Genetics

 Case Stories & Diagnoses

Case Study: Genetic Testing and Analysis Overview

1. Fetal Diagnosis and Testing

• Patient Profile:
• 20-week pregnant woman
• Conditions: Poor fetal growth, aortic arch abnormality
• Diagnostic Tests:
• Combined Tests & NIPT
• Result: Low-risk for trisomy 13, 18, and 21
• Amniocentesis
• First Confirmation: Trisomy 21 (positive)
• Reported Negative in NIPT
• Second Confirmation: Reconfirmed Trisomy 21
• Findings and Implications:
• Placental Analysis:
• Issue: Placental mosaicism with trisomy 21 cells not detected by NIPT
• Highlight: Limitations in NIPT detection capabilities

2. Chromosomal Alterations and Genetic Analysis

• Testing Method:
• FISH (Fluorescence in situ Hybridization):
• Application: Identify chromosome 22 alterations
• Patient Symptoms: Neonatal hypotonia, sucking difficulty, sepsis, cleft palate, bilateral hearing loss, DiGeorge syndrome
• Result: Alterations found in chromosome 22
• Genetic Findings:
• Mutation Identification:
• Pathogenic Mutation: Associated with clinical presentation
• Novel Mutation: Classified as a variant of uncertain significance

3. Gene Therapy Considerations

• Therapeutic Challenges:
• Specific criteria required for treatment administration
• Challenges: Due to the recent launch of the therapy, adherence is complex

Key Points to Study and Remember

• NIPT Limitations:
• Understanding the constraints and false-negative risks associated with NIPT
• Importance of Comprehensive Testing:
• Utilizing multiple diagnostic methods to confirm genetic anomalies
• Gene Therapy Protocols:
• Recognizing the challenges in administration criteria for gene therapies

Conclusion

Understanding the nuances of genetic testing, such as the limitations of NIPT and the importance of comprehensive diagnostic approaches, is crucial in managing genetic conditions and selecting appropriate treatments, like gene therapy.

 

 

 

 

Key Genetic Concepts and Mutations

1. Amino Acid Mutations
• GFR3 Gene: Missense mutation at positions 308 and 380 (glycine replaced by arginine).
• Impact: Significant biochemical effects due to changes in charged amino acids.
• Polymorphic Variants: Not all amino acid changes result in mutations or clinical pictures.
2. Mutations in CFTR Gene
• Cystic Fibrosis: Can be harmful or harmless.
• Pathogenicity: Depends on frequency and effect of the mutation.
3. Nonsense or Stop Mutations
• Effects: Cause premature stops, leading to shorter proteins.
• Example: Neurofibromatosis type 1 involves a stop mutation in the NS1 gene leading to truncated proteins.
4. Splicing Mutations
• Mechanism: Affects the “cut and sew” process of introns and exons.
• Consequences: Retention or loss of introns/exons, altering protein sequence.
• Splice Sites: Include 5’ donor and 3’ acceptor sites, marked by "U" and "AG" in introns.
5. Alternative Splicing
• PM1 Gene: Involved in muscle contraction; can present alternative splices from a single transcript.
• Expression: Different protein forms expressed in different tissues.

Practical Applications

• Clinical Implications: Accurate genetic analysis is crucial for diagnosing conditions like Neurofibromatosis type 1.
• Protein Impact: Software tools can simulate mutation effects on protein sequences to predict clinical phenotypes.
• Regulation: Cells can control splicing, creating alternative protein forms that cater to tissue-specific functions.

Study and Remember

• Splicing mutations play a crucial role in genetic expression and can lead to significant phenotypical changes.
• Understanding the genetic basis of diseases like Neurofibromatosis helps in clinical diagnosis and treatment decisions.

Recognize the role of specific mutations in broader genetic contexts, such as cystic fibrosis and neurofibromatosis type 1. 

 

 

 

 

Splice Variant in BNFTL1 Gene

• Background:
• Fetal molecular autopsies performed on fetuses with pregnancy interruptions due to severe morphological anomalies.
• Case Study: Identified a splice variant in the BNFTL1 gene in a fetus with congenital malformations.
• Clinical Features of the Fetus:
• Craniofacial Dysmorphisms
• Flat profile
• Nostril alterations
• Prominent, globular abdomen
• Skeletal Dysplasia
• Abnormal curvature of the femur
• Clubfoot
• Disproportion between trunk and pelvis
• Genetic Findings:
• Splice variant in BNFTL1 gene never previously described in literature.
• Mutation altered resulting protein, explaining the phenotype.
• Provided crucial information to parents about recurrence risk for future pregnancies.

