Chapter 07 Genetic Diseases PDF

Chapter 07 Genetic diseases Dra Verónica Veses Jiménez Chapter overview Classification of human diseases Pedigrees Monogenic disorders Chromosomal disorders Mitochondrial disorders 2 Classification of diseases Clinical: based on the diagnostic m...

Chapter 07 Genetic diseases Dra Verónica Veses Jiménez Chapter overview Classification of human diseases Pedigrees Monogenic disorders Chromosomal disorders Mitochondrial disorders 2 Classification of diseases Clinical: based on the diagnostic made after a medical exploration, supported on a phenotypic criteria. Molecular: based exclusively on genotypic criteria. 3 Clinical classification of human disease Based on the International Classification of Diseases published by the World Health Organization ICD is the standard diagnostic tool for epidemiology, health management and clinical purposes. The current version is ICD-11 (released in 2019, in effect from 2022). 4 Molecular classification of human disease Diseases can be classified in three big groups: – Exogenous – Genetic – Multifactorial 5 Exogenous diseases Are due to an external agent, such as a chemical agent, a drug, a parasite, bacteria, viruses…. It also includes nutritional diseases (lack of a particular nutrient) and prion diseases 6 Genetic disorders Can be further classified on the bases of: – Cell affected: Somatic (cancer) Germinal – According to the type of alteration: Monogenic: are caused by single mutation in one gene Chromosomal: in this case the fault is not an error in the DNA sequence but an excess or deficiency of the genes contained in the chromosomes – According to the type of chromosome affected: Nuclear Mitochondrial 7 Multifactorial diseases They are produced by a combination of small variations in genes that may predispose to a serious health problem. They tend to occur in families but do not have a characteristic pedigree pattern. Example: familial predisposition to breast or colon cancer. 8 Prevalence of disorders Multifactorial (common) – “Environmental” influences act on a genetic predisposition to produce a liability to a disease. – One organ system affected. – Person affected if liability above a threshold. Single gene (1% liveborn) – Dominant/recessive pedigree patterns (Mendelian inheritance). – Can affect structural proteins, enzymes, receptors, transcription factors. Chromosomal (0.6% liveborn) – Thousands of genes may be involved. – Multiple organ systems affected at multiple stages in gestation. – Usually de novo but can be inherited. 9 PEDIGREES 10 11  Why collect family history information? Patient concern Clinical feature Routine assessment Result of screening test Opportunistic 12 What information should you collect? Information depends on the context and reason for collecting it: – Establish biological relationships – Clarify the medical conditions that people have 3 generations For each person: – Full name – Date of birth (or age) – Date of death (or age died) – Medical information (age at diagnosis) 13 How should the information be recorded? Longhand notes Family history form Family tree 14  Drawing a family tree Marriage / Male Partnership (horizontal line) Female / Partnership that has ended Person whose sex is unknown P Offspring Pregnancy (vertical line) Miscarriag X weeks e Affected Male & Parents and Female Siblings Carrier Male & Female 15  Steps in taking and recording a genetic family tree: branch one Ask about your informant and his or her partner(s) and their children: “How many children have you had? Have you lost any children?” Be sensitive when trying to determine if partners are related by blood (a consanguineous relationship). 16 Branch 2: parents of the informant 17 Branch 3: brothers and sisters 18 And so on 19 Clues specific to the condition of concern Multiple closely related people with the same condition Disorders which occur at a younger age than usual (e.g. colon cancer, breast cancer, dementia) Sudden cardiac deaths in people who seemed healthy Three or more pregnancy losses Medical problems in children of parents related by blood Congenital anomalies, dysmorphic features and developmental delay 20 www.geneticseducation.nhs.uk 21 MONOGENIC DISEASES Monogenic or Mendelian diseases They are collected and updated in the online version of "Mendelian Inheritance in Man '(OMIM) There are five models of monogenic disease, based on the chromosomal location of the gene locus and the character of the resulting phenotype: autosomal dominant autosomal recessive X-linked dominant X-linked recessive Y-linked 23 Autosomal Dominant Disorders One mutated copy of the gene in each cell is sufficient for a person to be affected by an autosomal dominant disorder. In some cases there are new mutations, although, usually, an affected person inherits the condition from an affected parent. 