X-linked Dominant (XLD) Lecture PDF

X-linked dominant (XLD) X-linked ? sex chromosome or Dominant ? Genotype XdXd XDXD XDXd...

X-linked dominant (XLD) X-linked ? sex chromosome or Dominant ? Genotype XdXd XDXD XDXd Xd XD XD= Mutant allele Xd = Normal allele Phenotype Unaffected Affected Affected Unaffected Affected X-linked dominant (XLD) The patterns of inheritance depend on the following: 1. Chromosomal location of the gene locus A. On an autosome (chromosomes 1 to 22) B. On a sex-chromosome (X and Y chromosomes) C. In the mitochondrial DNA 2. Whether the phenotype is: A. dominant expressed when only one gene copy has a pathogenic variant (mutation). B. recessive expressed only when the two gene copies have the pathogenic variant (mutation). In XLD Homozygous and heterozygous females are affected Males have one X chromosome (Hemizygous) X-linked dominant (XLD) Alleles segregation Allele segregation: the two alleles for each gene are separated into two different gamete cells. Unaffected Affected Affected Unaffected Affected Xd Y XD Y XD Xd Y Xd Y XD Xd XD 50% 50% 50% 50% 50% 50% XD= Mutant allele Xd = Normal allele During gametogenesis, the two alleles for a gene are separated into two different gamete cells (sperms in males and ova in females) (recall meiosis). If one allele is mutant and the other is normal (heterozygous), 50% of gametes carry the mutant allele, and 50% carry the normal allele. X-linked dominant (XLD) Genetic Risks Unaffected Possibilities Xd Y For a heterozygous affected mother: Affected Y Xd ½ (50%) healthy child ½ (50%) affected child Xd XD Xd XD Unaffected XD= Mutant allele Affected Xd = Normal allele X-linked dominant (XLD) Genetic Risks Affected Possibilities XD Y For a hemizygous affected Unaffected father: Y XD 100% affected female child Xd 100% healthy male child Xd Xd Xd Unaffected XD= Mutant allele Affected Xd = Normal allele X-linked dominant (XLD) Family pedigree XD: Mutant allele Xd: Normal allele I XD XdXd Normal Male Affected Male II XDXd Xd Xd XdXd Xd XDXd Normal Female Affected Female III XdXd XD XdXd XD XdXd Xd XdXd XD XDXd Xd IV XDXd XDXd XDXd Xd Xd Xd Xd XDXd XD XDXd XdXd Xd X-linked dominant (XLD) Family pedigree Pedigree analysis Transmission The disease passes from generation to generation (i.e., parents to offspring). Affected individuals have at least one affected parent (Vertical transmission). NO male-to-male transmission (to exclude X-linked). All female offspring of an affected male are affected. X-linked dominant (XLD) CLINICAL APPLICATION Rett Syndrome (OMIM 312750) Familial Rett Syndrome inherited as an X-linked dominant disease. The disease is due to a mutation in the MECP2 gene, an essential gene for brain development. In general, affected girls appear normal up to 18 months when development arrest occurs. Common findings include: regression of acquired skills such as language, stereotypic movements, microcephaly, seizures, and mental retardation. X-linked recessive (XLR) Why? X-linked ? sex chromosome < or Male more than female Recessive? Genotype XdXd XDXD XDXd Xd XD XD= Mutant gene Xd = Normal gene Phenotype Unaffected Affected Unaffected Unaffected Affected Carrier X-linked recessive (XLR) The patterns of inheritance depend on the following: 1. Chromosomal location of the gene locus A. On an autosome (chromosomes 1 to 22) B. On a sex-chromosome (X and Y chromosomes) C. In the mitochondrial DNA 2. Whether the phenotype is: A. dominant expressed when only one gene copy has a pathogenic variant (mutation). B. recessive expressed only when the two gene copies have the pathogenic variant (mutation). In XLR Homozygous female is affected, while heterozygous is a carrier. Male is either affected or healthy. Females are less commonly affected because they must inherit two mutant alleles to have the disease. X-linked recessive (XLR) Alleles segregation Allele segregation: the two alleles for each gene are separated into two different gamete cells. Unaffected Unaffected Affected Carrier Unaffected Affected Xd Y XD Y XD Xd Y Xd Y XD Xd XD 50% 50% 50% 50% 50% 50% XD= Mutant allele Xd = Normal allele During gametogenesis, the two alleles for a gene are separated into two different gamete cells (sperms in males and ova in females) (recall meiosis). If one allele is mutant and the other is normal (heterozygous), 50% of gametes carry the mutant allele, and 50% carry the normal allele. X-linked recessive (XLR) Alleles segregation Unaffected Possibilities Xd Y For a heterozygous carrier mother: Unaffected Carrier For female child Y Xd ½ (50%) healthy ½ (50%) healthy carrier XD= Mutant allele Xd For male child Xd = Normal allele ½ (50%) healthy XD Xd ½ (50%) affected XD Unaffected A carrier female has 50% chance to have an affected male child, Affected 0% to have an affected female child. Unaffected (Carrier) X-linked recessive (XLR) Family pedigree XD: Mutant allele Xd: Normal allele I Xd XDXd Normal Male Affected Male Normal Female II XD Xd XdXd XD Xd XDXd XDXd Affected Female Carrier Male III Xd XD XDXd XDXD XDXD XD XDXd Xd Carrier Female IV XDXd Xd XdXd XD XD XDXd XdXd Xd X-linked recessive (XLR) Family pedigree Pedigree analysis Transmission Affected males can