Genetic Diseases Notes PDF

Genetic Diseases Dr. Nuruddin Mohammed Nur  Learning Outcomes 1. Understand 2. Understand Mendelian Disorders Cytogenetic Disorders  Introduction to Genetics What are genetic disorders? Disorders caused by mutations in genes or chromosomes. Main Categories: Mendeli...

Genetic Diseases Dr. Nuruddin Mohammed Nur  Learning Outcomes 1. Understand 2. Understand Mendelian Disorders Cytogenetic Disorders  Introduction to Genetics What are genetic disorders? Disorders caused by mutations in genes or chromosomes. Main Categories: Mendelian Disorders Cytogenetic Disorders Importance of understanding genetic disorders: - Diagnosis, treatment, and genetic counseling.  Mendel's Laws: Law of Segregation Law of Independent Assortment Mendelian Inheritance Types of Mendelian Overview Inheritance: Autosomal Dominant Autosomal Recessive X-linked Dominant X-linked Recessive  Mendel's Laws of Inheritance Alleles segregate during Law of Segregation: gamete formation; each gamete carries one allele. Genes for different traits Law of Independent assort independently of Assortment: one another. Mendel's Laws of Inheritance  Autosomal Dominant Inheritance Definition: One copy of the mutated gene causes the disorder. Key Features: Affects males and females equally. 50% chance of passing to offspring. Examples: Marfan Syndrome Huntington's Disease. Autosomal Dominant Pedigree  Cause: Mutation in FBN1 gene (fibrillin-1 protein). Autosomal Dominant Features: - Marfan Tall stature, long limbs, cardiovascular Syndrome issues, ocular abnormalities. Diagnosis: Genetic testing, clinical criteria (Ghent criteria)  Cause: CAG trinucleotide repeat expansion in HTT gene. Autosomal Dominant Features: - Progressive neurodegeneration, involuntary Huntington’s movements, cognitive decline. Disease Diagnosis: Genetic testing for CAG repeat count.  Autosomal Recessive Inheritance Definition: Two copies of the mutated gene are needed to cause the disorder. Key Points: Parents are usually carriers (asymptomatic). 25% chance of having affected children. Examples: Cystic Fibrosis, Sickle Cell Anemia. Autosomal Recessive Inheritance  X-Linked Recessive Inheritance Definition: Mutations on the X chromosome, primarily affecting males. Key Points: Females are carriers and usually unaffected. No male-to-male transmission. Examples: Hemophilia A, Duchenne Muscular Dystrophy.  X-Linked Definition: One mutated X chromosome causes the disorder in both sexes. Dominant Inheritance Key Points: Affected males pass to all daughters but not sons. More females affected due to two X chromosomes. Examples: Rett Syndrome, Fragile X Syndrome.  Diagnostic Techniques for Mendelian Disorders Genetic Testing: Sanger sequencing, next-generation sequencing (NGS). Biochemical Tests: Metabolic screening for enzyme deficiencies. Clinical Evaluation: Family history, physical examination.  Definition: Disorders caused by chromosome number or Cytogenetic structure abnormalities. Types: Disorders Numerical Abnormalities (e.g., Trisomy 21, Turner Syndrome). Overview Structural Abnormalities (e.g., Deletions, Duplications).  Numerical Trisomy 21 (Down Syndrome): - Extra chromosome 21. Chromosomal - Symptoms: Intellectual disability, Abnormalities facial features. Turner Syndrome: - Monosomy X (45,X). - Symptoms: Short stature, webbed neck. Trisomy 21 – Down Syndrome Extra Chromosome at chromosome 21 Male, Trisomy 21 (Down’s) 2n = 24 47  Trisomy 13 – Patau Syndrome 47, XX or XY, +13 serious eye, brain, circulatory defects as well as cleft palate. 1:5000 live births. Children rarely live more than a few months. Patau Syndrome  Cause: Monosomy X (missing X chromosome in females). Cytogenetic Features: Short stature, Disorders - webbed neck, primary Turner amenorrhea. Syndrome Diagnosis: Karyotyping, prenatal ultrasound (cystic hygroma).  Turner Syndrome the ONLY viable monosomy No Barr bodies (randomly inactivated X chromosome) are present in a buccal smear  Deletions: Missing Structural chromosome segment (e.g., Cri- du-chat syndrome). Chromosomal Abnormalities Duplications: Extra segment of a chromosome (e.g., Charcot- Marie-Tooth disease). Translocations: Segment attached to another chromosome (e.g., Philadelphia chromosome). Single Chromosome Disorders 1. Deletion Genetic material is missing2. 