Postnatal Diagnosis

• Scenario:
• Patient with facial dysmorphisms and clinical features suggesting a chromosomal genetic disease.
• Analysis Considerations:
• Excludes suspicions of Down syndrome, Klinefelter syndrome, or sex chromosome alterations.
• Techniques:
• Traditional Karyotype: Does not show balanced translocations but identifies micro-alterations.
• Molecular Karyotype: More complete, can identify micro-alterations.
• FISH: Effective for large area syndromes like Williams or George syndrome.
• Practice:
• Common uses: Molecular karyotype and SNP arrays both prenatally and postnatally.
• Prenatal Diagnosis: Occasionally uses QF-PCR.
• Traditional Karyotype: Used for healthy couples, potential carriers of balanced translocations, and cases of miscarriage or infertility.
• Forensic Medicine: Uses many markers to observe entire chromosomal structure.
• FISH: Analyzes main aneuploidies (chromosomes 13, 18, 21, X, Y).

 

 

 

Genetic Analysis and Diagnosis

• Case Study: Waardenburg Syndrome
• A family was referred by an ENT for possible sensorineural hearing loss.
• Genetic analysis revealed a mutation related to Waardenburg syndrome.
• Key clinical details:
• The mother had dyed a tuft of white hair, which was a missed detail.
• The grandfather had heterochromia of the iris, which was also undetected.
• The child only exhibited bilateral deafness.
• Conclusion: Importance of detailed examination and thorough questioning in genetic diagnosis to accurately assess disease risks and transmission.

Historical Example of Consanguinity

• Habsburgs of Spain: Charles II
• Background: The Habsburg family inbreeding led to genetic issues.
• Health Issues:
• Growth and language delay
• Short stature
• Epilepsy
• Frequent infectious diseases
• Dental problems
• Analysis: High levels of consanguinity led to recessive genetic diseases.
• Family Tree Insight:
• Charles II was a product of close familial marriages, intensifying genetic conditions.
• Both his grandmother and great-grandmother were Margaret of Austria, illustrating high inbreeding.

Conclusion: Demonstrates the genetic risks and increased expression of recessive diseases due to inbreeding.

 

 

Important Concepts to Study and Remember

Phenocopy

• Definition: An environmentally caused condition that mimics a genetically induced trait.
• Example:
• A father and son both exhibit deafness.
• Father: Deafness due to neonatal meningitis infection.
• Son: Deafness caused by a recessive genetic mutation.
• Key Takeaway: Clinical evaluation is essential to distinguish between genetic and environmental causes of a phenotype. Misdiagnosis can occur if the clinical context is ignored.

Genetic Heterogeneity

• Definition: Different genetic mutations can lead to the same clinical phenotype.
• Types:
• Locus Heterogeneity: Different genes causing the same phenotype.
• Example: Deafness can be caused by mutations in several different genes.
• Allelic Heterogeneity: Different mutations within the same gene causing the disease.
• Example: Cystic fibrosis.

Clinical Variability and Communication

• Definition: Differences in clinical presentation among individuals with the same genetic condition.
• Example: Variability in heart disease phenotypes.
• Importance: Clear communication between specialists, like cardiologists, is crucial for correct diagnosis and management due to overlapping phenotypes and potential phenocopies.

Key Points

• Clinical Evaluation: Essential in genetic analysis to differentiate between phenocopies and genetic conditions.
• Genetic and Allelic Heterogeneity: Important concepts in understanding the complexity of genetic disorders.

Specialist Communication: Vital to avoid misdiagnosis due to clinical variability and complex genetic interactions.

 

 

Schematic Overview: Genetic Counseling and Case Studies

1. Deafness and Gene Therapy

• Gene Involved: OTOF (codes for Ferlin protein)
• Therapy: Gene therapy for OTOF mutations
• Limitations: Effective only at specific mutation-dependent time points, patient selection is stringent due to costs
• Case Discussion: Identified two variants (strong pathogenic significance vs. uncertain impact)
• Next Steps: Study the specific role of uncertain variants

2. Genetic Risk Assessment

• Counseling Approach:
• Assess risk for referred disorder and other family conditions (e.g., retinitis pigmentosa, thalassemia)
• Disease Types:
• Mendelian: Risk is clear
• Multifactorial: Complex risk estimation due to genetic and environmental interplay

3. Cardiomyopathy Case Study

• Condition: Arrhythmogenic ventricular cardiomyopathy
• Family History: No cardiac disease history
• Methodology:
• Whole genome sequencing, SNP array, MinION technology
• Findings: Large deletion of 3 megabases including three specific genes

4. Skeletal Dysplasia Case

• Patient: One-year-old child
• Symptoms: Disproportionate bone growth, short stature
• Diagnosis: Metaphyseal skeletal dysplasia via TRIPV4 gene variant
• Transmission: Autosomal dominant

5. Fetal Morphological Defects

• Example: Reduced corpus callosum, invisible septum pellucidum leading to pregnancy termination
• Diagnosis: De novo ARID1B gene variant, Coffin-Siris syndrome

