Genetic Disorders Lecture PDF

Categories of Genetic Disorders Types of genetic disorders I- Single gene disorders -Due to pathogenic variants (mutations) in individual genes. II- Cytogenetic disorders - Due to defects in chromosomes or part of a chromosome. III- Multifacto...

Categories of Genetic Disorders Types of genetic disorders I- Single gene disorders -Due to pathogenic variants (mutations) in individual genes. II- Cytogenetic disorders - Due to defects in chromosomes or part of a chromosome. III- Multifactorial disorders -Due to defects in two or more genes along with environmental factors (additive effect) Categories of Genetic Disorders Single gene disorders affected affected Single-gene disorders, also known as monogenic disorders, are genetic disorders caused by mutations in a single gene. A mutation Single-Gene Disorders Single-gene disorders are characterized by their inheritance (transmission) patterns in families. Identification of the inheritance pattern is critical to clinical counseling and risk assessment for families (calculate the chances of having a child with the disease or the risk for other relatives to be affected). Single-Gene Disorders 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). Locus (Plural Loci ): The position of a gene on a chromosome. Single-Gene Disorders 22 autosomes or Sex-chromosome Single-Gene Disorders For genes on the autosomal chromosomes (and X-chromosomes in females), each person has two copies; one from each chromosome (homologous chromosomes) inherited from each parent. For genes on the Y chromosome (and X-chromosome in the male), each person has one gene copy. A gene Maternal allele Maternal chromosome A gene Paternal allele Paternal chromosome Homologous chromosomes are pair of chromosomes with similar genes inherited from each parent. Single-Gene Disorders Genotype is the combination of alleles of a gene on homologous chromosomes. Maternal chromosome A gene Normal allele Mutant allele Mutant allele Normal allele Normal allele Mutant allele A gene Alleles Alleles Alleles Normal : Normal Normal : Mutant Mutant : Mutant Genotype Genotype Genotype Paternal Homozygous Heterozygous Homozygous chromosome Locus: Position of a gene on a chromosome. Single-Gene Disorders Genotypes for single gene disorders (traits): Homozygous: identical alleles at a locus Heterozygous: different alleles at a locus hemizygous: male for alleles at X and Y chromosomes Single-Gene Disorders Pedigree I A first step to establish a pattern of inheritance of a particular II disease within a family is to obtain information about the 1 2 3 family history and summarize it in a pedigree. A pedigree is a graphical representation of the family tree with standard symbols. Single-Gene Disorders Pedigree I The pedigree starts with the first person through whom the family came to medical attention, called the index or II proband. 1 2 3 Relatives of the index are classified as follows: Parents, siblings, and offspring are first-degree. Grandparents, grandchildren, uncles, aunts, nephews, and nieces are second-degree. First cousins are third-degree Couples who have one or more ancestors in common are consanguineous. Single-Gene Disorders Pedigree Pedigree symbols Normal Male Affected Male Heterozygous Male Normal Female Affected Female Heterozygous Female Single bar indicates Double bar indicates a Index or proband marriage consanguineous couple (marriage between relatives) I Romanic numbers for First generation generations II Second generation 1 2 3 Arabic numbers for birth order The proband (II-2) is an affected female with two healthy siblings (II-1 and II-3). Single-Gene Disorders Pedigree Pedigree analysis Steps for evaluating a pedigree to determine the pattern of inheritance: 1. Transmission Vertical: The disease passed from generation to generation (i.e., parents to offspring) Horizontal The disease appears in one generation (phenotypically healthy parents with affected offspring). 