Department of Pathology بسم الله الرحمن الرحيم Genetic Disorders Dr. Mohammed Sami Saeed Department of Pathology

The completion of the human genome project has been a landmark event in the study of human diseases. We now know that humans have about 30,000 genes Powerful technologies now allow applications of the human gene sequences in the analysis of human diseases.

However, it is also known that 30,000 genes can give rise to greater than 100,000 proteins. In addition, very recent studies indicate that fully formed proteins can be sliced and stitched together to give rise to peptides. On average, any two individuals share 99.9% of their DNA sequences. Thus, the remarkable diversity of humans is encoded in about 0.1% of our DNA However, this 0.1% represents about 3 million base pairs

The genetic diseases encountered in medical practice represent only the tip of the iceberg, that is, those with less extreme genotypic errors permitting full embryonic development and live birth. It is estimated that 50% of spontaneous abortuses during the early months of gestation have a demonstrable chromosomal abnormality; there are, in addition, numerous smaller detectable errors and many others still beyond our range of identification. About 1% of all newborn infants possess a gross chromosomal abnormality, and approximately 5% of individuals under age 25 develop a serious disease with a significant genetic component.

DNA structure Double helix. Nucleotides. Sugar phosphate backbone Purines and pyrimidine bases Purines : Adenine A Guanine G Pyrimidines : Cytosine C Thymine T

DNA replication

The Human Genome The human genome is all of the genetic information stored in the chromosomes of a human, organized as 46 chromosomes Gene is a region of DNA that produces a functional RNA molecule.

The gene concept Exons. Introns. Promoters. Enhancers. Terminator.

Genetics means the study of a single or few genes and their phenotypic effects. Genomics is the study of all the genes in the genome and their interactions. Proteomics is the measurement of all proteins expressed in a cell or tissue.

Chromosomes consist of a DNA-protein complex Chromatid. One of the two identical parts of the chromosome Centromere. The point where the two chromatids touch. Short arm: p (4) Long arm: q

Hereditary disorders Those disorders that are derived from parents & transmitted through generations. Therefore, they are called familial. Congenital Means born with, so congenital disorders are those disorders that are present at birth. Not all genetic disorders are present during infancy. Some of the congenital diseases have no any genetic defect (e.g. congenital syphilis).

Mutation: is a permanent change in DNA which occurs either in the germ cells (transmitted through the generations), or in the somatic cells (not transmitted). Mutations that affect germ cells give rise inherited disease Mutations that arise in somatic cells are important in the genesis of cancers and some congenital malformations Mutation can be classified into 1. Gene mutation (most common and clinical significant) 2. Genome mutation (alteration in total number of chromosomes) 3. Chromosome mutation (structural changes in chromosomes)

Gene mutation: could be Point mutation That results from the substitution of a single nucleotide base by a different base (called missense mutation) leading to replacement of one amino acid by another. The best e. g. is sickle cell anemia in which glutamic acid is substituted by valine. In certain other conditions, a point mutation may change an amino acid-codon (sequences) into a chain termination codon or stop codon & called non-sense mutation as in β-Thalassemia.

3.Trinucleotide repeat mutation. 2. Frame-shift mutation Which results from insertion or deletion of one or 2 base pairs that alters the reading frame of the DNA strand. A change in 3 or more base pairs leads to missing of one or more amino acids. 3.Trinucleotide repeat mutation. Such type of mutation leads to amplification of a sequence of 3 nucleotides as in fragile X chromosome syndrome in which there is a 250 or more repeat of CGG. (normally up to 29). 4. Mutations within non-coding sequences Deleterious effects may also result from mutations that do not involve the exons. Point mutations involving these regulatory sequences may lead to total lack of transcription.

Human diseases are classified into 3 categories 1. Genetically determined diseases 2. Environmentally determined diseases 3. Genetically & Environmentally determined diseases Virtually all diseases (except trauma) have a genetic component.

Genetic disorders are of 4 main types 1. Single-gene mutation with large effects. Most of these disorders follow the mendelian role, so called mendelian disorders. 2. Chromosomal disorders (genome or chromosomal mutation) Multifactorial also called polygenic. This group is applied to most human diseases like DM & HT. Miscellaneous disorders (disorders with non-classical single gene mutation)

A/ Single-gene mutation (Mendelian disorders) Most of these conditions are hereditary. They follow one of the following disorders Autosomal disorders. Autosomal dominant disorders. Autosomal recessive disorders. Sex- linked disorders. X-linked disorders. Y-linked disorders.

