GENETIC DISORDER

Genetic Disorders

Overview

  • Instructor: Dr. Vaishali Yagain, Associate Professor, Dept of Anatomy, USM-KLE-IMP, Belagavi

Lesson Plan

  • Class Learning Outcomes:

    1. Describe the different types of genetic disorders.

    2. Describe the modes of inheritance.

    3. Provide examples of genetic disorders.

  • Pre-Learning Tasks:

    1. Describe the human genome and the concept of inheritance.

    2. Be able to draw and describe family pedigree.

  • Learning Task:

    • Describe the modes of inheritance.

  • Post-Learning Task:

    • Types of genetic disorders with examples.

  • References:

    • (i) Sadler, T W. Langman’s Medical Embryology, 12th edition (2011). Lippincott Williams & Wilkins, Philadelphia

    • (ii) S D Gangane, Human Genetics, 4th edition.

    • (iii) Moore, K.L., Dalley, A.F., Agur, A.M.R. Clinically Oriented Anatomy, 8th edition (2017). Williams & Wilkins, Philadelphia.

    • (iv) Anthony L. Mescher, Junqueira's Basic Histology: Text and Atlas, 16th Edition (2021). McGraw-Hill Education.

    • (v) Richard Drake, A. Wayne Vogl, Adam Mitchell, Gray's Anatomy for Students, 4th Edition (2019). Elsevier.

Learning Outcomes

  1. Describe the different types of genetic disorders.

  2. Describe the modes of inheritance.

  3. Provide examples of genetic disorders.

Impact of Genetic Diseases

  • Spontaneous Abortions: Occur due to genetic issues.

  • Congenital Abnormalities: Affect 2-3% of newborn infants.

  • Childhood Impact:

    • 50% of cases of blindness, deafness, and learning disabilities attributed to genetic factors.

  • Adult Life Health:

    • Cancer incidence: 1%

    • Cancers such as ovarian, breast, and colon: 5-10%

    • Cardiovascular diseases, diabetes, hypertension: 50%.

When to Suspect a Genetic Disorder

  • Clinical Indicators:

    • Dysmorphic features suggesting chromosomal syndrome.

    • Unexplained mental handicaps.

    • Multiple congenital abnormalities.

    • Unexplained stillbirth or recurrent miscarriages.

    • Female with unexplained short stature or primary infertility.

    • Ambiguous sexual development or certain types of cancer.

  • DNA Analysis: Recommended in the above scenarios.

Investigations for Genetic Disorders

  • Methods:

    • Pedigree chart.

    • Karyotyping.

    • FISH (Fluorescent In Situ Hybridization).

    • RFLP (Restriction Fragment Length Polymorphisms).

    • PCR (Polymerase Chain Reaction).

    • DNA sequencing.

    • Mutation scanning.

    • Single-Strand Conformational Polymorphism.

    • Denaturing Gradient Gel Electrophoresis.

    • Denaturing High-Performance Liquid Chromatography.

    • Southern Blot Analysis.

Pedigrees

  • Definition: A pedigree is a chart or family tree mapping genetic disorders in a family.

  • Symbols Used:

    • Circle represents a female.

    • Square represents a male.

    • Horizontal line denotes marriage.

    • Completely shaded shapes indicate individuals with the trait.

    • Unshaded shapes indicate neither the trait nor being a carrier.

    • Half-shaded shapes indicate carriers.

Types of Genetic Disorders

  1. Chromosomal Disorders: Abnormality in the structure or number of chromosomes.

  2. Single Gene Disorders: Caused by a single mutant gene, known as Mendelian disorders.

    • Patterns of Inheritance:

    • Autosomal dominant.

    • Autosomal recessive.

    • X-linked recessive.

    • X-linked dominant.

  3. Multifactorial Inheritance: Result of gene-environment interaction (e.g., infectious agents, drugs).

Modes of Inheritance

  1. Autosomal Dominant:

    • Traits appear in every generation.

    • Affected individuals have affected parents.

    • Equal proportion of affected and unaffected offspring.

    • Examples: Huntington's disease, myotonic dystrophy, neurofibromatosis type 1, Marfan syndrome, achondroplasia.

  2. Autosomal Recessive:

    • Trait appears only in homozygous state.

    • Unaffected individuals can have affected children if both parents are heterozygous.

    • Typically appears in siblings.

    • Examples: Cystic fibrosis, phenylketonuria, sickle cell anemia, thalassemia.

  3. X-Linked Inheritance:

    • Involves genes on the X chromosome; inheritance differs in males and females.

    • X-Linked Recessive Disorders: Higher incidence in males; affected males transmit to daughters only, unaffected sons.

      • Examples: Hemophilia, Duchenne muscular dystrophy.

    • X-Linked Dominant Disorders: Affected males transmit the trait to daughters, not to sons.

      • Examples: Rett syndrome, Incontinentia pigmenti.

  4. Y-Linked Inheritance:

    • Genes are only passed from father to son.

    • Affected males transmit traits to all sons.

    • Example: Hairy pinna (recognizable trait).

Examples of Genetic Disorders

  • Single Gene Disorders:

    • Autosomal Dominant: E.g., tuberous sclerosis, Huntington’s disease.

    • Autosomal Recessive: E.g., albinism, cystic fibrosis.

    • X-Linked: E.g., Duchenne muscular dystrophy, hemophilia.

  • Mitochondrial Disorders: E.g., MERRF, LHON.

  • Multifactorial Disorders: Interaction of gene and environment, examples include insulin-dependent diabetes, epilepsy.

  • Somatic Cell Disorders: E.g., various cancers.

Prevalence of Disorders

  • Autosomal Dominant Disorders:

    • Huntington's disease: 1 in 15,000.

    • Marfan syndrome: 1 in 4,000.

    • Neurofibromatosis: 1 in 2,500.

    • Familial hypercholesterolemia: 1 in 500.

  • Autosomal Recessive Disorders:

    • Cystic fibrosis: 1 in 3,000.

    • Sickle cell anemia: 1 in 500.

    • Tay-Sachs disease: 1 in 12,000.

  • X-Linked Disorders:

    • Duchenne muscular dystrophy: 1 in 7,000.

    • Hemophilia: 1 in 10,000.

Detailed Examples of Disorders

  • Achondroplasia:

    • Caused by a gene mutation; associated with advanced paternal age.

    • Characteristics: large head with prominent forehead, short limbs, normal torso.

  • Huntington’s Disease:

    • Caused by an abnormal dominant allele; symptoms include clumsiness, irritability, and typically appears by age 40.

  • Cystic Fibrosis:

    • Caused by an abnormal gene on chromosome 7 affecting ion transport; results in mucus buildup in the lungs leading to infections.

    • Symptoms: difficulty breathing, malnutrition due to blocked digestive enzymes.

  • Sickle Cell Disease:

    • Caused by mutation in gene on chromosome 11, alters shape of red blood cells affecting oxygen delivery.

    • Symptoms include chronic pain and reduced immune response.

  • Neurofibromatosis:

    • Characterized by tumors in the nervous system; symptoms include café au lait spots and neurofibromas.

  • Marfan Syndrome:

    • A connective tissue disorder characterized by disproportionate limb length, flexible joints, and heart abnormalities.

Special Considerations in Genetic Counseling

  • Important for parents with children having serious congenital conditions to understand recurrence risks and available options.

  • Steps in Genetic Counseling:

    1. Establishment of a diagnosis.

    2. Estimation of recurrence risk.

    3. Communication of relevant information sympathetically.

Conclusion

  • Genetic disorders significantly impact individuals and families, necessitating comprehensive understanding and effective counseling strategies.