9. Pedigrees and Inheritable Genetic Diseases

Pedigrees and Inheritable Genetic Diseases

Pedigrees Overview

  • A pedigree is a diagram that traces a specific genetic trait through several generations.

  • Purpose: Helps predict the future likelihood of the trait appearing in descendants.

  • Genetic counselors gather phenotypic data from as many family members as possible to construct the pedigree.

  • Methodology: Works backward from the current individual, applying rules of dominant and recessive inheritance to establish relationships and inheritance patterns.

Pedigree Symbols

  • Male: □

  • Female: ○

  • Unaffected: O

  • Affected: ●

  • Marriage line: ⊢

  • Consanguineous marriage (between close relatives): ⊢

  • Heterozygous for recessive allele: ☐

  • Separated or divorced: ⊣

  • Deceased: 𐫝

  • Index case (propositus): ▲

  • Nonidentical twin: n

  • Identical twin: =

  • Heterozygous carrier for X-linked recessive allele: ●♂ / ●♀

Pedigree Examples

  • Y-Linked Disorder: Examples from provided images demonstrating inheritance patterns specific to Y-linked traits.

  • Mitochondrial-Linked Disorder: Examples demonstrating how mitochondrial disorders are passed through maternal lineage.

  • Autosomal Recessive: Illustration of traits that are commonly inherited in an autosomal recessive manner.

  • Autosomal Dominant: Pedigree showing the typical inheritance pattern of autosomal dominant disorders.

  • X-linked Recessive: Diagram depicting X-linked recessive inheritance.

  • X-linked Dominant: Example showing the inheritance pattern of X-linked dominant traits.

Linkage Analysis

  • Definition: Linkage analysis is an indirect approach used to identify the presence of genetic mutations among family members.

  • Applications: Primarily for assessing carrier status and prenatal diagnosis when the disease-causing mutation is unidentified by direct methods.

  • Markers Used:
      - Highly polymorphic DNA markers such as:
        - Restriction Fragment Length Polymorphisms (RFLPs)
        - Variable Number Tandem Repeats (VNTRs)
        - Short Tandem Repeats (STRs)

  • Statistical Analysis: Utilized to determine gene linkage.
      - Statistical methods help in identifying which markers associate with a gene of interest during recombination.

  • Informative Markers: The markers employed must allow for differentiation between the normal and mutant alleles.

  • Cautions: When studying X-linked disorders, ensure the certainty of paternity.

RFLP Linkage Analysis

  • Overview: A quick analysis technique for allele type; involves digestion of DNA with restriction enzymes.

  • Gel Electrophoresis: Fragments analyzed through this technique to visualize variations in fragment patterns called restriction fragment length polymorphisms (RFLPs).

  • Uses: RFLPs aid in determining haplotypes during genetic assessments.

Linkage Analysis Example

  • Scenario: A couple has one affected child with an autosomal recessive disorder and two unaffected children. After the child passes away, the couple desires to know if their next child will inherit the disorder.

  • Steps:
      1. RFLP gels are performed for genes of interest.
      2. Alleles are identified based on parental inheritance patterns.
      3. Results organized into a definitive chart for allele distribution.
      4. Phase alleles using offspring to clarify parental contributions.
      5. Analyze remaining alleles to determine risk for the fetus's genetic condition.
      6. Update pedigree with new information post-analysis.

Molecular Basis of Common Inherited Diseases

  • Target diseases covered:
      - Cystic Fibrosis (Autosomal Recessive)
      - Duchenne Muscular Dystrophy (X-linked Recessive)
      - Sickle Cell Anemia (Autosomal Recessive)
      - Huntington’s Disease (Autosomal Dominant)

Cystic Fibrosis

  • Description: Cystic Fibrosis is characterized by a triad of symptoms:
      - Chronic obstructive pulmonary disease
      - Exocrine pancreatic insufficiency
      - Elevated sodium and chloride concentrations in sweat.

  • Incidence: Affects approximately 1 in 3000 Caucasian newborns.

  • Genomic Basis: CF is an autosomal recessive disorder caused by mutations in the CFTR gene, responsible for coding the cystic fibrosis transmembrane conductance regulator protein which regulates fluid transport.

