Seminario 12 Herencia monogénica autosómica dominante y recesiva - Sebastián Giusti

Classical Inheritance Patterns in Genetic Diseases

Introduction to Classical Inheritance

• The class focuses on analyzing classical inheritance patterns, specifically autosomal inheritance related to genetic diseases.

• Monogenic or Mendelian alterations refer to clinical presentations determined by pathogenic allelic variants present in a single gene.

Mendelian Principles

Dominance and Recessivity

• Mendelian traits manifest according to principles originally described by Gregor Mendel, including the principle of dominance.

• Dominant traits require only one pathogenic variant for manifestation, while recessive traits necessitate two pathogenic variants (one from each parent).

• Dominant variants are typically represented with uppercase letters, whereas recessive ones use lowercase letters.

Phenotype vs. Genotype

• It is crucial not to confuse phenotypic characteristics (healthy vs. sick) with genotypic designations (normal vs. pathogenic alleles).

• Textbooks often misuse terminology regarding dominant and recessive alleles, conflating genotype and phenotype levels.

Segregation and Independent Assortment

Principle of Segregation

• The first law of Mendel states that during gamete formation, allelic variants segregate into different cells.

• Punnett squares illustrate the probabilities of forming zygotes with various allele combinations from parental gametes.

Independent Assortment

• The second law indicates that alleles for different genes assort independently during gamete formation.

• This independence allows for equal probability of symptoms appearing in individuals regardless of their sex chromosomes (XX or XY).

Recurrence Patterns in Generations

Identifying Mendelian Disorders

• Recurrence of affected individuals across generations is an early indicator of a Mendelian disorder.

Inheritance Patterns in Genetics

Overview of Genetic Inheritance Patterns

• The discussion focuses on two inheritance patterns: autosomal dominant and autosomal recessive, with sex-linked inheritance to be covered later.

• The classification is based on the location of the gene responsible for pathogenic variants causing symptoms. The current focus is on pathogenic variants present in autosomes (chromosomes 1-22).

Characteristics of Autosomal Dominant Inheritance

• Autosomal dominant inheritance shows affected individuals across multiple generations, where each affected individual has at least one affected parent, with no significant gender differences observed among those affected.

• Affected individuals typically have a heterozygous genetic constitution, inheriting a single pathogenic variant from one parent; homozygosity for such variants is often lethal.

• There is a consistent pattern where every affected individual has an affected ancestor, indicating no skipping of generations. This leads to the conclusion that at least one parent must also be affected.

Recurrence Risk in Offspring

• The risk of recurrence for offspring of affected individuals is approximately 50%, as they usually pair with unaffected partners who do not carry any pathogenic variants. This can be illustrated using a Punnett square showing potential genotypes from such pairings.

• Applying Mendel's second law regarding independent assortment helps understand how gametes distribute chromosomes during reproduction, affecting the likelihood of passing on traits associated with the pathogenic variant.

Case Study: Achondroplasia

• Achondroplasia serves as a classic example of an autosomal dominant condition, occurring in about 1 in 25,000 births and characterized by short stature and disproportionate limb lengths due to proximal shortening. Other features include distinct facial characteristics and lumbar lordosis leading to spinal stenosis complications.

• The physiological process impacted by achondroplasia involves endochondral ossification—the growth mechanism for long bones—where cartilage tissue extends before being replaced by bone through mineralization processes involving chondrocytes located at growth plates during development.

Molecular Insights into Achondroplasia

Understanding Achondroplasia: Genetic Insights

Genetic Basis of Achondroplasia

• Prior to 1994, achondroplasia was recognized as a monogenic condition due to its inheritance pattern, but the specific gene and protein involved were unknown until this research identified them.

• The implicated gene is a receptor for a mitogen, specifically the fibroblast growth factor receptor 3 (FGFR3), which is a common type of tyrosine kinase receptor that initiates intracellular signaling cascades upon ligand binding.

• Individuals with achondroplasia predominantly carry a mutation known as G380R, which is a point mutation that substitutes one amino acid for another in the protein sequence.

• This mutation results in an arginine residue replacing glycine at position 380 of the polypeptide chain, classified as a missense mutation due to the change in codon and corresponding amino acid.

• Surprisingly, this mutation leads to a gain-of-function effect; receptors with this pathogenic variant exhibit increased activity compared to normal levels.