6. Cystic Fibrosis Probability and Genetic Testing

• Scenario: Roberto (potential CF carrier) and Sara's genetic counseling
• Analysis:
• Probability of Roberto being a carrier
• Importance of genetic tests for both partners

7. BRCA1 Genetic Testing for Cancer

• Family History: Breast cancer in Sara's family
• Ethical Considerations: Offering preventative genetic tests
• Preventive Actions: Possible mastectomy and salpingectomy

8. Gene Therapy Advances

• Example: Luxturna for RPE65 mutations (retinitis pigmentosa)
• Challenges: Cost, patient eligibility, treatment centers

9. Gene Therapy for Deafness

• Gene Involved: Ferlin gene for sensorineural deafness
• Therapy: Intra-cochlear injection, ongoing research

10. Cell Therapy for Epidermolysis Bullosa

• Case: Syrian boy treated with stem cells for skin restoration
• Result: Complete skin healing, long-term follow-up

11. Spinal Muscular Atrophy (SMA)

• Genetic Basis: SMN1 gene deletion
• Therapies: Gene therapy, antisense oligonucleotide therapy

12. Gene Editing Technology

• Technique: CRISPR-Cas9 for "cut and paste" gene correction
• Challenges: Complexity and application in human genome editing

13. Unethical Gene Editing

• Case: Chinese scientist's CRISPR-Cas9 modification of embryos
• Ethical Issues: Lack of scientific evidence, condemned by community

14. Narrative Medicine and Genetics

• Integration: Using art and history to recognize genetic conditions

Study and Teaching: Enhancing medical education through artistic analysis

 

 

CASE 2 

 

Case Study: Skeletal Dysplasia

1. Background:
• Focus on skeletal dysplasias, specifically metaphyseal skeletal dysplasia.
• Patient: One-year-old child with a clinical suspicion of metaphyseal skeletal dysplasia.
2. Patient Details:
• Accompanied by healthy older sister and healthy parents.
• Parents' health metrics: Mother is 165 cm tall and weighs 82 kg. No skeletal abnormalities in parents.
3. Prenatal Observations:
• Normal pregnancy until the third trimester.
• Ultrasound revealed humerus and femur lengths below normal limits.
• Importance of prenatal ultrasound technology advancements noted.
4. Postnatal Observations:
• Disproportion between trunk and limbs observed by neonatologist.
• Chest x-ray: Small, peculiarly shaped rib cage.
• Limbs x-ray: Deformed scapulae, shortened humeri, and femurs.
5. Genetic Analysis:
• Genetic testing revealed a "de novo" variant in the TRIPV4 gene.
• TRIPV4 gene is crucial for bone and cartilage development and maintenance.
6. Clinical Diagnosis:
• Diagnosis confirmed as metaphyseal skeletal dysplasia.
• Condition is rare with autosomal dominant transmission.
7. Conclusion:
• From prenatal suspicion to postnatal confirmation through genetic analysis.
• Diagnosis explained the phenotypic abnormalities observed.

Study and Remember:

• Importance of gathering comprehensive prenatal and postnatal information for accurate diagnosis.
• Role of genetic analysis in confirming conditions like metaphyseal skeletal dysplasia.
• Understanding skeletal dysplasia and its autosomal dominant transmission pattern.

 

 

 

CASE 3

 

Schematic Overview: Genetic Evaluation of Early Morphological Defects

1. Importance of Genetic Analysis

• Objective: To identify genetic causes of pregnancy loss.
• Impact: Helps estimate the risk of recurrence in future pregnancies.

2. Challenges in Prenatal vs. Postnatal Diagnosis

• Knowledge Gap: Limited literature on fetal genetic analysis.
• Prenatal Suspicions: Morphological anomalies like dysmorphisms can be suspected in fetuses, but confirming them postnatally in children or adults remains challenging.

3. Case Study: Spontaneous Pregnancy

• Initial Screening: Normal first trimester screening.
• Ultrasound Findings:
• Reduced Corpus Callosum: Indicating potential connectivity issues between cerebral hemispheres.
• Invisible Septum Pellucidum: A membrane separating brain ventricles, absence leading to pregnancy termination.

4. Post-Termination Evaluation

• Dysmorphological Assessment:
• Noted characteristics: Hypoplasia, flattened face, micrognathia, low-set ears.
• Radiological Confirmation: Validated ultrasound anomalies post-mortem.

5. Genetic Analysis

• Techniques Used:
• FCR Analysis: Checked for chromosomal anomalies, results were normal.
• DNA Analysis in Trio: Conducted with septal material (fetus and parents).
• Findings: Identification of a de novo variant in the ARID1B gene.