24 Examples of autosomal dominant disorders Familial hypercholesterolemia Myotonic dystrophy Neurofibromatosis I Huntington disease Achondroplasia 25 Case-study: Achondroplasia is a form of short-limbed dwarfism Patients have average-size trunk, short arms and legs with particularly short upper arms and thighs and macrocephaly Other symptoms include apnea, obesity, and recurrent ear infections Two specific mutations in the FGFR3 gene are responsible for almost all cases of achondroplasia. 26 Inheritance of Achondroplasia Achondroplasia is inherited in an autosomal dominant pattern About 80 % of people with achondroplasia have average-size parents; these cases result from new mutations in the FGFR3 gene. In the remaining cases, people with achondroplasia have inherited an altered FGFR3 gene from one or two affected parents 27 New hope: Voxzogo™ https://www.elmundo.es/ tecnologia/innovacion/ working-progress/ 2023/02/14/63ea7fbde4d4 d86c0b8b45bb.html 28 Autosomal Recessive Disorders Recessive conditions clinically manifest only when a person has two copies of the mutant allele. Usually the parents are unaffected (carriers). 29 Examples of Autosomal Recessive diseases Tay-Sachs: rare disorder in genetically isolated groups (Jewish populations of North America),characterized by blindness associated with mental retardation, and premature death. Hemochromatosis Phenylketonuria Cystic fibrosis 30 Case study: Cystic fibrosis Characterized by the buildup of thick, sticky mucus that can damage many of the body's organs. Common signs and symptoms include progressive damage to the respiratory system and chronic digestive system problems. It id due to mutations in the CFTR gene, which provides instructions for making a channel that transports chloride ions into and out of cells. When is not functional, mucus become very thick clogging the airways and various ducts. 31 Inheritance of Cystic fibrosis It is inherited in an autosomal recessive pattern. Usually the parents each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition. The disease occurs in 1 in 2,500 to 3,500 white newborns (one of the most frequent genetic disease in Caucasians). Cystic fibrosis is less common in other ethnic groups. 32 X-linked Dominant Disorders X-linked dominant disorders are caused by mutations in genes on the X chromosome In females (who have two X chromosomes), a mutation in one of the two copies of the gene in each cell is sufficient to cause the disorder. In males (who have only one X chromosome), a mutation in the only copy of the gene in each cell causes the disorder. 33 Examples of X-linked dominant diseases Chondrodysplasia punctata: calcification around joints. Hypophosphatemic rickets: bone demineralization. Fragile X syndrome: learning disabilities and cognitive impairment. Some forms of retinitis pigmentosa: a degenerative disease of the retina. 34 Case study: retinitis pigmentosa is a group of related eye disorders that cause progressive vision loss. In people with retinitis pigmentosa, vision loss occurs as the light-sensing cells of the retina gradually deteriorate. The signs and symptoms of retinitis pigmentosa are most often limited to vision loss. When the disorder occurs by itself, it is described as nonsyndromic. Mutations in more than 60 genes are known to cause non-syndromic retinitis pigmentosa. 35 Inheritance of retinitis pigmentosa Mutations in the RHO gene are the most common cause of autosomal dominant retinitis pigmentosa. At least 35 genes have been associated with the autosomal recessive form. The most common of these is USH2A. Changes in at least six genes are thought to cause the X-linked form of the disorder. Together, mutations in the RPGR and RP2 genes account for most cases of X- linked retinitis pigmentosa. 36 X-linked Recessive disorders Females will only have the disorder if two mutated copies are received Males will have the disorder as they only have one X chromosome (hemizygosis) 37 Examples of X-linked recessive diseases Duchenne Muscular Dystrophy: affects one in every 3,500 born in the United States of America. The life expectancy of the patients is around 20 years. Color blindness Hemophilia 38  Blindness: X-linked recessive disease What numbers do you see in each panel? 1. Normal vision of colors: A: 29, B: 45, C: --, D: 26 2. Red-green color blindness: A: 70, B: --, C: 5, D: -- 3. Blindness red: A: 70, B: --, C: 5, D: 6 4. Blindness green: A: 70, B: --, C: 5, D: 2 39 Case study: Hemophilia is a bleeding disorder that slows the blood clotting process. The major types of this condition are hemophilia A (also known as classic hemophilia or factor VIII deficiency) and hemophilia B (also known as Christmas disease or factor IX deficiency). Although the two types have very similar signs and symptoms, they are caused by mutations in different genes. 