Complex Disorders and Polygenic Inheritance
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Questions and Answers

What type of disorders are determined by the interaction of multiple genetic factors and environmental and lifestyle factors?

  • Polygenic disorders
  • Chromosomal disorders
  • Multifactorial or complex disorders (correct)
  • Mendelian disorders

    • What is the characteristic of polygenic disorders?

  • Interplay of variants in many genes, each exerting a small additive effect (correct)
  • Non-interplay of variants in many genes, each exerting a large effect
  • Interplay of variants in a single gene, exerting a large effect
  • No interplay of variants in a single gene, exerting a small effect

    • Which of the following is a common cause of infertility, miscarriage, congenital malformations, and intellectual disability?

  • Polygenic disorders
  • Chromosomal disorders (correct)
  • Multifactorial disorders
  • Mendelian disorders

    • What is the prevalence of chromosomal disorders in live births?

    <p>1 in 200 live births</p> Signup and view all the answers

    What is an example of a structural abnormality in chromosomal disorders?

    <p>All of the above</p> Signup and view all the answers

    Which of the following disorders is always genetic, but sometimes hereditary with a mendelian inheritance pattern?

    <p>Cancer</p> Signup and view all the answers

    What is the primary purpose of newborn screening in Italy?

    <p>To diagnose 49 diseases including cystic fibrosis and congenital hypothyroidism</p> Signup and view all the answers

    What is the significance of Articolo 6, legge 104, 05/02/1992 in the context of newborn screening in Italy?

    <p>It is a law that mandates newborn screening for 49 diseases</p> Signup and view all the answers

    What is the purpose of reconstructing the pedigree in the genetic counseling process?

    <p>To show family relationships and establish a diagnosis</p> Signup and view all the answers

    What is the role of genetic testing in the genetic counseling process?

    <p>To confirm a diagnosis after informed consent</p> Signup and view all the answers

    What is the purpose of gathering information about personal and family clinical history in the genetic counseling process?

    <p>To identify potential genetic disorders and establish a diagnosis</p> Signup and view all the answers

    What is the significance of the publication by Stark and Scott in Nat Rev Genet (2023)?

    <p>It launches large-scale genomic newborn screening studies internationally</p> Signup and view all the answers

    What is the purpose of specialist visits in the genetic counseling process?

    <p>To confirm a diagnosis through specialist evaluation</p> Signup and view all the answers

    What is the role of biochemical assays in newborn screening?

    <p>To screen for specific serum analytes</p> Signup and view all the answers

    What is the primary methodology used to test for multiple variants in the CHD7 gene, which is associated with CHARGE syndrome?

    <p>Targeted NGS of the CHD7 gene</p> Signup and view all the answers

    What is the characteristic of the clinical features of RASopathies?

    <p>Distinct facial features and developmental delays</p> Signup and view all the answers

    What is the advantage of NGS gene panels?

    <p>Allows simultaneous testing of multiple clinically- and genetically-related conditions</p> Signup and view all the answers

    What is the primary purpose of newborn screening for hereditary diseases?

    <p>To identify diseases that cause permanent disability or death if not identified and treated early</p> Signup and view all the answers

    What is the number of pathogenic variants identified in the CHD7 gene associated with CHARGE syndrome?

    <p>Over 500</p> Signup and view all the answers

    What is a reason for referral to genetic counseling in the preconceptional period?

    <p>Genetic disorder present or suspected in family history</p> Signup and view all the answers

    What is the name of the signaling pathway involved in RASopathies?

    <p>RAS-MAPK signaling pathway</p> Signup and view all the answers

    What is the clinical feature of CHARGE syndrome that affects the eye?

    <p>Coloboma</p> Signup and view all the answers

    What is a key aspect of genetic counseling for patients or relatives at risk of an inherited disorder?

    <p>Explaining the probability of developing or transmitting the disorder</p> Signup and view all the answers

    In which scenario is genetic counseling typically referred to?

    <p>When a patient has a family history of a genetic disorder</p> Signup and view all the answers

    What is a reason for referral to genetic counseling in the postnatal period?

    <p>Child with developmental delay or intellectual disability</p> Signup and view all the answers

    What is discussed during genetic counseling for patients or relatives at risk of an inherited disorder?

    <p>The nature and consequences of the disorder and the options for its management</p> Signup and view all the answers

    In which scenario is genetic counseling not typically referred to?

    <p>When a patient is undergoing routine health check-ups</p> Signup and view all the answers

    What is a reason for referral to genetic counseling in the oncologic period?