6. Diagnosis Confirmation

• Syndrome Identified: Coffin-Siris syndrome.
• Clinical Heterogeneity: Symptoms vary greatly among affected individuals with the ARID1B gene mutation.

Key Points to Study and Remember

• Genetic Analysis: Crucial in understanding morphological defects and potential syndromes.
• Clinical Heterogeneity: Recognizing variable symptoms in genetic syndromes aids in accurate diagnosis and management.

Importance of Multidisciplinary Approach: Collaboration among geneticists, obstetricians, and pediatricians is vital for comprehensive care.

 

CASE 4

 

Schematic Overview: Postnatal Care and Genetic Analysis of Coffin-Siris Syndrome

1. Patient Overview
• Age & Origin: 3-year-old boy; Mother from Dominican Republic, Father Italian.
• Family History: No malformations or genetic pathologies in family.
2. Clinical Presentation
• Symptoms: Nystagmus, facial dysmorphisms, poor appetite, difficulty feeding, no language development, delayed motor skills, growth below normal.
• Developmental Delay: Evident from neonatal period.
3. Genetic Analysis
• Method: Genetic analysis in trio (parents and child).
• Findings: Mutation in ARID1B gene; confirms Coffin-Siris syndrome diagnosis.
4. Syndrome Characteristics
• Features: Varied clinical presentation; facial abnormalities, hypotonia, cardiac and gastrointestinal malformations.
• Neurological Symptoms: Seizures observed.
5. Diagnosis Complexity
• Challenges: Different presentation in prenatal vs. postnatal stages.
• Wide Heterogeneity: Symptoms vary significantly among individuals.
6. Clinical Management
• Importance of Accurate Genetic Analysis: Essential to determine genetic conditions both prenatally and postnatally.
• Role of Functional Experiments: Crucial to assess pathogenicity of splice variants.
7. Genetic Counseling Implications
• Need for Comprehensive Evaluation: Beyond literature manifestations; focus on patient's specific characteristics.

Parental Guidance: Clear communication on diagnosis, implications for future pregnancies, and uncertainty of variant significance.

 

 

CASE 5

 

 

Schematic Overview: Genetic Counseling and Testing

1. Genetic Counselor's Assessment

• Patient: Sara, 30 years old, plans to get pregnant. No genetic disease diagnosis.
• Partner: Roberto, 33, brother has cystic fibrosis.

2. Cystic Fibrosis Carrier Probability

• Concern: Autosomal recessive inheritance.
• Probability: Roberto has a 2/3 chance of being a healthy carrier.
• Testing: Recommend CFTR gene sequencing.
• Action if Carrier: Test Sara to determine if she is also a carrier.
• Probability for Child: 50% chance of being a healthy carrier if Sara is healthy.

3. Familial Cancer Risk Assessment

• Maternal Family: Barbara (mother) has stage 3 breast cancer; Ginevra (cousin) also has breast cancer.
• Genetic Testing: BRCA1 variant identified in family.
• Action: Recommend Sara to undergo BRCA1 genetic testing.

4. Ethical Considerations in Genetic Testing

• Pros: Early risk identification and preventive actions.
• Cons: Potential anxiety and stress.
• Preventive Actions: Potential for mastectomy and salpingectomy.

5. Communication Strategy

• Ethical Communication: Sensitive delivery of positive diagnosis.
• Support: Address family dynamics and mental health implications.

6. Additional Family Health Considerations

• Father: Francesco responds poorly to antidepressants, indicating pharmacogenetic implications.
• Complications: Depression, type 2 diabetes.
• Action: Medical lifestyle interventions.

7. Down Syndrome and Prenatal Testing

• Family Case: Cristina, 42, has a child with Down syndrome.
• Recommendation: Chorionic villus sampling, amniocentesis for chromosomal abnormalities.

8. Genetic Conditions and Pharmacogenetics

• Example: Lidia's son with sensorineural deafness due to aminoglycosides.
• Genetic Testing: SLC26A4 gene for drug response.

9. Treacher Collins Syndrome Awareness

• Relevant Condition: Facial malformations due to TCOF1 gene mutations.
• Characteristics: No correlation between genotype and phenotype.

Key Points to Study and Remember

• Genetic Testing: Importance for carrier identification and risk estimation.
• Family History: Critical for assessing genetic predispositions.
• Ethical Considerations: Balancing risk identification with potential anxiety.
• Communication: Sensitive delivery of genetic test results and implications.
• Preventive Measures: Consideration of preventive surgeries and monitoring.

Comprehensive Approach: Multidisciplinary strategy involving geneticists, oncologists, and family support.

