Seminario 10 PARTE B Introducción a la Genética Medica - María Paz Bidondo

Introduction to Medical Genetics

Overview of Genotype and Phenotype

• María Pazvidondo introduces the seminar, focusing on genotype, which refers to specific sequences that are generally genes and their alleles.

• Discussion includes concepts like homozygosity, heterozygosity, and compound heterozygosity in relation to phenotypes.

• The relationship between genotype and phenotype is explored through clinical examples, assessing healthy versus affected individuals within families or populations.

Mechanisms Behind Genetic Variants

• Questions arise regarding the molecular mechanisms that link genetic variants with phenotypic outcomes.

• Emphasis on how genomic information enhances understanding of health and disease processes.

Role of Medical Geneticists

Training and Specialization

• Medical geneticists typically start as general physicians before specializing in medical genetics through a residency program lasting three to four years.

• The National Center for Medical Genetics (Senagem) offers a four-year specialization located at Hospital Rivadavia in Buenos Aires.

Clinical Applications

• Clinical geneticists assess risks by identifying variants that help determine carrier status for various conditions through genetic counseling.

• Prenatal testing methods include ultrasound for morphological assessments and neonatal screenings for metabolic diseases.

Diagnosis and Treatment Strategies

Types of Genetic Disorders

• Discussion on diagnosing monogenic disorders caused by single genes versus polygenic or multifactorial disorders.

Personalized Medicine Approaches

• Genetic variants can guide treatment choices, particularly in adult diseases such as neurodegenerative or oncological conditions.

• Pharmacogenomics aims to tailor therapies based on individual genetic profiles to minimize adverse effects while maximizing efficacy.

Consultation Process in Genetics

Patient Interaction Steps

• The consultation process mirrors other clinical practices; it begins with taking a detailed family history (anamnesis).

• Creation of a genealogical tree helps identify risk factors and specific signs related to health issues.

Diagnostic Integration

• Initial diagnostic hypotheses are formed based on patient history, leading to potential referrals for specialized consultations (e.g., endocrinology, neurology).

Genetic Counseling and Family History Analysis

Importance of Literature Review in Genetic Counseling

• Conducting a literature review helps identify phenotypes similar to those of patients, confirming or rejecting hypotheses based on existing data.

• If a hypothesis is confirmed, genetic counseling follows, detailing specific diagnoses, follow-up guidelines, recurrence risks, and quality of life improvements for patients and families.

Role of Family Trees in Risk Assessment

• The focus will be on constructing family trees (genealogies), which are essential for identifying risk factors that aid in diagnosis and prevention.

• Gathering information through genealogical inquiries allows for early detection of affected individuals and ensures access to health resources for families.

Identifying Risk Factors

• Maternal age at birth over 35 years increases the likelihood of chromosomal abnormalities like trisomy 18; however, it does not guarantee occurrence.

• Advanced paternal age can lead to new pathogenic mutations due to increased cycles during spermatogenesis.

Consanguinity and Recurrent Pregnancy Losses

• Relationships among relatives (e.g., cousins) increase the risk for certain genetic conditions classified as autosomal recessive or multifactorial.

• Families reporting recurrent pregnancy losses may indicate balanced translocations affecting gestation outcomes.

Systematic Data Collection in Genealogy

• Collecting detailed family histories includes noting instances of cognitive disabilities or gestational issues to inform health assessments.

• Standardized nomenclature for genealogies has been developed internationally since the 1990s by groups like Benet, ensuring consistency across different countries.

Visual Representation in Genealogy

• Medical professionals must be proficient in creating genealogical charts using standardized symbols: squares for males, circles for females, and rhombuses for unspecified genders.

Genealogical Symbols and Their Meanings

Understanding Genealogical Representation

• The speaker discusses the importance of using symbols in genealogical charts to represent various conditions, indicating that horizontal stripes signify one condition while shaded areas denote another.

• When representing individuals, numbers are used inside shapes to indicate the quantity of people of a specific gender, simplifying complex family structures into more manageable representations.

• A distinction is made between the "consultant" (the person seeking advice) and the "proband" (the individual being studied), with arrows used to indicate these roles on the chart.

Identifying Affected Individuals

• If the consultant is also affected by a condition, they become the proband for genetic testing; otherwise, they remain as just a consultant in the chart.

• The speaker emphasizes that it’s crucial for the proband to be directly related to the consultation process, ensuring accurate data collection for genetic studies.

Representing Pregnancy and Loss

• Fetal losses are represented differently based on their nature: stillbirths are marked distinctly from abortions, with specific symbols denoting gestational age at loss.

• For spontaneous abortions before 24 weeks, different symbols (triangles for early losses) are utilized to differentiate them from later-term losses or elective terminations.

Symbolism in Genetic Studies

• The use of shading indicates whether an individual was affected by a condition during pregnancy or after birth; this helps clarify data when analyzing genetic links.

• Specific letters within shapes denote pregnancy status versus proband status; 'P' outside indicates proband while 'P' inside signifies pregnancy.