    <p>Familial aggregation of cancer</p> Signup and view all the answers

    What is the purpose of the ACMG Standards and Guidelines for variant classification in mendelian diseases?

    <p>To provide a framework for classifying variants based on the weight of evidence</p> Signup and view all the answers

    What is the classification of a variant that is likely causative of a disease with 90% certainty?

    <p>Likely pathogenic</p> Signup and view all the answers

    What is the purpose of the Online Mendelian Inheritance in Man (OMIM) catalog?

    <p>To provide a comprehensive list of genetic disorders</p> Signup and view all the answers

    How would you search for inherited diseases of the thyroid gland in OMIM?

    <p><em>thyroid</em></p> Signup and view all the answers

    What is the purpose of the ORPHANET portal?

    <p>To provide information on rare diseases and orphan drugs</p> Signup and view all the answers

    What is the purpose of GeneReviews?

    <p>To provide detailed information on specific genetic disorders</p> Signup and view all the answers

    What does the symbol '%' indicate in OMIM?

    <p>A mendelian phenotype or phenotypic locus with an unknown molecular basis</p> Signup and view all the answers

    What is the classification of a variant that is not causative of a disease?

    <p>Benign</p> Signup and view all the answers

    What is the key characteristic of autosomal dominant inheritance?

    <p>Each child of an affected parent has a 50% risk of being affected</p> Signup and view all the answers

    What is the name of the inheritance pattern where the disease is transmitted through the maternal line?

    <p>Mitochondrial/maternal</p> Signup and view all the answers

    What is the risk of disease in offspring of an affected parent in autosomal dominant inheritance?

    <p>50%</p> Signup and view all the answers

    What is the characteristic of X-linked dominant inheritance?

    <p>The disease is equally common in both sexes</p> Signup and view all the answers

    What is the type of inheritance where the disease is transmitted by either sex to offspring of either sex?

    <p>Autosomal dominant</p> Signup and view all the answers

    What is the name of the inheritance pattern where the disease is transmitted through the paternal line?

    <p>Y-linked</p> Signup and view all the answers

    What is the risk of disease for an offspring when both parents are affected heterozygotes?

    <p>75%</p> Signup and view all the answers

    In autosomal recessive inheritance, what is the role of the parents of affected individuals?

    <p>They are asymptomatic carriers (heterozygotes)</p> Signup and view all the answers

    What is the risk of disease for an offspring when both parents are carriers (heterozygotes)?

    <p>25%</p> Signup and view all the answers

    What is the characteristic of homozygotes compared to heterozygotes in autosomal recessive inheritance?

    <p>Homozygotes have a more severe phenotype</p> Signup and view all the answers

    What type of mating results in a 50% risk of disease for an offspring?

    <p>Affected x healthy</p> Signup and view all the answers

    In autosomal recessive inheritance, what is the genotype of an unaffected parent?

    <p>either Aa or AA</p> Signup and view all the answers

    What is the characteristic of autosomal recessive inheritance?

    <p>Two carrier parents are required to transmit the disease</p> Signup and view all the answers

    What is the pattern of inheritance when an affected individual has unaffected parents?

    <p>Autosomal recessive</p> Signup and view all the answers

    In X-linked dominant inheritance, what is the risk of disease for daughters of an affected mother?

    <p>100%</p> Signup and view all the answers

    What is the carrier risk for an individual with an affected parent and a healthy carrier?

    <p>2/3</p> Signup and view all the answers

    In a family with a history of X-linked dominant inheritance, what is the risk of disease for sons of an affected father?

    <p>0%</p> Signup and view all the answers

    What is the characteristic of affected individuals in a family with X-linked dominant inheritance?

    <p>Vertical transmission only</p> Signup and view all the answers

    What is the risk of disease for offspring of a healthy carrier and an affected parent?

    <p>25%</p> Signup and view all the answers

    What is the characteristic of affected individuals in a family with autosomal dominant inheritance?

    <p>Males and females are equally likely to be affected</p> Signup and view all the answers

    What is the carrier risk for an individual with two healthy parents?

    <p>Not applicable</p> Signup and view all the answers

    What is the risk of recurrence for offspring of two healthy carriers?

    <p>25%</p> Signup and view all the answers

    What is the risk of disease transmission from an affected father to his sons?

    <p>0%</p> Signup and view all the answers

    What is the risk of a daughter being a carrier if her mother is a carrier?

    <p>50%</p> Signup and view all the answers

    Why are females more frequently affected than males in X-linked recessive inheritance?

    <p>Because males only have one X chromosome</p> Signup and view all the answers

    What is the risk of a son being affected if his mother is a carrier?