2. Duplication Genetic material is present twice 3. Inversion Genetic material is “flipped” Translocations  Philadelphia chromosome : Translocation between 9 and 22 results in the formation of a hybrid gene ,which leads to Chronic myelogenous leukemia (CML) Philadelphia A specific chromosomal abnormality that is associated with CML(95%). Chromosome Due to a reciprocal translocation Or designated as t(9;22)(q34;q11), which means an exchange of genetic material between region q34 of chromosome 9 Philadelphia and region q11 of chromosome 22. Translocation Translocation is a highly sensitive test for CML, since 95% of people with CML have this abnormality. Not sufficient to diagnose CML, since it is also found in ALL (25–30% in adult and 2–10% in pediatric cases) and occasionally in AML.  Karyotyping: Diagnostic Visualizes entire chromosome set. Techniques for FISH (Fluorescence In Situ Hybridization): Identifies chromosomal regions. Cytogenetic Array CGH(Comparative Genomic Disorders Hybridization) : Detects microdeletions or duplications.  Definition: A technique to visualize the complete set of chromosomes in a cell, arranged in pairs by size and shape. Procedure: 1. Cells are cultured, arrested during metaphase, and stained. 2. Chromosomes are visualized under a microscope. Applications: Karyotyping Detect numerical abnormalities (e.g., Trisomy 21, Turner Syndrome). Identify large structural changes (e.g., translocations, deletions). Example: Diagnosis of Down Syndrome: Karyotype shows an extra chromosome 21 (47,XX,+21 or 47,XY,+21).  Definition: A molecular technique that uses fluorescent Fluorescence probes to bind specific DNA sequences on chromosomes. Procedure: In Situ 1. DNA probes labeled with fluorescent dyes are hybridized to patient chromosomes. Hybridization 2. Fluorescent signals are analyzed under a specialized microscope. (FISH) Applications: Detect specific chromosomal abnormalities (e.g., microdeletions, duplications). Identify structural rearrangements (e.g., Philadelphia chromosome in chronic myeloid leukemia). Example: Detecting DiGeorge Syndrome: FISH probe identifies a deletion on chromosome 22q11.2.  Definition: A high-resolution technique to detect copy number variations (CNVs) across the entire genome. Procedure: 1. Patient DNA and control DNA are labeled Array with different fluorescent dyes. Comparative 2. Both samples are hybridized to a microarray chip containing genomic probes. Genomic 3. Fluorescence intensity differences reveal gains or losses of DNA. Hybridization Applications: (Array CGH) Detect submicroscopic chromosomal abnormalities not visible by karyotyping. Evaluate complex cases with developmental delays, autism, or intellectual disabilities. Example: Diagnosis of Prader-Willi Syndrome: Array CGH shows a deletion in the 15q11-q13 region.  Case Study 1 Case: A 6-year-old male with developmental delays, distinct facial features (flat nasal bridge, upslanting palpebral fissures), and congenital heart defect. Questions: 1. What is the likely diagnosis? 2. Which diagnostic tests would confirm it? 3. What are the genetic counseling implications?  Case Study 2 Case: A 35-year-old male with progressive involuntary movements (chorea), mood disturbances, and a family history of similar symptoms in previous generations. Questions: 1. What is the likely diagnosis? 2. Which diagnostic tests would confirm it? 3. What are the genetic counseling implications?  Case Study 3 Case: A 12-year-old female with short stature, webbed neck, and delayed onset of puberty. Physical exam reveals lymphedema of hands and feet during infancy. Questions: 1. What is the likely diagnosis? 2. Which diagnostic tests would confirm it? 3. What are the genetic counseling implications?  Case Study 4 Case: A 2-year-old male with delayed motor milestones, weakness, and elevated serum creatine kinase levels. Family history reveals male relatives with similar symptoms. Questions: 1. What is the likely diagnosis? 2. Which diagnostic tests would confirm it? 3. What are the genetic counseling implications?  Case Study 5 Case: A newborn with failure to thrive, severe immune deficiencies, and a history of recurrent infections. Questions: 1. What is the likely diagnosis? 2. Which diagnostic tests would confirm it? 3. What are the genetic counseling implications?  Mendelian Disorders: Inherited per Mendel's laws (dominant/recessive patterns). Cytogenetic Disorders: Summary Chromosome abnormalities (numerical or structural). Importance: Diagnosis, counseling, and personalized treatment. Questions and Discussion THANK YOU