Consequences of FGFR3 Mutation

• The hyperactivity induced by the G380R mutation causes apoptosis in chondrocytes—cells expressing this receptor—which contributes significantly to early termination of bone elongation and associated symptoms of achondroplasia.

• This scenario exemplifies how an allelic variant can become hyperfunctional (hypermorphic allele), often correlating with dominant traits where one copy suffices for symptom manifestation.

• A similar phenomenon occurs with loss-of-function mutations characterized by antagonism, where normal function is inhibited by the mutated allele.

Implications for Family History and Inheritance Patterns

• Analyzing pedigrees reveals instances where affected individuals appear without prior family history; approximately 80% of achondroplasia cases arise from de novo mutations.

• When an affected individual has no family history, it suggests fresh mutations may have occurred in one parent’s germline cells, potentially passed on to offspring.

• Evidence indicates many de novo mutations originate from paternal lineage due to differences in male versus female gametogenesis and their respective rates of cellular replication over time.

Age Factors and Mutation Rates

• As age increases in fathers, so does the number of mitotic cycles during sperm production; thus older paternal age correlates with higher risks for new mutations appearing in offspring.

• This understanding allows exceptions within autosomal dominant inheritance patterns; notably when there are de novo mutations present without affected ancestors.

Generational Skips and Exceptions

Understanding Incomplete Penetrance and Autosomal Inheritance

The Concept of Incomplete Penetrance

• Discussion on individuals with pathogenic variants who do not have affected parents, but an affected grandparent. This raises questions about generational skipping in genetic inheritance.

• Clarification that the generational skip refers to the phenotypic manifestation of symptoms rather than the presence of a pathogenic variant, which can be passed down without expression.

• Introduction of "penetrance," defined as the probability that an individual with a specific genotype will express the expected phenotype.

• Examples of 100% penetrant conditions like achondroplasia, contrasted with conditions exhibiting incomplete penetrance where not all carriers show symptoms (e.g., retinoblastoma).

• Factors influencing reduced penetrance include environmental influences or other genes, necessitating case-by-case analysis to understand molecular mechanisms behind incomplete penetrance.

Exceptions in Autosomal Dominant Patterns

• Explanation of de novo mutations as exceptions to typical inheritance patterns where affected individuals usually have at least one affected parent; incomplete penetrance helps explain generational skips.

Understanding Autosomal Recessive Inheritance

Characteristics and Patterns

• Explanation that recessive traits require two pathogenic variants (one from each parent), leading to siblings often being affected if both parents are carriers.

• Mention of consanguinity increasing the likelihood of autosomal recessive disorders due to shared genetic backgrounds among relatives.

Implications for Genetic Counseling

• Discussion on how rare pathogenic variants are less likely to be shared between unrelated individuals, making consanguineous unions more significant for recessive trait expression.

• Regularities observed in autosomal recessive inheritance patterns indicate that when multiple siblings are affected, it is often due to both parents being carriers.

Risk Assessment and Punnett Squares

• Probability assessment indicates a 25% chance for offspring from carrier parents (represented by lowercase letters in Punnett squares) to inherit both pathogenic variants and exhibit symptoms.

Genetic Inheritance Patterns and Cystic Fibrosis

Understanding Genetic Carriers

• Two affected individuals suggest both parents are carriers of a pathogenic variant, indicated by a black dot in their symbols. All offspring from an affected individual will be obligatory carriers of this variant.

Punnett Square Analysis

• In a Punnett square scenario, an affected individual with two pathogenic variants mates with an unaffected individual presumed to have no pathogenic variants due to their rarity in the population.

Offspring Predictions

• The offspring from this pairing will all be heterozygous carriers of the pathogenic variant. These individuals are also considered obligatory carriers due to their genetic inheritance.

Identifying Other Carriers

• While there may be other carriers within the family, predicting them solely based on biological relationships is not feasible; molecular diagnostic techniques are required for confirmation.

Gender Distribution in Genetic Disorders

• Both males and females can equally inherit autosomal recessive disorders since these variants distribute independently of sex chromosomes, affecting both genders similarly.

Risk Factors for Autosomal Recessive Diseases

• Specific risk factors include consanguinity and geographic or cultural isolation. Closed communities often lead to increased endogamy, raising the likelihood of homozygosity for rare pathogenic variants.