    <p>50%</p> Signup and view all the answers

    What is the characteristic of X-linked recessive inheritance?

    <p>Affected males transmit the disease phenotype to their daughters</p> Signup and view all the answers

    What is the chance of a daughter being an obligate carrier if her father is affected?

    <p>100%</p> Signup and view all the answers

    What is the characteristic of male-to-male transmission in X-linked recessive inheritance?

    <p>It is not possible</p> Signup and view all the answers

    What is the role of the mother in X-linked recessive inheritance?

    <p>She may be a carrier</p> Signup and view all the answers

    What is a characteristic of X-linked recessive inheritance?

    <p>Disease manifests in a previous generation</p> Signup and view all the answers

    What is a characteristic of mitochondrial/maternal inheritance?

    <p>Disease is transmitted by affected mothers to all offspring</p> Signup and view all the answers

    What is a common feature of autosomal recessive and X-linked recessive inheritance?

    <p>Consanguinity increases the risk of inheriting the condition</p> Signup and view all the answers

    What is the characteristic of Y-linked inheritance?

    <p>Affected males always have an affected father</p> Signup and view all the answers

    What is the characteristic of apparent Y-linked inheritance?

    <p>Causative gene is not normally on the Y chromosome</p> Signup and view all the answers

    What is a characteristic of carrier risk for an X-linked recessive disorder?

    <p>50% risk of inheriting the disorder</p> Signup and view all the answers

    What is the significance of consanguinity in autosomal recessive inheritance?

    <p>Increases the risk of inheriting a recessive condition</p> Signup and view all the answers

    What is a characteristic of affected females in X-linked recessive inheritance?

    <p>They may transmit the disease to some offspring</p> Signup and view all the answers

    What percentage of patients with severe developmental disorders have a pathogenic DNM in a protein-coding gene?

    <p>&gt;40%</p> Signup and view all the answers

    What is the estimated number of SNVs that arise per cell division in early human embryogenesis?

    <p>3</p> Signup and view all the answers

    What type of mosaicism occurs when a DNM arises in the first few cell divisions after fertilization?

    <p>High-level mosaicism</p> Signup and view all the answers

    What is a characteristic of somatic mosaicism?

    <p>The mutation occurs in somatic cells at any stage of life</p> Signup and view all the answers

    What is the average prevalence of developmental disorders caused by DNMs?

    <p>1/448 to 1/213 births</p> Signup and view all the answers

    How many genes were enriched in damaging DNMs in the DDD Study published in Nature in 2017?

    <p>94</p> Signup and view all the answers

    What is a consequence of postzygotic DNMs?

    <p>Mosaicism</p> Signup and view all the answers

    What determines the degree of mosaicism caused by a DNM?

    <p>The timing of the DNM</p> Signup and view all the answers

    What is germline mosaicism?

    <p>A type of mosaicism that occurs in the germline during early embryonic development and can be transmitted to offspring</p> Signup and view all the answers

    What is gonosomal mosaicism?

    <p>A type of mosaicism that occurs during early embryogenesis involving both germ cell and somatic cell lineages</p> Signup and view all the answers

    What is the characteristic of germline mosaicism in monogenic disorders?

    <p>It is suspected when 2 or more offspring present with an autosomal dominant condition, and there is no family history of the condition</p> Signup and view all the answers

    What is the challenge in detecting mosaicism?

    <p>It is difficult to detect, especially low-level mosaicism</p> Signup and view all the answers

    What is an example of a rare genetic disorder caused by postzygotic somatic mutations?

    <p>Segmental neurofibromatosis type 1</p> Signup and view all the answers

    What is the characteristic of somatic mosaicism in segmental neurofibromatosis type 1?

    <p>Manifestations are limited to a segment of the body</p> Signup and view all the answers

    What is the significance of analyzing various tissues, even single cells, in detecting mosaicism?

    <p>It is necessary for detecting low-level mosaicism</p> Signup and view all the answers

    What is the purpose of comparing affected vs. unaffected tissues in detecting mosaicism?

    <p>To confirm the diagnosis of mosaicism</p> Signup and view all the answers

    What is the main advantage of using NGS and droplet digital PCR for detecting paternal germline mosaicism?

    <p>They provide a more accurate estimate of risk of recurrence</p> Signup and view all the answers

    What is the unit of measurement used to express the frequency of a variant in a specimen?

    <p>Variant allele frequency (VAF)</p> Signup and view all the answers

    What is the purpose of dividing samples into thousands of water-in-oil droplets in ddPCR technology?

    <p>To run multiple PCR amplifications in parallel</p> Signup and view all the answers

    What is the mechanism of FRET in Taqman probes?