CASE 6

Case 6: Pharmacogenetics and Genetic Syndromes

1. Pharmacogenetics Example
• Subject: Lidia's three-year-old son with profound deafness.
• Treatment: Cochlear implant post-aminoglycoside treatment, which can affect hearing if used early in life.
• Genetic Testing: Consideration of the SLC26A4 gene to determine drug response.
2. Treacher Collins Syndrome (TCS)
• Background: Sara's cousin from Lidia's previous relationship diagnosed with TCS.
• Also Known As: Franceschetti-Klein syndrome.
• Characteristics: Mandibulofacial dysostosis with symmetrical skeletal malformations of ear, eyes, face.
• Causes: Mutations in genes for craniofacial development; most common in TCOF1 gene.
• Transmission: Autosomal dominant or de novo mutation.
• Phenotypic Variability: No strict genotype-phenotype correlation, making severity prediction difficult.
• Impact: Does not impair intelligence or fertility.
3. Clinical Presentation and Management
• Phenotypic Variability: Significant clinical heterogeneity and expression variability.
• Diagnostic Challenges: Poor correlation complicates symptom prediction and diagnosis.
• Management: No cure, but measures can improve life quality.
• Social Implications: Emphasis on acceptance and inclusion.
4. Educational and Social Insights
• Community Interaction: Exploration of experiences and societal reactions.
• Personal Impact: Awareness of the social challenges faced by children with TCS.

Important Concepts to Study and Remember

1. Pharmacogenetics
• Understand the genetic basis affecting drug response.
• Recognize the role of specific genes like SLC26A4 in drug efficacy.
2. Treacher Collins Syndrome
• Identify clinical features and genetic causes of TCS.
• Comprehend the absence of strict genotype-phenotype correlation.
• Evaluate the implications of variable symptom expression in genetic conditions.
• Acknowledge the importance of supportive measures for quality of life improvement.
3. Social Interaction and Education
• Foster awareness and inclusion for individuals with genetic conditions.
• Encourage understanding and empathy through educational initiatives.

 

CASE 7

Gene Therapy for Retinal Dystrophies

Condition Overview

• Disease: Retinitis Pigmentosa
• Characteristics: Degenerative process of retina, begins with rods
• Symptoms: Difficulty seeing in low light, worsens with disease progression
• Inheritance: Variable, generally rare
• Associated Gene: RPE65, crucial for transforming light to nervous signals

Gene Therapy Strategy

• Target Gene: RPE65
• Therapy Name: Luxturna
• Approval: FDA (USA), EMA (Europe), AIFA (Italy)
• Eligibility: Patients must be at least one year old
• Treatment Centers: Limited, requires specialized training
• Therapy Administration
• Method: Subretinal injection
• Procedure: Treat one eye first, then the other after six days
• Evaluation: Retinal function and vision assessed through tests

Considerations and Results

• Cost: Approximately €500,000
• Eligibility Parameters: Retinal degeneration and function
• Note: Advanced degeneration may hinder therapy
• Results: Significant improvements in visual function and mobility

Case Study

• Patient Profile: Mutation in RPE65 gene, diagnosed with retinitis pigmentosa
• Outcome: Not enrolled in protocol due to good electroretinogram response
• Future Considerations: Inclusion possible if condition worsens

Important Considerations

• Delicacy of Treatment: Case-by-case evaluation needed
• Potential Risks: Possible damage to healthy cells

Recommendations: Careful analysis of patient's situation before intervention

 

 

CASE 8

 

Case Study: Family Experience with U.S. Healthcare System

Overview:

• Context: Family in the U.S. navigating private healthcare system.
• Challenges: Financial hardship and limited access to treatments.
• Outcome: Overcoming obstacles through determination and support.

Reflections:

• Healthcare Disparities: Differences in access to treatment compared to public systems.
• Stories of Hope: Successes and difficulties highlight systemic challenges.

Key Points from the Family's Experience

1. Early Diagnosis and Screening:
• Initial Concerns: Suspected autism at birth.
• Current Practices: Newborn screening identifies issues early.
• Challenges: Need for thorough investigations to exclude other conditions.
2. Sensory Deprivation Misinterpretation:
• Historical Context: Deafness misinterpreted as intellectual disability.
• Marginalization: Incorrect diagnosis led to social exclusion.
3. Awareness and Experimental Treatments:
• Child’s Awareness: Despite visual impairment, recognizes condition.
• Experimental Therapy: Uncertainty about outcomes, potential life changes.
4. Complex Genetic Interventions:
• Defective Gene Replacement: Not routine; limited data.
• Potential: Significant advancements in genetic disease treatment.
5. Progress in Genetics and Advanced Therapies:
• Success Stories: Restored sight in some patients.
• Challenges: Ongoing research for other genetic mutations.
• Personalized Approach: Custom treatment based on mutation and vector capabilities.

Conclusion:

• Ongoing Research: Personalized approaches needed for genetic therapies.
• Impact: Life-changing potential for patients with successful treatment.