40 Inheritance of hemophilia Changes in the F8 gene (codes for are coagulation factor VIII ) responsible for hemophilia A, while mutations in the F9 gene (codes for coagulation factor IX ) cause hemophilia B. Hemophilia A and hemophilia B are inherited in an X- linked recessive pattern. 41 Y-linked disorder A condition is considered Y-linked if the mutated gene that causes the disorder is located on the Y chromosome. 42 Case study: Chromosome Y infertility It is a condition that affects the production of sperm. Includes: – Azoospermia: no sperm cells are produced – Oligospermia: smaller than usual number of sperm cells – Teratozoospermia: sperm cells that are abnormally shaped or do not move properly Y chromosome infertility is usually caused by deletions of genetic material in regions of the Y chromosome called azoospermia factor (A, B, or C). 43 Inheritance of Y-linked sterility Because Y chromosome infertility impedes the ability to father children, this condition is usually caused by new deletions on the Y chromosome and occurs in men with no history of the disorder in their family. When men with Y chromosome infertility do father children, they pass on the genetic changes on the Y chromosome to all their sons. As a result, the sons will also have Y chromosome infertility. Daughters will be unaffected. 44 OMIM 45 CHROMOSOMAL DISORDERS Chromosomal disorders Numerical Structural 47 Chromosomal abnormalities Numerical: – Euploidy: correct and exact number of chromosomes – Aneuploidy: loss or gain of one or more chromosomes – Polyploidy: addition of one or more complete haploid set of chromosomes 48 Common Aneuploidies Monosomy: loss of a single chromosome, usually the X or the Y, since loss of one autosome is generally incompatible with life. Trisomy: presence of an extra chromosome. – Only three autosomal numerical disorders are compatible with life (trisomy of 21, 13 and 18). – Trisomy of the sexual chromosomes have phenotypes are less severe than those associated with autosomes, mainly due to the X chromosome inactivation and the low content of genes in Y chromosome. 49 Source of numerical disorders There are usually caused by: – Non-disjunction of homologous chromosomes in prophase I of meiosis. Their frequency correlates with maternal age. – Non-disjunction of sister chromatids in prophase II of meiosis. The frequency also correlates with maternal age. – Non-disjunction can also occur during an early mitotic division in the developing zygote. In this later case there is no correlation with maternal age and there is mosaicism. 50 Non-disjunction originates disomic and nullisomic gametes 51 Chromosomal abnormalities Structural: they usually result from chromosome breakage with subsequent reunion in a different configuration. They can be: – Balanced: no loss or gain of genetic material. – Unbalanced: incorrect amount of chromosome material with serious clinical effects. 52 Balanced versus unbalanced 53 Structural abnormalities Translocation Inversions Insertions and deletions Rings 54 Source of structural chromosomal mutations Recombination between non-allelic homologous regions of the genome. Usually, repeat regions located on the same chromosome, or in different chromosomes recombine. They usually occur during gametogenesis. 55 Translocations A chromosome alteration in which a whole chromosome or segment of a chromosome becomes attached to or interchanged with another whole chromosome or segment 56 Types of Translocations They can be: – Reciprocal: involves breakage of at least two chromosomes with exchange of the fragments. Usually the chromosome number remains at 46. – Robertsonian: results from the breakage of two acrocentric chromosomes (13, 14, 15, 21 and 22) at or close to their centromers, with subsequent fusion of their long arms (centric fusion). The short arms are lost. This has no clinical significance for the individual (they contain only genes for ribosomal RNA, with multiple copies in other chromosomes). 57 Reciprocal vs Robertsonian 58 Inversions Is a two-break rearrangement involving a single chromosome in which a segment is reversed in position. They can be: – Pericentric: involves the centromer – Paracentric: involves only one arm Inversions are balanced rearrangements with no effects on the individual (unless one of the breakpoints has disrupted an important gene). 59 Paracentric versus Pericentric 60 Insertions and deletions Insertions occur when a segment of one chromosome becomes inserted into another chromosome Deletions involves loss of a part of a chromosome and results in monosomy for that segment of the chromosome. Deletions larger than 2% of the haploid genome are usually incompatible with life 61 Rings A ring chromosome is formed when a break occurs on each arm of a chromosome, leaving two sticky ends on the central portion that reunite as a ring The two distal chromosomal fragments are lost, and if the affected chromosome is an autosome, the effects are very serious. 