    <p>The quencher absorbs energy released by the reporter fluorophore</p> Signup and view all the answers

    What is the main application of real-time quantitative PCR assay?

    <p>To quantify the amount of a specific DNA sequence</p> Signup and view all the answers

    What is the main advantage of using droplet digital PCR over traditional PCR methods?

    <p>Improved precision</p> Signup and view all the answers

    What is the purpose of using allele-specific fluorescently-labelled probes in the Taqman assay?

    <p>To increase the specificity of the assay</p> Signup and view all the answers

    What is the main limitation of using non-affected tissues for detecting paternal germline mosaicism?

    <p>They are not accessible</p> Signup and view all the answers

    What is the effect of the exonuclease activity of Taq polymerase on the annealed probe during PCR amplification?

    <p>It releases the fluorophore, increasing the fluorescence signal.</p> Signup and view all the answers

    What is the purpose of using two parallel assays with allele-specific probes in genotyping?

    <p>To discriminate between the normal and variant alleles.</p> Signup and view all the answers

    What is the characteristic of droplet digital PCR (ddPCR) workflow?

    <p>PCR reagents are partitioned into picoliter to nanoliter droplets.</p> Signup and view all the answers

    What is the characteristic of Alport syndrome?

    <p>It is a hereditary glomerulopathy featured by haematuria, proteinuria, and progressive renal failure.</p> Signup and view all the answers

    What is the purpose of partitioning PCR reagents into picoliter to nanoliter droplets in ddPCR?

    <p>To allow for the detection of very low-level somatic mosaic variants.</p> Signup and view all the answers

    What is the significance of the fluorescence intensity of each individual droplet in ddPCR?

    <p>It is directly proportional to the quantity of template DNA.</p> Signup and view all the answers

    What is the advantage of ddPCR in detecting very low-level somatic mosaic variants?

    <p>It allows for the detection of very low-level somatic mosaic variants with high precision.</p> Signup and view all the answers

    What is the purpose of using Taqman assay in ddPCR?

    <p>To detect the presence of a specific gene variant.</p> Signup and view all the answers

    What is the purpose of using unique molecular identifiers (UMIs) in sequencing?

    <p>To improve consensus calls and remove PCR-derived duplicates</p> Signup and view all the answers

    Why do de novo mutations (DNMs) occur more often in paternal germ cells than in maternal germ cells?

    <p>Because sperm undergo more cell divisions than eggs</p> Signup and view all the answers

    According to the figure illustrating the paternal age effect, what happens to the number of genome replications in the male germline as paternal age increases?

    <p>It increases</p> Signup and view all the answers

    What is the approximate number of cell divisions that sperm undergo by the age of 40 years?

    <p>650</p> Signup and view all the answers

    Why is the paternal age effect observed in de novo mutations?

    <p>Because the number of genome replications in the male germline increases with paternal age</p> Signup and view all the answers

    What is the approximate ratio of paternally derived DNMs to maternally derived DNMs?

    <p>3:1</p> Signup and view all the answers

    What is the purpose of long sequencing reads in the context of DNMs?

    <p>To improve mappability, even across repeat regions</p> Signup and view all the answers

    What is the significance of the difference in germline biology between males and females?

    <p>It explains the paternal age effect</p> Signup and view all the answers

    What is the term for the probability that a genotype will manifest itself in a particular phenotype?

    <p>Penetrance</p> Signup and view all the answers

    What is the reason why a child with an autosomal dominant disease is born to unaffected parents?

    <p>Incomplete penetrance</p> Signup and view all the answers

    What is the term for the degree to which a phenotype is expressed by a particular genotype?

    <p>Expressivity</p> Signup and view all the answers

    What is the example of a congenital limb malformation caused by a dominant mutation in the DLX5 gene?

    <p>Split hand/foot malformation I (SHFM1)</p> Signup and view all the answers

    What is the term for the phenomenon where a single genotype can cause a range of different phenotypes?

    <p>Variable expressivity</p> Signup and view all the answers

    What is the term for the correlation between a particular genotype and the resulting phenotype?

    <p>Genotype-phenotype correlation</p> Signup and view all the answers

    Why is the utility of genotype-phenotype correlation hampered?

    <p>Due to heterogeneity in the phenotypic expression of a disease</p> Signup and view all the answers

    What is the term for the phenomenon where a disease-causing genotype is not expressed in every individual?

    <p>Incomplete penetrance</p> Signup and view all the answers

    What was the aim of the analysis by Chen et al. in their 2016 study?