2. Sex differences (ratio of female vs. male) 3. Pattern Does the condition pass from male-to-male only (suggest Y-linked) Does the condition pass from father-to-daughter only (no father-to-son transmission) (suggest X- linked) Does the condition pass from unaffected female (suggest X-linked recessive) Does the condition appear to skip generation Does the parent or one of them are affected Single-Gene Disorders Patterns of inheritance for single gene disorders (traits): Autosomal Dominant (AD) Autosomal Recessive (AR) X-linked (dominant or recessive) Y-linked Autosomal Dominant (AD) 22 autosomes Autosomal? or Equally can be affected Dominant? Genotype dd DD Dd D= Mutant allele d= Normal allele Phenotype Unaffected Affected Affected Autosomal Dominant (AD) 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 AD Homozygous and heterozygous for the mutant allele are affected. Male and female are equally affected Autosomal Dominant (AD) Alleles segregation Allele segregation: the two alleles for each gene are separated into two different gamete cells. Affected Affected Dd Dd D= Mutant allele d= Normal allele d D d D 50% 50% 50% 50% 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. Autosomal Dominant (AD) Alleles segregation Allele segregation: the two alleles for each gene are separated into two different gamete cells. Unaffected Affected dd Dd D= Mutant allele d= Normal allele d d d D 50% 50% 50% 50% 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. Autosomal Dominant (AD) Genetic Risks Unaffected dd d d Possibilities d ½ (50%) healthy Affected Dd dd dd ½ (50%) affected D Dd Dd Unaffected Affected D= Mutant allele d= Normal allele Autosomal Dominant (AD) Genetic risk Father d d Father d d dd Mother dd Mother d D DD Dd D D Father d D Dd Mother d Dd D D= Mutant allele d= Normal allele Autosomal Dominant (AD) Family pedigree D: Mutant allele d: Normal allele I dd Dd Normal Male II Dd dd Dd dd Dd dd Affected Male Normal Female III Affected Female dd Dd dd Dd dd Dd dd Single bar indicates marriage IV Dd Dd dd Autosomal Dominant (AD) Family pedigree Pedigree analysis Transmission Vertical: The disease passes from generation to generation (i.e., parents to offspring). Affected individuals have at least one affected parent (Vertical transmission). Male-to-male transmission (to exclude X-linked) Males and females are equally affected Autosomal Dominant (AD) CLINICAL APPLICATION Marfan Syndrome (OMIM 154700) Inherited as an autosomal dominant Due to a mutation in FBN1 gene encoding fibrillin, a gene is required for connective tissue's structural integrity. Affects the skeletal system, eyes, and cardiovascular system Clinical features include tall stature, long fingers, bilateral subluxation of the lens, floppy mitral valve, aortic aneurysm, and aortic dissection. Autosomal Dominant (AD) CLINICAL APPLICATION Examples of autosomal dominant diseases Autosomal Recessive (AR) 22 autosomes Autosomal? or Equally can be affected Recessive? Genotype dd DD Dd D= Mutant allele d= Normal allele Phenotype Unaffected Affected Unaffected Carrier Autosomal Recessive (AR) 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 AR Only homozygous for the mutant allele is affected. Heterozygous is a carrier Males and females are equally affected Autosomal Recessive (AR) Alleles segregation Allele segregation: the two alleles for each gene are separated into two different gamete cells. Unaffected Unaffected Carrier Carrier Dd Dd D= Mutant allele d= Normal allele d D d D 50% 50% 50% 50% 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. Autosomal Recessive (AR) Genetic Risks Carrier Dd d D Possibilities d ¼ (25%) healthy Carrier Dd dd Dd ¼ (25%) affected D ½ (50%) carrier Dd DD Unaffected D= Mutant allele Affected d= Normal allele Unaffected (Carrier) Autosomal Recessive (AR) Inheritance of AR Father d d Father d d dd Mother dd Mother d D DD Dd D D Father d D Dd Mother d Dd D Unaffected D= Mutant allele Affected d= Normal allele Unaffected (Carrier) Autosomal Recessive (AR) Family pedigree D: Mutant allele d: Normal allele I Dd dd Normal Male II Affected Male dd Dd dd dd dd Dd dd Normal Female Affected Female III dd Dd Dd Dd dd Carrier Male Carrier Female IV Dd dd DD DD Double bar indicates a consanguineous marriage (mating between relatives) Autosomal Recessive (AR) Family pedigree Pedigree analysis Transmission horizontal: Unaffected (carrier) parents can have affected offspring (horizontal transmission) Phenotypically unaffected parents with affected offspring may be related to each other (consanguineous) Male-to-male transmission (to exclude X-linked) Males and females are equally affected Autosomal Recessive (AR) CLINICAL APPLICATION Sickle cell anemia (OMIM 603903) Inherited as an autosomal recessive Due to a mutation in the HBB gene which codes for the hemoglobin protein. , the O2 transport protein in red blood cells (RBSs). Lethal as homozygous and heterozygous generally unaffected. In KSA, the disease frequency is between 2% to 27%. Most common in eastern regions, then southwest*. pre-marriage screening was established to reduce the disease prevalence. * Ann Saudi Med. 2011 May-Jun; 31(3): 289–293. Autosomal Recessive (AR) Examples of autosomal Recessive diseases