⸻

 

 

CASE 9

 

 

Schematic Overview: Hearing and Hearing Loss

1. Auditory System Complexity
• Inner ear cells lack regeneration ability.
• Permanent damage from aminoglycosides.
• Mammals vs. other animals: limited regeneration in mammals.
2. Gene Therapy for Deafness
• Goal: Preserve inner hair cells.
• Challenges: High cell specificity, varying gene expression.
• Accessibility issues for treatment.
3. Current Therapies
• Hearing aids and cochlear implants for severe deafness.
• Gene therapy: Experimental status.
4. Recent Developments
• Ferlin gene therapy: Potential treatment for sensorineural deafness.
• Administration: Intra-cochlear injection.
• Debates: Gene therapy vs. cochlear implants.
5. Case Study and Progress
• First patient received gene therapy in one ear, implant in the other.
• Positive early outcomes reported.
• Limited treatment centers globally.
6. Future Implications
• Hope for new therapies.
• High cost limits accessibility.
• Ongoing debates and research in gene therapy.

Important Points to Remember

• Inner ear cell regeneration is largely absent in mammals.
• Gene therapy is still in experimental stages with promising but limited results.
• Cochlear implants remain a primary treatment option for irreversible deafness.
• Accessibility and cost are significant barriers to wider adoption of new therapies.

Conclusion

• Continued advancements in gene therapy could potentially revolutionize treatment for deafness, but ethical, financial, and technical challenges remain.
• Comprehensive understanding of genetic factors is crucial for developing effective therapies.

 

 

CASE 10

 

Schematic Overview: Cell Therapy for Junctional Epidermolysis Bullosa (JEB)

Background

• Condition: Junctional Epidermolysis Bullosa, also known as "Butterfly Disease."
• Symptoms: Extremely fragile skin, prone to blisters and erosions, resembling burn wounds.
• Genetic Cause: Mutations in three genes, potentially leading to severe and lethal forms.

Case Study: Syrian Boy

• Context: The boy arrived in Germany in 2015, war refugee.
• Condition upon Arrival: 80% of body covered with burned, infected skin.
• Therapy Application:
• Stem cells extracted from a small healthy skin patch.
• Cells grown in the lab and genetically modified with healthy laminin 332 gene.
• Transplantation of modified cells into the boy's body.

Outcomes

• Healing: Approximately 80% of damaged skin restored.
• Duration: 21-month follow-up showed complete healing with no new blisters.
• Published Findings: Documented in Nature journal, showcasing successful gene-modified cell therapy.

Emotional Impact

• Personal Account: Colleague's seminar in Trieste highlighted the emotional impact of the success story.
• Significance: Demonstrates life-changing potential of cell therapy, offering hope for severe genetic disorders.

Key Points to Study and Remember

• Gene Therapy: The application of genetically modified stem cells in treating genetic skin disorders.
• Impact: Full restoration of skin functionality and elasticity.
• Emotional and Ethical Considerations: Understanding the broader implications of successful therapy on patients' lives and the medical community.

Future Implications: Potential expansion of similar therapies to other genetic conditions, emphasizing personalized medicine.

 

 

 

CASE 11

 

Spinal Muscular Atrophy (SMA)

• Disease Overview:
• SMA is a serious genetic neurodegenerative disorder with autosomal recessive inheritance.
• Primarily linked to homozygous deletion of the SMN1 gene affecting motor neuron survival.
• Leads to progressive muscle weakness.
• Prevalence:
• Affects about 1 in 11,000 births.
• Carrier frequency is 1 in 50, which underscores the importance of carrier screening.
• Forms of SMA:
• Type 1: Infants, usually fatal within 2 years due to respiratory failure.
• Type 2: Onset before 18 months; children cannot walk or sit.
• Type 3: Onset after age 2; affected individuals can live to adulthood with walking difficulties.
• Type 4: Adult form; progresses slowly and occurs in the third decade of life.
• Current Therapies:
• Antisense Oligonucleotide Therapy: FDA approved in 2016, modulates gene expression, requiring periodic injections.
• Gene Therapy: A more recent innovation marking significant advancement.
• Screening and Diagnosis:
• Mandatory newborn screening for the SMN1 gene allows for early intervention through gene therapy.
• Early diagnosis is crucial as symptoms appear around six months after birth.
• Implications:
• Importance of introducing carrier screening in national health systems.
• High health insurance costs present challenges, especially in the United States.

Key Points to Remember

• Genetic Transmission: Autosomal recessive pattern, requiring two copies of the defective gene.
• Early Diagnosis: Enables immediate initiation of treatment, improving patient outcomes.
• Therapeutic Advances: Ongoing development of gene therapies brings hope to families affected by SMA.
• Public Health Impact: Emphasizes the need for cost-effective carrier screening and newborn screening programs.