    <p>To analyze the Exome Aggregation Consortium (ExAC) data set for the presence of individuals with pathogenic genotypes implicated in Mendelian pediatric disorders</p> Signup and view all the answers

    What percentage of the ExAC data set had genotypes implicated in rare Mendelian disorders?

    <p>2.8%</p> Signup and view all the answers

    How many ExAC individuals had genotypes implicated in severe Mendelian early onset disorders?

    <p>18</p> Signup and view all the answers

    What was the number of unrelated individuals analyzed in the ExAC data set?

    <p>60,706</p> Signup and view all the answers

    What was excluded from the analysis of the ExAC data set?

    <p>Individuals with severe pediatric disease</p> Signup and view all the answers

    What was the source of the WES data analyzed in the study?

    <p>17 studies</p> Signup and view all the answers

    What is an example of a condition that exhibits variable expressivity?

    <p>Type 1 Waardenburg syndrome</p> Signup and view all the answers

    What is the factor that affects the penetrance and expressivity of Hemochromatosis?

    <p>Age and sex</p> Signup and view all the answers

    What is the inheritance pattern of Familial male limited precocious puberty?

    <p>Sex-limited autosomal dominant</p> Signup and view all the answers

    What is the result of a gain-of-function variant in the LHCGR gene?

    <p>Increased levels of sex steroids</p> Signup and view all the answers

    What is the characteristic of Type 1 Waardenburg syndrome?

    <p>Affects the eyes, hair, and skin</p> Signup and view all the answers

    What is the main function of the G6PD enzyme in red blood cells?

    <p>To maintain levels of reduced glutathione (GSH)</p> Signup and view all the answers

    What is the reason for the lower penetrance of Hemochromatosis in women?

    <p>Loss of iron via menstruation</p> Signup and view all the answers

    What is the type of inheritance pattern of glucose-6-phosphate dehydrogenase (G6PD) deficiency?

    <p>X-linked recessive</p> Signup and view all the answers

    What is the term for the phenomenon where individuals with the same mutation exhibit different degrees of severity or different features of a condition?

    <p>Variable expressivity</p> Signup and view all the answers

    What is the factor that affects the severity of Hemochromatosis?

    <p>All of the above</p> Signup and view all the answers

    What is a trigger for hemolytic anemia in G6PD deficiency?

    <p>All of the above</p> Signup and view all the answers

    What is genetic compensation, also known as genetic buffering?

    <p>An organism with a pathogenic mutation does not develop the expected adverse phenotype due to compensatory actions of another gene or genes</p> Signup and view all the answers

    What is the approximate number of people worldwide affected by G6PD deficiency?

    <p>400 million</p> Signup and view all the answers

    What is the effect of mosaicism on disease severity in genetic disorders?

    <p>Mosaicism typically decreases disease severity, but the degree of decrease depends on the degree of mosaicism and its tissue distribution</p> Signup and view all the answers

    What is an example of an epigenetic mechanism that affects penetrance and expressivity?

    <p>All of the above</p> Signup and view all the answers

    What is a physiological factor that can affect penetrance and expressivity of genetic disorders?

    <p>All of the above</p> Signup and view all the answers

    What is the purpose of the 'Resilience Project'?

    <p>To identify healthy individuals resilient to highly penetrant forms of genetic childhood disorders</p> Signup and view all the answers

    What is the significance of the study by Chen et al. (2016) in the context of Mendelian diseases?

    <p>It demonstrates that incomplete penetrance is a common phenomenon in Mendelian diseases</p> Signup and view all the answers

    What is the name of the characteristic that can cause Mediterranean G6PD deficiency?

    <p>Favism</p> Signup and view all the answers

    What is the primary methodology used in the 'Resilience Project' to identify healthy individuals resilient to Mendelian diseases?

    <p>All of the above</p> Signup and view all the answers

    What is the number of genes believed to cause 584 distinct severe Mendelian childhood disorders in the 'Resilience Project'?

    <p>874</p> Signup and view all the answers

    What is the significance of the identification of resilient individuals in the context of Mendelian diseases?

    <p>It may provide insights into the mechanisms of Mendelian diseases and new therapeutic strategies</p> Signup and view all the answers

    What is the primary goal of the bioinformatic analysis of existing genomic data in the 'Resilience Project'?

    <p>To identify healthy individuals resilient to highly penetrant forms of genetic childhood disorders</p> Signup and view all the answers

    What is the significance of the study by Tarailo-Graovac et al. (2017) in the context of Mendelian diseases?