Importance of Data Quality

• To ensure effective analysis in genealogical studies, it's essential that charts include information spanning at least three generations—grandparents, parents, and children—to provide context.

Genealogical Analysis and Genetic Variants

Understanding Genealogical Symbols

• The speaker discusses the representation of carriers in genealogical trees, emphasizing that unaffected individuals who are carriers should be marked with a dot at the center of their figure.

• Clarification is made regarding symbols: an external symbol indicates a proband (the individual being studied), while an internal symbol represents pregnancy. Carriers do not use 'P' but rather a central dot.

Data Quality and Genetic Evaluation

• A case study is introduced involving a female individual who is affected by a genetic condition, confirmed through reliable testing indicated by an asterisk.

• The findings reveal two variants: one confirmed deletion related to cystic fibrosis and another uncertain variant, highlighting the complexity of genetic conditions requiring multiple variants for expression.

Genotype Analysis

• Discussion on parental genotypes shows that the father carries one variant while the mother has wild type; this illustrates how both parents contribute to potential genetic conditions in offspring.

• The analysis includes details about a male fetus affected by trisomy 18, which leads to various malformations detectable via ultrasound and karyotyping.

Family Structure Interpretation

• The genealogical tree spans three generations, organized from oldest to youngest. It identifies Ana as a 15-year-old female with some health issues indicated by her shaded figure.

• Ana's family structure is detailed, including her siblings and parents. Relationships are visually represented through horizontal lines for couples and vertical lines for descendants.

Health Conditions and Risk Factors

• Information about Ana’s grandfather Jorge reveals he passed away from acute myocardial infarction at age 77, providing context for familial health history.

• Further examination shows Ana has been diagnosed with Down syndrome (trisomy 21), confirmed through karyotyping indicating she has an extra chromosome.

Maternal Age Considerations

• Beatriz, Ana's mother, had her at age 40; this detail introduces maternal age as a risk factor associated with chromosomal abnormalities like trisomy 21.

Complex Family Dynamics

• The discussion shifts to other family members’ histories, including previous pregnancies and relationships outside of current partnerships. This highlights complexities in family structures affecting genetic counseling.

Understanding Genetic Symbols and Family Structures

Genetic Relationships and Symbolism

• The use of symbols to indicate consanguinity is introduced; for example, a double line represents first cousins.

• Differentiation between monozygotic (identical) and dizygotic (fraternal) twins is explained, highlighting genetic similarities and differences.

• In cases involving assisted reproduction, the role of gamete donors is clarified, with specific notation for donor sperm indicated by "D."

Infertility and Personal Decisions

• Distinctions are made regarding couples without children based on personal choice versus defined infertility issues.

• Various reasons for infertility are discussed, including medical conditions like aspermia or endometriosis.

Genealogy and Confidentiality in Research

• The importance of standardized symbols in genealogical trees is emphasized, particularly when studying significant genetic variants linked to diseases like amyotrophic lateral sclerosis (ALS).

• A case study from a scientific article illustrates how gender information can be anonymized while still conveying essential genetic data.

Gender Identity Representation in Genetics

Gender vs. Sex: Understanding the Differences

• The distinction between sex assigned at birth based on external genitalia and gender identity is explored.

• A standardized approach to graphically represent both sex at birth and self-identification as male, female, or non-binary is presented.

Visual Representation of Gender Identity

• The method of assigning gender based on external genitalia at birth is described; this includes categories such as male or female.

• Examples illustrate how individuals assigned male at birth may identify differently later in life; visual symbols are used to denote these identities accurately.

Implications for Health Monitoring

• Considerations for health monitoring are discussed concerning individuals' anatomical characteristics versus their gender identity.

Gender Identity and Genetic Patterns in Reproductive Health

Understanding Gender Assignment and Self-Identification

• The discussion begins with a case of an individual assigned female at birth who identifies as male. The speaker emphasizes the importance of recognizing gender identity through symbols, such as squares for male identification.

• Another example is presented where an individual assigned female at birth identifies as non-binary. The use of different shapes (circle for female, diamond for non-binary) illustrates how gender perception varies among individuals.

• Acknowledgment that some individuals may not have a sex assigned at birth due to ambiguous genitalia. This highlights the complexity of gender identity beyond traditional binary classifications.

Reproductive Choices in Transgender Individuals

• A transgender man is discussed who has a partner; they opted for surrogacy using their gametes to conceive, showcasing modern reproductive technologies available to LGBTQ+ couples.

• The concept of surrogacy is further explored, including scenarios involving egg donation and double donation, indicating diverse family-building options within the community.

Analyzing Genetic Patterns in Family Trees

• The speaker introduces the concept of analyzing genealogical patterns to understand genetic conditions across generations. A vertical pattern indicates affected individuals across multiple generations from the same lineage.

• Vertical inheritance patterns are linked to autosomal dominant traits, suggesting that certain genetic conditions can be traced through direct father-son transmission.