Important Considerations

• Clinical Management: Historically focused on supportive care to manage symptoms until recent therapeutic advancements.
• Ethical Concerns: High cost of treatment and healthcare accessibility remain significant issues.

Future Directions: Continuous research and development aim to refine gene therapy, potentially offering more permanent solutions.

 

 

CASE 12

Schematic Overview: Gene Editing Technology

1. Introduction to Gene Editing

• Definition: Innovative technology allowing for "cut and paste" genomic corrections.
• Comparison with Gene Therapy: Focuses on correcting defects directly rather than replacing genes.

2. Nobel Prize Recognition

• Awardees: Emanuele di Scarpe Entier and Jennifer Doudna received the 2020 Nobel Prize in Chemistry.
• Discovery: Utilized a bacterial defense system to edit genomes.
• Impact: Rapid global adoption for diverse applications.

3. Applications and Potential

• Fields of Use: Employed in cell biology to reproduce genetic variants for study.
• Revolutionary Impact: Despite early-stage applications, it's significantly advancing medicine.

4. Current Status and Future Prospects

• Development Stage: Human gene editing is still early and lacks validated clinical results.
• Potential Uses: Capable of treating various conditions by correcting mutations.

5. Key Points to Study and Remember

• Complexity: While easily explained, it's complex in application and refinement.
• Personalized Therapy: Aims to correct individual mutations, moving towards personalized medicine.

Ongoing Research: Continuous advancements needed for effective and widespread application.

 

 

CASE 13

 

Key Case: CRISPR-Cas9 Genetic Modification

1. Background
• Year: 2018
• Location: Hong Kong conference
• Scientist: Chinese researcher
• Technique: CRISPR-Cas9
• Target: DNA modification of twin girls, nicknamed "Liu Nana"
2. Purpose
• Intended Outcome: Immunity to HIV
• Scientific Basis: Claimed CCR5 gene editing for HIV protection
• Target Population: Inspired by Northern European gene traits
3. Scientific Community's Response
• Lack of Evidence: No peer-reviewed publications
• Criticism: Strong disapproval for ethical and scientific violations
• Legal Consequences:
• Sentenced to 3 years in prison
• Fined for medical regulation breach
4. Ethical and Scientific Concerns
• Random Genome Modification:
• Potential Immune System Weakening: Mutation could be harmful
• Rare Mutation in Asian Populations: Raises further risks
• Disease Protection: Concerns over negative effects on other virus defenses
5. Implications for Personalized Medicine
• Necessity: Importance of considering population-specific medicine
• Example: Asian populations needing tailored approaches
6. Public Opinion and Polls
• Polls Conducted: Post-incident in the UK
• Results:
• 83% favor germline editing for curing diseases
• Opposition: Against using technology for eugenics (e.g., enhancing intelligence)

Summary

• Scientific and Ethical Repercussions: The case highlights severe shortcomings in adhering to scientific proof and ethical practices.
• Public Perception: Prominent support for medical applications of gene editing but significant concerns about eugenics.

Lessons for Future Research: Underlines the requirement for extensive evidence and ethical scrutiny in genetic research.

 

CASE 14

 

Schematic Overview: Narrative Medicine and Pathologies in Art

Introduction to Narrative Medicine

• Concept: Explores genetic diversity and applications through art.
• Objective: Enhance doctor-patient dialogue and clinical sign recognition.
• Application: Use historical art to teach medical diagnostics and genetics.

Historical Pathological Conditions in Art

• Craniosynostosis: Identified in figurines; Crouzon syndrome noted in Cook Islands art.
• Dermatological Diseases: Analyzed in paintings at the National Gallery, London.
• Chondropathy: Represented differently across centuries.

Influence of Artists' Conditions

• Van Gogh: Migraines, psychiatric conditions influenced style.
• Monet and Kahlo: Physical conditions evident in their works.

Recognizing Medical Signs in Art

• Breast Cancer: Early signs noted in paintings by Ghirlandaio and Raphael.
• Thyroid Goiter: Common in Renaissance paintings due to diet.
• Syphilis: Depicted in art from 1523 onwards.

Art as a Diagnostic Tool

• Van Gogh's Use of Yellow: Possible medication side effects.
• Alzheimer’s Impact: Captured in self-portraits over time.
• Marfan Syndrome: Skeletal alterations observed in historical art.

Genetic Conditions Portrayed in Art

• Polydactyly: Seen in Raphael’s “Marriage of the Virgin.”
• Neurofibromatosis Type 1: Suspected in Piero della Francesca’s work.
• Achondroplasia: Depicted in paintings from the 1600s.

Educational Implications

• Goal: Foster observation skills essential for medical diagnosis.
• Impact: Stimulates curiosity and enriches cultural understanding.
• Book Publication: Upcoming text for students linking genetic signs to art.