Mendelian disorders: Are due to single gene mutation of large effect. About 80-85% of these mutations are familial, the remainder represent new mutations. Although gene expression is usually described as dominant or recessive, in some cases, both of the alleles of a gene pair may be fully expressed in the heterozygote a condition called codominance. Histocompatibility and blood group antigens are good examples of such.

Phenotype means the clinical expression Phenotype means the clinical expression. Could be physiological (height, color) or pathological (DM, HT). Pleiotropism is a single gene defect that may lead to many phenotypic effects as in sickle cell anemia. Genetic heterogeneity means mutations at several gene-loci that lead to the same clinical disorder as in Phenylketonuria. .

Features of Autosomal Dominant Disorders: male female 50% probability Affected Patient (heterozygous)

Manifested in the heterozygous state. At least one parent is usually affected. Males & females are affected & both can transmit the disorder. When one parent is affected, half of their children have the chance of getting the condition. New mutation plays an important role. In some cases the condition appears as a new mutation (i.e. both parents are not affected). Many such mutations occur in the germ cells of older fathers.

The onset may be delayed in some cases like in Huntington disease. Some persons inherit the disorder but are phenotypically normal this phenomenon is called reduced penetrance. In others the mutant gene is expressed differently among individuals this is called variable expressivity. Non-enzyme proteins are affected usually: Proteins involved in regulation of metabolic pathways. Key structural proteins such as collagen & spectrin are commonly affected.

E.g. Neurofibromatosis, Huntington disease, adult polycystic kidney disease, familial polyposis coli, hereditary spherocytosis, von Willebrand disease, Marfan disease, osteogenesis imperfecta, Achondroplasia, familial hypercholesterolemia.. etc

Autosomal Recessive Disorders: female male 25% diseased, 50% carriers

They represent the largest group of Mendelian disorders. Appear only when both alleles have the same gene mutation (i.e. manifested in the homozygous state). Both parents are usually heterozygous but are phenotypically normal (asymptomatic heterozygous or carriers). Siblings of carrier parents have the chance of one in four to be affected. Usually increased in the marriage between relatives.

Onset is frequently early in life. The expression is mostly uniform. Complete penetrance is common. New mutation is rare. In many cases enzymes are affected E.g., Sickle cell anemia, cystic fibrosis, juvenile polycystic kidney disease, phenylketonuria, glycogen storage diseases, galactosemia, α-1 antitrypsin deficiency, Hemochromatosis, Thalassemia, Lysosomal storage diseases…etc

Sex linked disorders: Almost all these disorders are X-linked. The only Y-linked disorder is the hairy ears. Most of the X-linked disorders are X-linked recessive. The only X-linked dominant disorders are vitamin D-resistant rickets and Alport's syndrome (Hereditary glomerulonephritis with nerve deafness)

X-linked disorders X X X Y X X Y X X Y X X X = affected X

Features of X-linked disorders Females are carriers & males are affected. The carrier females transmit the disorder only to their sons which have the chance of 50% to be affected. The affected male cannot transmit the disease to sons, but all the daughters are carriers.

Heterozygous females rarely express the disease when there is Inactivation of the other X-chromosome. Father is affected & mother is a carrier. Female has one affected X-chromosome as in Turner syndrome. E.g. of X-linked disorders; Duchenne muscular dystrophy, hemophilias, G6PD, fragile X syndrome.

Biochemical and molecular basis of Mendelian disorders: Virtually any type of protein may be affected. The mechanisms involved can be classified into 5 categories: Alteration in the structure, function or quantity of structural proteins. Defects in membrane receptors and transport system. Enzyme defects. Defects in proteins that regulate cell growth Adverse drug reactions.

1/ Diseases caused by mutations in non-enzymatic structural proteins Marfan syndrome: Autosomal dominant disorder of connective tissue that affects fibrillin 1 (a glycoprotein that is secreted by fibroblast) encoded by FBN1 gene (mapped on chr.15). Prevalence, 3 per 10 000 & 75% are familial. Fibrillin 1 is a scaffold for deposition of elastin. Its mutation leads to multiple systemic effects. The main 3 systems affected are the skeleton, eye & cardiovascular system.

Morphology of Marfan Syndrome Skeletal abnormalities include long legs, arms & fingers, hyperextensibility of joints, depressed sternum Ocular changes are bilateral subluxation of the lens CVS abnormalities are aortic aneurysm, aortic incompetence, floppy mitral valve & heart failure

Other examples Sickle cell anemia, Thalassemia and Hereditary spherocytosis

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