    <p>It demonstrates that incomplete penetrance is a common phenomenon in Mendelian diseases</p> Signup and view all the answers

    Study Notes

    Multifactorial Disorders

    • Determined by the interaction of multiple genetic and environmental factors
    • Polygenic, meaning the interplay of variants in many genes, each exerting a small additive effect
    • Individuals inherit an increased risk of developing a disease (susceptibility)
    • Familial aggregation without a clear-cut inheritance pattern
    • Include pediatric and adult disorders, such as:
      • Congenital defects (e.g. cleft lip/palate, neural tube defects)
      • Acquired diseases (e.g. diabetes, Crohn's disease, asthma, autism, hypertension)

    Chromosomal Disorders

    • Due to chromosomal abnormalities occurring during gametogenesis or following fertilization
    • Numerical abnormalities:
      • Polyploidy
      • Aneuploidy
    • Structural abnormalities:
      • Deletion
      • Insertion
      • Inversion
      • Translocation
    • Common cause of infertility, miscarriage, congenital malformations, and intellectual disability
    • Present in 1 in 200 live births

    Genetic Counselling

    • Patients or relatives, at risk of an inherited disorder, are advised of:
      • The nature and consequences of the disorder
      • The risks and benefits of genetic testing
      • The probability of developing or transmitting the disorder
      • Options for the management of the disorder

    Reasons for Referral

    • Preconceptional:
      • Genetic disorder present or suspected in family history
      • History of repeated miscarriages
      • Assisted reproduction
    • Prenatal:
      • History of previous child with birth defect, developmental delay, or other genetic condition
      • Carriers of recessive condition
      • Abnormal ultrasound or maternal serum screening results
    • Postnatal (infancy to adulthood):
      • Newborn with multiple birth defects or positive neonatal screening results
      • Child with developmental delay, sensory impairment, intellectual disability, or other suspected genetic condition
      • Adult with suspected adult-onset disease
    • Oncologic:
      • Familial aggregation of cancer

    Newborn Screening

    • Purpose: early identification of diseases that cause permanent disability or death if not identified and treated early
    • Biochemical assays for specific serum analytes:
      • Tandem mass spectrometry
      • Immunoassays
      • Enzyme assays
    • Identifies newborns at risk, confirmed with diagnostic molecular tests
    • In Italy, 49 diseases are screened nationally, including:
      • Cystic fibrosis
      • Congenital hypothyroidism
      • Phenylketonuria (PKU)
      • Other metabolic diseases

    Large-Scale Genomic Newborn Screening

    • Studies launching internationally
    • Cohort sizes and proposed screening approaches are shown
    • TBD (to be determined)
    • WGS (whole-genome sequencing)

    Genetic Counselling Process

      1. Establishing the diagnosis:
      • Gathering information (personal and family clinical history, even of those deceased)
      • Reconstructing the pedigree (diagram showing family relationships)
      • Specialist visits (e.g. ophthalmology, cardiology, neurology)
      • Genetic testing (informed consent, cytogenetic and/or molecular testing)

    Testing for Multiple Variants in a Single Gene

    • Example: CHARGE syndrome
      • Rare congenital disorder
      • Clinical features: Coloboma of the eye, Heart defects, Atresia of the choanae, Retardation of growth and development, Genitourinary abnormalities, and Ear anomalies and deafness
      • Causative gene: CHD7
      • > 500 pathogenic variants
      • Methodology: Targeted NGS of CHD7 gene

    Testing for Variants in a Panel of Genes

    • Example: RASopathies
      • Group of developmental syndromes
      • Caused by variants in genes of RAS-MAPK signalling pathway
      • Clinical features: distinct facial features, developmental delays, cardiac defects, growth delays, neurologic issues, and gastrointestinal difficulties
      • Methodology: NGS gene panel targeting coding sequences of 32 RAS-MAPK genes

    Exome Sequencing

    • Useful when:
      • Clinical classification of variants
      • ACMG Standards and Guidelines (2015)
      • Five tiers of variant classification for mendelian diseases based on weight of evidence

    Online Resources

    • Online Mendelian Inheritance in Man (OMIM)
      • Catalog of inherited disorders
      • McKusick-Nathans Department of Genetic Medicine, Johns Hopkins Medicine (USA)
      • https://www.omim.org
    • ORPHANET: the portal of rare diseases and orphan drugs
    • GeneReviews – NCBI Bookshelf