Cystic Fibrosis: A Case Study

Prevalence in Argentina

• Cystic fibrosis is notably prevalent in Argentina, particularly among Caucasian populations, with carrier rates as high as 1 in 30 and an incidence rate of 1 in every 2000 births.

Historical Context and Diagnosis

• Initially described in 1938, cystic fibrosis was differentiated from celiac syndrome through autopsy findings revealing mucous blockages across various organs including lungs and pancreas.

Clinical Symptoms

• Children with cystic fibrosis exhibit symptoms such as low weight, fatty stools, respiratory issues like cough with sputum production, and pneumonia. High sodium chloride levels in sweat aid early diagnosis via sweat tests developed by Paul Santa in 1953.

Genetics Behind Cystic Fibrosis

Identification of CFTR Gene

• The CFTR gene responsible for cystic fibrosis was identified in 1989. It encodes a chloride channel critical for ion transport across epithelial cells.

Pathogenic Variants

• Over 100 pathogenic variants have been identified within the CFTR gene; however, some mutations are more common than others.

Common Mutation Example

Understanding CFTR Mutations and Their Impact on Cystic Fibrosis

Classification of CFTR Mutations

• The mutations affecting the CFTR gene are classified into six classes based on their impact on protein activity. This classification is not unique to cystic fibrosis but applies broadly to various genetic mutations.

• Classes 1, 2, and 3 mutations result in a near-total absence of functional protein activity, while later classes exhibit diminished function without complete loss.

Functional Consequences of Mutations

• Pathogenic variants can be categorized into two main types: null alleles (complete loss of function) and hypofunctional alleles (reduced but not absent function). Null alleles may arise from misfolding or degradation of the protein product.

• Hypofunctional alleles lead to decreased chloride channel activity without total dysfunction, contributing to varying clinical presentations among individuals with cystic fibrosis.

Inheritance Patterns

• Many pathogenic variants associated with loss of function display recessive inheritance patterns due to haploinsufficiency; one active allele can maintain physiological function, preventing symptoms unless both alleles are non-functional.

• Symptoms manifest only when both maternal and paternal alleles exhibit loss-of-function mutations, reinforcing the recessive nature of these traits.

Variable Expressivity in Cystic Fibrosis

Understanding Variable Phenotypes

• The concept of variable expressivity refers to the range of severity in phenotypic manifestations among individuals with cystic fibrosis; some may experience severe symptoms while others have milder forms.

Mechanisms Behind Variability

• Allelic heterogeneity contributes significantly to this variability; different pathogenic variants can affect protein structure and function differently, leading to diverse clinical outcomes even among genetically similar individuals. For instance, homozygous individuals for class 2 mutations may present differently than those homozygous for class 4 mutations.

• Compound heterozygosity also plays a role where individuals carry distinct pathogenic variants that influence symptom severity through varied mechanisms impacting chloride channel functionality.

Genetic Modifiers Affecting Disease Severity

Role of Modifier Genes

• Other genes within the genome can modify disease expression by influencing how severely symptoms manifest in patients sharing identical CFTR mutation profiles; this includes variations that regulate inflammatory responses which are critical given the frequent pulmonary infections seen in cystic fibrosis patients.

Therapeutic Implications

• Identifying specific pathogenic variants is crucial as certain treatments target particular mutations; for example, Ivacaftor enhances chloride channel activity specifically for class 3 mutations but would be ineffective against classes 1 and 2 where no functional channels exist on cell membranes.

Understanding Genetic Phenotypes and Environmental Influences

The Role of Allelic Variants in Inflammatory Responses

• Individuals with less potent allelic variants may exhibit more severe symptoms due to their reduced ability to induce an inflammatory response.

Environmental Factors Affecting Phenotype Expression

• Environmental factors can significantly influence the severity of phenotype manifestation, particularly in individuals from socioeconomically disadvantaged backgrounds where health and nutritional conditions are lacking.

Impact of Socioeconomic Conditions on Health

• An individual with limited access to material resources for nutrition and health is likely to experience a greater severity in phenotype expression compared to someone with better access.

Application of Mendelian Genetics in Medical Contexts

• The focus should not solely be on memorizing clinical signs and symptoms but rather on applying Mendelian genetics concepts to interpret various medical entities.

Suggested Research Exercise for Students