62 CASE STUDIES 63 Trisomy of chromosome 21: Down syndrome Frequency of occurrence is correlated with maternal age: – 1/1250 for mothers aged 15-19 – 1/385 for mothers aged 35 years – 1/25 for mothers over 45 years Phenotype: – Hypotonicity – characteristic facial features (flat nasal bridge, low-set ears, mouth open and tongue protruding, external palpebral fissure) – short stature, short neck, short and broad hands with a single palmar crease – mental retardation (IQ between 30 and 60) – Congenital heart disease in 1 in 3 patients At the genetic level, 95% of patients have trisomy 21, and 4% have a "Robertsonian translocation" between chromosome 21q and the long arm of the another acrocentric chromosome (usually 14 or 22) 64 Down Syndrome Karyotype 65 Trisomy 18: Edwards syndrome Frequency of occurrence: 1/7500. Phenotype: – Hypertonia – cardiac malformations – Hands closed with the second finger superimposed on the third and fifth on the fourth fist – foot rocker – large, malformed and low-set ears – Mental retardation – Poor postnatal survival, with a life expectancy of months 66 Trisomy 13: Patau syndrome Frequency of occurrence: between 1/20000 and 1/25000. Phenotype: – severe mental retardation – severe CNS malformations, cardiac and urogenital – microcephaly, microphthalmia or absence of eyes – foot rocker – malformed ears – cleft lip and palate – Poor postnatal survival, with a life expectancy of months. 50% of patients die within the first month of life 67  Trisomy XXY: Klinefelter syndrome Frequency of occurrence: – 1/1000 male births (total 1/2000) – maternal or paternal origin Phenotype: – tall and thin patients – hypogonadism, infertility – learning disabilities – difficulties of social integration 68 Trisomy XYY Frequency of occurrence: – 1/1000 male births (total 1/2000) – Origin: paternal non-disjunction in meiosis II resulting in sperm YY Phenotype: – tall and thin patients – normal development – possible learning difficulties – related to attention problems, hyperactivity and impulsivity 69 Trisomy XXX Frequency of occurrence: – 1/1000 births women (total 1/2000) – usually maternal origin, associated with age Phenotype: – normal patients – higher percentage of infertility – deficits in intelligence tests – anomalous behavior at puberty 70 Monosomy X: Turner syndrome Frequency of occurrence: – 1/4000 newborn females – usually of paternal origin Phenotype: – short stature – gonadal dysgenesia – thorax width apart with nipples – renal and cardiovascular abnormalities – normal or superior intelligence but impaired spatial perception 71 Turner´s Karyotype 72 XX males and XY Females The Y chromosome plays a major role in the development of the male reproductive system (including the testis determining gene). During male meiosis the X and Y chromosomes are paired at the ends of their short arms (these segments are called pseudoautosomal regions, regions Xp, Yp and Xq, Yq). When this recombination during meiosis takes place outside the pseudoautosomal region of Xp / Yp can cause two types of anomalies: XX males and XY females. 73 XX males and XY Females Incidence (both): 1/20000 Male patients are phenotypically male with karyotype 46, XX, carrying the testis determining region (SRY gene) translocated on the short arm of the X. Female patients are phenotypically female with karyotype 46, XY, having lost the testis-determining region of the Y chromosome. 74 Structural disorders: Cri du chat Caused by an spontaneous deletion of the end of the short (p) arm of chromosome 5 Infants have characteristic high-pitched cry that sounds like that of a cat. Incidence: between 1/20.000 and 1/ 50.000 Phenotype: – intellectual disability – microcephaly – hypotonia – affected individuals also have distinctive facial features, including widely set eyes (hypertelorism), low-set ears, a small jaw, and a rounded face. 75 MITOCHONDRIAL DISEASES Mitochondrial diseases Are a clinically heterogeneous group of disorders that arise as a result of dysfunction of the mitochondrial respiratory chain. It is estimated that 1 in 4,000 people has a mitochondrial disorder. They can be caused by mutation of genes encoded by either nuclear DNA or mitochondrial DNA (mtDNA). 