    Monogenic Inheritance Patterns

    • Autosomal dominant inheritance:
      • Each affected person has an affected parent (vertical transmission)
      • Each child of an affected parent has a 50% risk of being affected
      • Not transmitted by unaffected individuals
      • Males and females are equally likely to be affected
      • Transmitted by either sex to offspring of either sex
    • Autosomal recessive inheritance:
      • Affected children born to unaffected parents
      • Parents of affected individuals are asymptomatic carriers (heterozygotes)
      • Each child of a mating between carrier parents has a 25% risk of being affected
      • Affected individuals in a family are usually siblings (horizontal transmission)
      • Males and females are equally likely to be affected
    • X-linked dominant inheritance:
      • Affected individuals have an affected parent (vertical transmission)
      • Affected males transmit the disease phenotype to all daughters and no sons
      • Both female and male offspring of affected females have a 50% risk of inheriting the phenotype
      • Females are more frequently affected than males
    • X-linked recessive inheritance:
      • Predominantly affects males
      • Affected males born to unaffected parents; mother is asymptomatic obligate carrier
      • Each son of a female carrier has a 50% chance of being affected; each daughter of a female carrier has a 50% chance of being a carrier
      • No male-to-male transmission of disease phenotype; all daughters of an affected male are obligate carriers
    • Y-linked inheritance:
      • Affects only males
      • Affected males always have an affected father (vertical transmission)
      • All sons of affected males are affected
    • Mitochondrial/maternal inheritance:
      • Affects both sexes
      • Transmitted by affected mother (maternal inheritance) to all offspring (with frequent exceptions)
      • Not transmitted by affected father to any of his offspring (with extremely rare exceptions)

    Risk of Recurrence and Carrier Risk

    • Autosomal dominant inheritance:
      • Risk of disease = 50% (Aa)
      • Risk of disease = 75% (homozygotes)
    • Autosomal recessive inheritance:
      • Risk of disease = 25% (aa)
      • Carrier risk = 1/2 (a priori) or 2/3 (a posteriori)
    • X-linked dominant inheritance:
      • Risk of disease: daughters = 100%, sons = 0% (affected mother); daughters = 50%, sons = 50% (affected father)
    • X-linked recessive inheritance:
      • Risk of disease: sons = 50%, daughters = 0% (carrier mother); sons = 0%, daughters = 0% (non-carrier mother)
      • Carrier risk = 100% (mother), 50% (daughter)

    Consanguinity and Y-Linked Inheritance

    • Consanguinity increases the risk of inheriting a recessive condition
    • Apparent Y-linked inheritance:
      • Due to a Y chromosome structural abnormality, not a normal Y-linked trait

    Using Random Tags or Unique Molecular Identifiers (UMIs)

    • UMIs decrease the number of false positives by making consensus calls from all reads with the same UMI
    • UMIs can be used to remove PCR-derived duplicate reads to determine accurately the allelic ratio

    Long Sequencing Reads

    • Long sequencing reads improve mappability, even across difficult genomic regions such as those containing repeats
    • Long reads can be used to phase mutations and generate haplotypes, to help identify the parent of origin of a mutation

    Parental Origin of Germline DNMs

    • >80% of DNMs are of paternal origin, arising during spermatogenesis
    • DNMs increase in number with parental age – more pronounced with paternal ageing (paternal age effect)
    • The sperm produced by a 20-year-old male has gone through ∼190 cell divisions (mitoses), and this number increases to ∼650 by the age of 40 years

    Paternal Age Effect

    • Estimated genome replications in the male germline versus number of de novo mutations (DNMs) in offspring
    • >40% of patients with a severe developmental disorder have a pathogenic DNM in a protein-coding gene
    • Developmental disorders caused by DNMs have an average prevalence of 1/448 to 1/213 births, increasing with parental age

    Postzygotic DNMs can lead to Mosaicism

    • Presence in an individual of two or more genetically different cell lines, all derived from one original zygote
    • 3 SNVs estimated to arise per cell division in early human embryogenesis
    • Degree of mosaicism depends on timing of DNM: high-level mosaicism present in many different tissues, including germline, or low-level mosaicism restricted to a small number of somatic cells or a single tissue

    Mosaicism

    • Three types of mosaicism depending on timing and cell type (somatic vs. germline):
      • Somatic mosaicism: mutation occurs in somatic cells at any stage of life, cannot be transmitted to offspring
      • Germline/gonadal mosaicism: mutation occurs in germline during early embryonic development, can be transmitted to offspring
      • Gonosomal mosaicism: mutation occurs during early embryogenesis involving both germ cell and somatic cell lineages, can be transmitted to offspring

    Detection of Mosaicism

    • Difficult to detect, especially low-level mosaicism
    • May be tissue-specific, may or may not be detectable in blood
    • Ideally requires: (i) analysis of various tissues, even single cells, and (ii) comparison of affected vs. nonaffected tissues
    • Paternal germline mosaicism quantified in sperm using NGS and droplet digital PCR, expressed as variant allele frequency (VAF)