Horizontal Patterns and Incomplete Penetrance

• A horizontal pattern is introduced where affected individuals appear within the same generation but may not show consistent inheritance patterns, often associated with autosomal recessive traits.

• An example tree shows three generations with both affected and unaffected individuals. It raises questions about incomplete penetrance—where not all carriers express the phenotype despite having the genotype.

Implications of Genetic Findings

• Discussion on genotypes reveals heterozygous and homozygous conditions among affected family members, emphasizing variability in expression even among genetically similar individuals.

Incomplete Penetrance Case Study

Overview of Family Tree and Genetic Conditions

• The case discusses incomplete penetrance, where an individual has the genotype but is not affected. Diego, a 15-year-old in the third generation, has mitral insufficiency.

• Diego's father, Esteban (45 years old), also suffers from mitral insufficiency and has experienced aortic dissection and lens dislocation.

• Diego's mother, Silvia (40 years old), is unaffected. Neither Diego's siblings nor Silvia's parents show any signs of the condition.

Paternal Lineage Insights

• Esteban has twin sisters who both have mitral insufficiency and aortic dilation but have not progressed to dissection yet.

• One sister is pregnant; however, the notation indicates that the pregnancy itself is marked rather than her status as pregnant.

• Esteban’s father, Raúl (deceased at 69), suffered from endocarditis linked to his mitral valve issues and had similar complications as Esteban.

Discussion on Marfan Syndrome

• The discussion references Marfan syndrome, which can cause various organ alterations including those affecting the heart and eyes.

• The same pathogenic variant can lead to pleiotropic effects across different organs such as the aorta and lens.

• Variable expressivity within this family shows differing severities of symptoms: some with only dilation while others experience more severe conditions like dissection or lens luxation.

Patterns of Inheritance

• Observations indicate vertical patterns of inheritance across generations with varying severity among affected individuals.

• There appears to be no significant gender bias in affected individuals; however, none are transgender or assigned different genders at birth.

Clinical Implications for Future Generations

• The genealogy provides valuable insights into potential health risks for future offspring; further clinical evaluations are suggested for other children in the family.

• It may be important to monitor pregnancies closely for genetic variants associated with these conditions.

Albinism Case Study

Identification of Affected Individuals

• A new family tree reveals all affected individuals concentrated in generation four with albinism characterized by reduced skin pigmentation due to melanin deficiency.

Genetic Transmission Patterns

• This type of albinism follows an autosomal recessive pattern where affected individuals possess two pathogenic variants while carriers have one normal and one pathogenic variant.

Consanguinity Indicators

Understanding Genetic Relationships and Patterns

Genetic Connections in Family Trees

• The speaker discusses a family relationship where two individuals are first cousins, indicating that one of them may be a carrier of a genetic condition. Genotyping is suggested to identify the carrier.

• Affected individuals predominantly appear in the fourth generation, showcasing a horizontal inheritance pattern within the same family unit. There is no significant gender bias among affected individuals.

• One individual has all affected children, confirming their status as a carrier of a pathogenic variant. This highlights the importance of understanding familial genetic risks.

Case Study: Albinism in Aicuña

• The speaker recommends reading "Alicunia: Retrato de un continente," authored by Argentine geneticist Eduardo Castilla, which details high rates of albinism in Aicuña due to historical population isolation.

• The book illustrates how socio-economic factors contribute to genetic isolation and increased prevalence of certain traits like oculocutaneous albinism over generations.

Importance of Genealogies

• Genealogies visually represent biological relationships and can indicate clinical conditions or risk factors associated with specific entities like albinism.

• They allow for identification of inheritance patterns (vertical vs. horizontal), aiding in diagnosing autosomal dominant or recessive conditions through standardized symbols.

Standardization in Genetic Notation

• Emphasizing the need for internationally recognized genealogical symbols ensures effective communication across different regions and studies without confusion.

• Using standardized codes facilitates comparison between studies and enhances data analysis capabilities within bioinformatics frameworks.

Clinical Examination Protocol

• After gathering family history, a thorough physical examination is conducted on each family member, assessing various phenotypic traits systematically from head to toe.

• Detailed observations during examinations help identify clinical signs relevant for further investigation into specific conditions when initial suspicions are absent.

Utilizing Phenotype Data for Diagnosis

• Standardized coding systems (HP codes from Human Phenotype Ontology) are used to document phenotypic traits accurately, enabling efficient searches for potential diagnoses linked to observed symptoms.

• Tools like Phenomizer assist clinicians in correlating phenotype data with possible clinical diagnoses and associated genetic variants, streamlining targeted testing processes.

Genotype-Phenotype Correlation and Diagnostic Approaches

Overview of Genotype Analysis

• Discussion on the importance of conducting genotype-level searches for specific variants to establish correlations between genotype and phenotype, which can aid in diagnosis.

• Emphasis on the ongoing nature of this research, with plans for future seminars to continue exploring these topics in depth.

Inspirational Closing Thoughts