transmit the disease to their male grandchildren through female carriers (diagonal transmission). All affected males are connected to a carrier female. NO male-to-male transmission. More affected males in the pedigree than females. X-linked recessive (XLR) CLINICAL APPLICATION Hemophilia A (OMIM 306700) Is an X-linked recessive disorder. Due to a mutation in the F8 gene which causes a defect in the coagulating factor VIII, the blood clotting factor. Individuals with hemophilia bleed longer than ordinary people. The severity of the disease depends on factor VIII plasma level. It can be categorized into mild 6-30% of the normal level, moderate 2-5% of the normal level, and severe 1% of the normal level. X-linked recessive (XLR) CLINICAL APPLICATION Green Colorblindness (OMIM 303800) Red Colorblindness (OMIM 303900) Due to a mutation in one of the visual pigment genes or receptors (cons or rods) In the retina are photoreceptor cells (rod and cone cells). Cone cells contain proteins (opsins) that react to the wavelength of the three main colors red, green, and blue. The most common defects in human vision involve red and green color perception, which is inherited as XLR. X-linked recessive (XLR) Green Colorblindness (OMIM 303800) Red Colorblindness (OMIM 303900) Medical genetics 4th eddition by Jorde, Carey and Bamshad X-linked recessive (XLR) colormax.org/color-blind-test/ colorlitelens.com/color-blind-test.html X-linked recessive (XLR) Normal vision see 29 Normal vision see 42 Red-green color blind see 70 Red-color blindness see 2 Total color blind see nothing colormax.org/color-blind-test/ colorlitelens.com/color-blind-test.html Single Gene Disorders OMIM database Single Gene Disorders OMIM database OMIM stands for Online Mendelian Inheritance in Man Created in 1966 by Dr. Victor McKusick, and maintained by the Johns Hopkins University School of Medicine Comprehensive, publicly available database of human genes, genetic disorders, and traits Catalogs information on over 16,000 genes, as well as over 7,000 phenotypic traits. Each entry includes a detailed description of the gene, its functions, and the associated genetic disorder or trait, and mode of inheritance. Entries are indexed and searchable by a variety of criteria, including gene name, disease name, phenotype, and inheritance pattern Widely used by researchers, clinicians, and genetic counselors to aid in the diagnosis and management of genetic disorders Single Gene Disorders OMIM database An OMIM number is a unique identifier assigned to each entry in the OMIM database. It is a six-digit number that is used to uniquely identify a particular gene, genetic disorder, or phenotype in the database. OMIM numbers are widely used by researchers, clinicians, and genetic counselors to identify and study genetic disorders and traits. OMIM numbers are often referenced in scientific literature and genetic testing reports to identify the specific gene or disorder being studied or tested. For example, the OMIM number for the gene associated with Marfan syndrome is 134797, while the OMIM number for Sickle cell disease is 603903. Single Gene Disorders OMIM database Each indexed disease or gene has OMIM number Mitochondrial inheritance Mitochondrial inheritance Mitochondria are cytoplasmic organelles that contain their own genome. They are responsible for cellular respiration and energy production (ATP). Mitochondria are essential for normal cell function, therefore defects in respiration and energy production usually results in sever disease. Each cell contains multiple copies of mitochondrial DNA (mtDNA) (polyploid). Mitochondrial inheritance Mitochondrial inheritance During fertilization, all mitochondria from the sperms are subjected to degradation after fertilization, and the only source of mitochondria in the zygote is the ovum. Thus, only maternal mitochondrial DNA (mtDNA) is transmitted to the next generation in the family. Pedigrees of mitochondrial disorders (due to defects in the mtDNA) are typically inherited from the mother (maternal inheritance). Disorders due to defects in mtDNA are considered single-gene disorders. X-linked dominant (XLD) Family pedigree I Normal Male Affected Male II Normal Female Affected Female III IV Mitochondrial inheritance The patterns of inheritance depends on: 1. Chromosomal location of the gene locus A. On an autosome (chromosomes 1 to 22) B. On a sex-chromosome (X and Y chromosomes) C. In the mitochondrial DNA 2. Whether the phenotype is: A. dominant expressed when only one copy of the gene has a pathogenic variant (mutation). B. recessive expressed only when the two copies of the gene have the pathogenic variant (mutation). In XLR Offspring of affected male are not affected Mitochondrial inheritance CLINICAL APPLICATION Mitochondrial replacement techniques (MTRs) can provide women with mitochondrial disorders a way to have normal biological children. One approach involves removing the nucleus from a healthy donor egg and replacing it with a nucleus taken from the egg cell of a woman with a rare mitochondrial disease. Nevertheless, MTRs are controversial and require extensive research to ensure their safety and effectiveness.