  • CFTR Function: Acts as a chloride channel and regulates other transport pathways in epithelial tissue.

CFTR Mutation Classes

  • Mutant Classes Overview:
      - Class I: No functional CFTR protein produced.
      - Class II: CFTR produced but misfolds, failing to reach the cell surface.
      - Class III: CFTR reaches the surface but does not open properly (gating defect).
      - Class IV: CFTR reaches surface but has faulty function (conductance defect).
      - Class V: Normal CFTR produced in insufficient quantities.

  • Common Mutations: G542X, R553X, F508del which account for a significant percentage of cases.

Potential Therapies for Cystic Fibrosis

  • Therapies Overview:
      - Read-through compounds: Permit the production of full-length CFTR proteins for Class I mutations.
      - Correctors: Assist defective CFTR in proper folding (e.g., lumacaftor).
      - Potentiators: Enhance the function of normal CFTR channel (e.g., ivacaftor).

Genetic Diagnosis of Cystic Fibrosis

  • Diagnosis can be performed by genotyping 23 gene variants or sequencing the CFTR gene via next-generation sequencing (NGS). The latter can identify more mutations than the standard 23 variant panel.

  • Limiting screening to these variants does not improve the effectiveness of detection in at-risk couples, allowing the possibility of up to 30% cases to be missed.

Duchenne Muscular Dystrophy (DMD)

  • Description: DMD is characterized by muscle wasting and progressive muscle weakness primarily affecting males (1 in 3,500 to 5,000 newborn males worldwide).

  • Genetic Basis: Caused by changes in the DMD gene, inherited in an X-linked recessive pattern.

  • Dystrophin Role: Part of a protein complex that supports muscle fibers, preventing injury during muscle contractions.

  • Gene Size: Largest human gene (79 exons, > 2,200 kb).

Common DMD Mutations

  • Variants include deletions (60-70% cases), point mutations (26%), exonic duplications (10-15%).

  • Most mutations lead to a disrupted reading frame, frequently resulting in premature stop codons and nonsense-mediated decay.

Diagnosis of DMD

  • Testing Levels:
      - Level 1: Detection of copy number variations (CNVs) through methods like MLPA.
      - Level 2: NGS for identifying single nucleotide polymorphisms (SNPs).
      - Level 3: RNA analysis to detect variants missed by DNA testing such as rearrangements and splice mutations.

Sickle Cell Anemia

  • Description: Sickle cell disease involves inherited disorders affecting hemoglobin, leading to crescent-shaped red blood cells blocking blood flow.

  • Incidence: Affects approximately 1 in 500 African Americans.

  • Genetic Cause: Mutation on the hemoglobin beta chain substitutes glutamic acid for valine at position six on chromosome 11.

Mutation Details for Sickle Cell Anemia

  • Mechanism: c.20A>T mutation (Glu7Val) leads to polymerization of hemoglobin, changing erythrocyte shape and decreasing flexibility.

Diagnosis of Sickle Cell Anemia

  • Genetic screening performed at birth detects the specific mutation using PCR and can confirm the presence of sickle cell disease.

Huntington’s Disease

  • Description: A neurodegenerative disorder caused by a defective gene on chromosome 4, resulting in autosomal dominant inheritance.

  • Incidence: 0.38 per 100,000 population.

  • Mutation Description: Mutation involves a CAG trinucleotide repeat, with normal ranges being 10-35 repeats, while affected individuals may have 36-120 or more.

Diagnosis of Huntington’s Disease

  • Characterized by analyzing the size of the PCR product for the CAG repeat.

  • Greater than 40 CAG repeats confirms the diagnosis of Huntington's disease.

Wolf-Hirschhorn Syndrome (WHS)

  • Description: WHS results from a hemizygous deletion on chromosome 4p16.3, characterized by various developmental issues.

  • Incidence: 1 in 50,000 live births, with a higher ratio of affected females to males.

  • Deletion Impacts: Growth retardation, microcephaly, congenital heart defects, and a distinctive facial phenotype known as "Greek Helmet" faces.

Genetic Testing and Management in WHS

  • Diagnosis through high-resolution GTG banding, FISH, and chromosomal microarrays.

  • Treatment focuses on managing individual symptoms, such as surgical interventions for heart defects or antiepileptic drugs for seizures.