    Detection of Mosaicism by NGS

    • NGS can detect mosaic variants using reads sorted by base, with positive reads grouped together
    • Mosaic variants are located within parallel vertical lines and are indicated by the letter of the substituted nucleotide

    Detection of Mosaicism by Droplet Digital PCR (ddPCR)

    • ddPCR technology uses microfluidics and surfactant chemistries to divide samples into thousands of water-in-oil droplets to run multiple PCR amplifications in parallel
    • ddPCR uses a combination of modification of the Taqman qPCR assay using allele-specific fluorescently-labelled probes

    Taqman Assay

    • Real-time quantitative PCR assay
    • TaqMan probes consist of sequence-specific oligonucleotides with a reporter (R) fluorophore covalently attached to the 5’-end and a quencher (Q) at the 3’-end
    • During PCR amplification, the exonuclease activity of Taq polymerase cleaves the annealed probe, releasing the fluorophore which will no longer be subject to quenching → increase in fluorescence signal proportional to quantity of template DNA

    ddPCR Workflow

    • A mixture of PCR reagents including fluorescent probes, primers, and genomic DNA is partitioned into picoliter to nanoliter droplets where theoretically less than one DNA molecule is distributed in one droplet
    • Each droplet represents a microreactor for PCR amplification using the Taqman assay
    • The fluorescence intensity of each individual droplet is detected and analysed

    Complications of Mendelian Inheritance Patterns

    • Incomplete penetrance: when individuals with a disease-causing genotype never develop any clinical signs or symptoms
    • Variable expressivity: affected individuals within a pedigree show different degrees of severity or different features of the condition
    • Genotype-phenotype correlation: clinically useful to guide diagnosis, prognosis, and management of genetic disorders, but utility is hampered by heterogeneity in phenotypic expression

    Incomplete Penetrance

    • Definition: probability that a genotype manifests itself in a given phenotype
    • Example: split hand/foot malformation I (SHFM1) - penetrance 70%
    • May cause occasional skipping of generations in dominant inheritance

    Variable Expressivity

    • Example: Type 1 Waardenburg syndrome - congenital hearing loss, pigment disturbances of iris, hair, and skin; different features of syndrome despite having the same mutation in PAX3
    • Factors affecting penetrance and expressivity: physiological factors (age, sex, hormonal factors), genetic mechanisms (repeat expansion, mosaicism, genetic modifiers, genetic compensation), epigenetic mechanisms, and environmental factors

    Factors Affecting Penetrance and Expressivity

    • Physiological factors: age, sex, hormonal factors (e.g., hemochromatosis - adult onset, increasing severity with age, variable expressivity between individuals with same genotype)
    • Sex-limited phenotypes: defect is autosomally transmitted but expressed in only one sex (e.g., familial male limited precocious puberty - AD inheritance, affected boys develop secondary sexual characteristics in early childhood)

    Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency

    • Inborn error of metabolism, most common hereditary enzyme defect (400 million people worldwide)
    • X-linked recessive inheritance
    • G6PD enzyme participates in pentose phosphate pathway to generate NADPH, critical role in RBCs for detoxification of reactive oxygen species (ROS)
    • Most subjects with G6PD deficiency are asymptomatic, but may develop hemolytic anemia when exposed to oxidative stress
    • Triggers for hemolytic anemia: bacterial and viral infections, fava beans and other legumes containing toxic alkaloid glycosides (favism)

    Data Mining of Genome Databases

    • Identifies healthy individuals with "pathogenic" genotypes for Mendelian disorders
    • "Resilience Project" aims to identify healthy individuals resilient to highly penetrant forms of genetic childhood disorders
    • Bioinformatic analysis of existing genomic data from 12 cohorts worldwide
    • Results: 13 adults with variants for 8 severe Mendelian conditions, with no reported clinical manifestation of the indicated disease
    • Conclusion: incomplete penetrance for Mendelian diseases is likely more common than previously believed
    • Identification of resilient individuals may provide a first step toward uncovering protective genetic variants that could help elucidate the mechanisms of Mendelian diseases and new therapeutic strategies

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    Related Documents

    Genetic Disorders PDF
    Monogenic Inheritance Patterns PDF
    De Novo Mutations And Mosaicism PDF
    Penetrance and Expressivity PDF

    Description

    Learn about complex disorders caused by the interaction of multiple genetic and environmental factors, including polygenic inheritance and susceptibility to disease. This quiz covers pediatric and adult disorders.

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