patterns of Inheritance The patterns of inheritance shown by single-gene disorders (inherited in a Mendelian fashion) depend chiefly on two factors: 1- Whether the chromosomal location of the gene locus is on an autosome (chromosomes 1–22), on a sex chromosome (X and Y chromosomes), or in the mitochondrial genome 2- Whether the phenotype is dominant (expressed when only one chromosome carries the pathogenic allele) or recessive (expressed only when both chromosomes of a pair carry pathogenic alleles at a locus) Dominant and Recessive Triats A phenotype is recessive if it's only expressed in homozygotes or compound heterozygotes who lack a wild-type allele, never in heterozygotes. Dominant inheritance pattern happens when a phenotype is expressed in heterozygotes as well as in homozygotes (or compound heterozygotes). In incompletely dominant inheritance, homozygotes or compound heterozygotes for pathogenic alleles are more severely affected than heterozygotes. Codominant inheritance happens when phenotypic expression of both alleles at a locus occurs in a compound heterozygote (e.g. ABO blood group). ABO Blood group The ABO blood group system is crucial in medical contexts such as blood transfusion and tissue transplantation. It involves three alleles (A, B, and O) at the ABO locus, forming a three-allele system. Alleles A and B govern expression of A or B carbohydrate antigens on red cells as a codominant trait, while allele O results in no expression of these antigens, being recessive. The difference between A and B antigens lies in the sugar molecule that makes up the terminal sugar on a glycoprotein called H. ABO Blood group There are four possible phenotypes: O, A, B, and AB. Type A individuals have antigen A, type B individuals have antigen B, type AB individuals have both antigens, and type O individuals have neither. When red blood cells lack antigen A, the serum contains anti-A antibodies, and vice versa for antigen B. Formation of anti-A and anti-B antibodies without prior blood transfusion is believed to be a response to the natural occurrence of A-like and B-like antigens in the environment, such as in bacteria. ABO Blood group Autosomal Patterns of Mendelian Inheritance Autosomal Recessive Inheritance Autosomal recessive diseases occur when individuals have pathogenic variants on both inherited alleles and no wild-type allele. Homozygotes or compound heterozygotes must inherit a pathogenic allele from each parent, both of whom are usually heterozygotes for that allele. The pathogenic variants responsible for recessive inheritance often lead to a loss-of-function mutation, reducing or eliminating the function of the gene product, such as enzymes. Autosomal Patterns of Mendelian Inheritance Autosomal Recessive Inheritance In heterozygotes, a remaining normal gene copy can compensate for the pathogenic allele and prevent the disease, but in homozygotes or compound heterozygotes, disease occurs. The risk of transmitting autosomal recessive disorders is 25% when both parents are carriers, as each parent passes an allele at random to their offspring. Autosomal recessive disorders can also occur when one parent is a carrier and the other has the disease, with a 50% risk of transmission. If both parents are affected by the identical condition, autosomal recessive disorders will always appear in offspring, as neither parent has a wild-type allele to transmit. Autosomal Patterns of Mendelian Inheritance Autosomal Recessive Inheritance Autosomal Patterns of Mendelian Inheritance Autosomal Recessive Inheritance Autosomal Patterns of Mendelian Inheritance Autosomal Dominant Inheritance More than half of all known Mendelian disorders are inherited as autosomal dominant traits. The risk and severity of dominantly inherited diseases in offspring depend on whether one or both parents are affected and whether the trait is pure dominant or incompletely dominant. Autosomal dominant inheritance can occur when one parent is heterozygous (D/d) and the other is homozygous for the normal allele (d/d). Each child of such parents has a 50% chance of inheriting the affected allele (D) and a 50% chance of inheriting the normal allele (d). Homozygotes for dominant phenotypes are rare in practice, but offspring of two affected individuals (D/d) could have a homozygous genotype (D/D) 25% of the time. Early lethality of the phenotype may limit the observation of individuals with a homozygous genotype. Autosomal Patterns of Mendelian Inheritance Autosomal Dominant Inheritance Autosomal Patterns of Mendelian Inheritance Autosomal Dominant Inheritance Autosomal Patterns of Mendelian Inheritance X-Linked Inheritance X-linked disorders can be classified as either X-linked recessive or Xlinked dominant based on the expression pattern. X-linked recessive conditions are expressed only in hemizygotes and never in heterozygotes, while X-linked dominant conditions are always expressed in heterozygotes as well as in hemizygotes. Determining whether a disease with an X-linked inheritance pattern is dominant or recessive can be challenging due to epigenetic regulation of X-linked gene expression in carrier females caused by X chromosome inactivation. Autosomal Patterns of Mendelian Inheritance X-Linked Inheritance Autosomal Patterns of Mendelian Inheritance X-Linked Recessive Inheritance Autosomal Patterns of Mendelian Inheritance X-Linked Dominant Inheritance Autosomal Patterns of Mendelian Inheritance X-Linked Dominant Inheritance Maternal Inheritance of Disorders Caused by Variants in the Mitochondrial Genome Mitochondrial inherited diseases does not show patterns typical of mendelian inheritance. The mitochondrial genome consists of 37 genes that encode 13 subunits of enzymes involved in oxidative phosphorylation, ribosomal RNAs, and transfer RNAs required for translating the transcripts of the mitochondriaencoded polypeptides. Pleiotropy is the rule in mitochondrial disorders (single genetic variant leads to a range of clinical manifestations across different tissues and organs in the body). Maternal Inheritance of Disorders Caused by Variants in the Mitochondrial Genome Features of mtDNA inheritance: 1- Maternal inheritance 2- Replicative segregation 3- Homoplasmy and heteroplasmy. Maternal Inheritance of Disorders Caused by Variants in the Mitochondrial Genome Features of mtDNA inheritance: 1- Maternal inheritance Sperm mitochondria are generally not present in the zygote. All children of a female homoplasmic for a pathogenic variant will inherit the variant; the children of a male carrying a similar variant will not. Maternal Inheritance of Disorders Caused by Variants in the Mitochondrial Genome Features of mtDNA inheritance: 1- Maternal inheritance Maternal Inheritance of Disorders Caused by Variants in the Mitochondrial Genome Features of mtDNA inheritance: 2- Replicative segregation The number of mtDNA copies per cell is not fixed and is substantially higher than the number of nuclear DNA copies. There is no fixed phase of the cell cycle for the replication of mtDNA. At cell division, the copies of mtDNA in each of the mitochondria in each cell sort randomly to the daughter cells. Maternal Inheritance of Disorders Caused by Variants in the Mitochondrial Genome Features of mtDNA inheritance: 3- Homoplasmy and heteroplasmy. Homoplasmy is the uniform presence of an identical mtDNA sequence. Hetroplasmy is the presence of variant sequence of mtDNA. The phenotypic expression of a pathogenic variant in mtDNA depends on a quantitative value. Maternal Inheritance of Disorders Caused by Variants in the Mitochondrial Genome Features of mtDNA inheritance: 3- Homoplasmy and heteroplasmy. Importance of The Family History in Medical Practice “To fail to take a good family history is bad medicine.” To determine the pattern of inheritance of a disorder in the family, forming a differential diagnosis, determining what genetic testing might be needed, and designing an individualized management and treatment plan for their patients. To allow the risk in other family members to be estimated so that proper management, prevention, and counseling can be offered to the patient and the family.