Research and Future Directions

• Concept Development: Adopted and expanded by research groups.
• Publication Plans: Book to be translated into English, teaching genetics via art.

Key Points to Study and Remember

1. Narrative Medicine: Enhances awareness of ethical and scientific implications of new technologies.
2. Art as Diagnostic Tool: Aids in identifying signs of pathologies.
3. Historical Disease Representation: Variability in depiction across eras.
4. Observation Skills: Crucial for medical professionals to prevent misdiagnosis.

Integration with Genetics: Links clinical signs and genetic conditions with historical art.

 

 

END CASE

 

Schematic Overview: Genetic Conditions in Historical Art and Narrative Medicine

1. Historical Portraits and Diagnoses
• Portrait Analysis:
• 1490 Irish Portrait: Man with grandson displaying Rhinophyma, characterized by nasal soft tissue alteration.
• 1600s Paintings: Presence of androgenetic alopecia (genetic hair loss).
• Mantegna's Art: Depictions of Down syndrome in baby Jesus portraits.
• 1800s Art: Spondyloepiphyseal dysplasia observed in historical paintings.
2. Genetic Conditions Represented in Art
• Hypertrichosis: AMD PES syndrome showing abnormal hair growth patterns.
• Mona Lisa: Suggested familial hypercholesterolemia, indicated by visible xanthelasma and lipoma.
• Autoimmune Disease of Orton: Exhibits protuberance in shingles.
3. Narrative Medicine in Art
• Practice: Uses art to foster empathy and attention in clinicians.
• Interpretation: Distinguishes between genuine deformities and artistic styles.
• Educational Objective: Encourages a deeper understanding of genetic conditions through historical representations.
4. Historical Genetic Discoveries
• Cangrande’s Mummy: DNA revealed Pompe disease, a glycogenosis due to enzyme deficiency.
• DNA Testing's Role: Highlights the potential insights into past diseases if DNA samples were available.
5. Educational Implications
• Scientific Curiosity: Encourages learning beyond exams, promoting a comprehensive cultural and scientific knowledge.

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Key Takeaways

• Art as a Diagnostic Tool: Enhances medical diagnostics through historical analysis and understanding of genetic diversity.
• Narrative Medicine: Strengthens doctor-patient interaction and clinical observation skills.

Integration with Genetics: Connects clinical signs with artistic depictions, enriching historical and medical education.

 

 

 

 

 

 

 

Schematic Overview: BRCA1, BRCA2, and Genetic Cancer Risk

1. Genetic Cancer Overview:

• Genes: BRCA1, BRCA2
• Role: DNA repair regulation.
• Mutations: Impair repair, increasing cancer risk.
• Cancer Types: Breast, ovarian, tubal, peritoneal, melanoma, Fanconi anemia.
• Prevalence: 5-10% of breast/ovarian cancers.
• Gender Impact: Affects both women and men (1-6% breast cancer risk in men).

2. Risk and Inheritance:

• Probability of Developing Cancer:
• BRCA1/BRCA2 mutation carriers: 40-90% risk of breast cancer, higher than general population (13%).
• Transmission: Hereditary mutations can be passed to offspring.
• Ethnic Prevalence: Higher mutation frequency in Ashkenazi Jews.

3. Preventive Measures:

• Surgery:
• Preventive Mastectomy: Adopted by some, e.g., Angelina Jolie.
• Bilateral Salpingo-Oophorectomy: Reduces ovarian cancer risk.
• Surveillance: Intensive monitoring is vital for early detection.

4. Other Genes Related to Cancer:

• APC Gene: Associated with familial adenomatous polyposis (FAP).
• Inheritance Pattern: Autosomal dominant.
• Risk: Development of colorectal cancer by age 50 if untreated.

5. Genetic Testing and Screening:

• Germline Testing: Conducted through blood for hereditary cancer risk.
• Somatic Testing: Analyzes tumor tissue.
• Preimplantation Diagnosis: To prevent transferring mutations to offspring.

6. Therapeutic Options and Research:

• Current Therapies: No definitive cancer cures yet; strategies vary based on genetic profile.
• Research and Evolution: Cancer cells mutate, altering therapeutic targets.
• Presymptomatic Testing: Recommended for those with familial history.

7. Ethical and Clinical Considerations:

• Ethical Dilemmas: Whether to test for BRCA mutations without symptoms.
• Treatment Decisions: Weighing options like mastectomy and salpingectomy.

Summary:

Understanding BRCA1 and BRCA2 mutations is crucial for managing cancer risk. Preventive strategies, including surgery and surveillance, can mitigate risks significantly. Genetic testing plays a pivotal role in identifying individuals at risk, enabling proactive measures. Despite advancements, the complexity of genetic cancer requires ongoing research and ethical deliberation.