77 Clinical features of mitochondrial diseases Some mitochondrial disorders only affect a single organ (e.g., Leber hereditary optic neuropathy). However, the majority involve multiple organ systems and affect those tissues that depend on intact oxidative phosphorylation (to satisfy high demands for metabolic energy), such as: – Brain – Heart – Liver – Skeletal muscle – Kidney – Endocrine and respiratory systems 78 I. Mitochondrial diseases due to nuclear genes Nuclear genetic disorders of the mitochondrial respiratory chain – mutated genes encoding structural subunits – mutated genes encoding assembly factors – mutated genes encoding translation factors Nuclear genetic disorders associated with multiple mtDNA deletions or mtDNA depletion Other disorders (e.g. Coenzyme Q10 deficiency) 79 II. Mitochondrial diseases due to mutations in mtDNA Rearrangements (deletions and duplications) Single-nucleotide variants tRNA genes rRNA genes 80 III. Secondary mitochondrial dysfunction in human diseases Ongoing research indicates that mitochondrial dysfunction can be linked to processes such ageing or neurodegeneration. However, the term mitochondrial disorder usually refers to primary disorders of mitochondrial metabolism affecting oxidative phosphorylation. 81 Clinical onset Until recently it was thought that mitochondria alterations occur in early childhood, however, recent developments have shown that: – The majority of mtDNA disorders occur in childhood – The majority of nuclear genetic mitochondrial disorders occur in adulthood 82 Mitochondrial disease inheritance pattern Mitochondrial DNA variants are transmitted by via maternal inheritance (only one case of paternal inheritance described in the literature). Nuclear gene variants may be inherited in an autosomal recessive, autosomal dominant, or X-linked manner. 83 84 85 CASE STUDIES 86 Leber hereditary optic neuropathy (LHON) is characterized by bilateral, painless, subacute visual failure that develops during young adult life Males are four to five times more likely than females to be affected The pathologic hallmark of LHON is the selective degeneration of the retinal ganglion cell layer and optic nerve. Affected individuals are usually entirely asymptomatic until they develop visual blurring affecting the central visual field in one eye; similar symptoms appear in the other eye two to three months later. In about 25% of cases, visual loss is bilateral at onset 87 Genetic cause of LHON Pathogenic variants in the mitochondrial genes that encode subunits of NADH dehydrogenase, MT-ND1, MT-ND2, MT-ND4, MT-ND4L, MT-ND5, and MT-ND6, are known to cause LHON Males have an approximate 50% lifetime risk and females an approximate 10% lifetime risk of developing visual failure Epidemiological research supports an increased risk for visual loss among heavy smokers, and to a lesser extent, heavy drinkers 88 Myoclonic epilepsy with ragged-red muscle fibers myopathy (MERRF) Is a multisystem disorder characterized by myoclonus (often the first symptom) followed by generalized epilepsy, ataxia, weakness, and dementia Common findings are hearing loss, short stature, optic atrophy, and cardiomyopathy The clinical diagnosis of MERRF is based on the following four "canonical" features: myoclonus, generalized epilepsy, ataxia, and ragged red fibers (RRF) in the muscle biopsy 89 Genetic cause of MERRF MT-TK, MT-TF, MT-TL1, MT-TI, and MT-TP are the genes in which pathogenic variants are known to cause MERRF. Mutations in MT-TK (mitochondrially encoded tRNA lysine; 8344A>G) are the most common cause of MERRF (80%) 90 Mytochondrial myopathy, Encephalopathy, Lactic Acidosis, and Stroke (MELAS) is a multisystem disorder with onset typically in childhood (2-10 years old) Symptoms are tonic-clonic seizures, recurrent headaches, anorexia, and recurrent vomiting. Exercise intolerance or proximal limb weakness can be the initial manifestation. Seizures are often associated with stroke-like episodes of transient hemiparesis 91 Genetic cause of MELAS The main genes involved in MELAS are: – MT-TL1, encoding tRNA leucine, accounts for 80% of cases of MELAS (3243A>G). – MT-ND5 NADH-ubiquinone oxidoreductase subunit 5. – Other mtDNA genes. Up to 15 extra pathogenic variants have been identified to cause MELAS 92 References Angel Herráez Sanchez, 2012. Biología molecular e Ingenieria Genética. Conceptos, Técnicas y Aplicaciones en Ciencias de la Salud (Spanish Edition). 2º Ed. Elsevier. http://www.who.int/classifications/icd/en/ NHS (www.geneticseducation/nhs/uk) US National Library of Medicine http://www.omim.org Peter D Turnpenny, 2011. Emery's Elements of Medical Genetics. 14th Edition. Churchill Livingstone. Saunders Elsevier , 2007 93 References II Robert L. Nussbaum MD FACP FACMG, 2007. Thompson & Thompson Genetics in Medicine. 7th Edition. Saunders. United Mitochondrial Disease Foundation: http://www.umdf.org/site/pp.aspx?c=8qKOJ0MvF7LU G&b=7929671 Mitochondrial Disorders Overview. Pagon RA, Adam MP, Ardinger HH, et al., editors. Seattle (WA): University of Washington, Seattle; 1993-2016 94