Genetic Disorders Chart - Inheritance Patterns PDF

Genetic Disorders Inheritance Patterns Autosomal Dominant Autosomal Recessiv...

Genetic Disorders Inheritance Patterns Autosomal Dominant Autosomal Recessive X-linked Recessive (one parent is typically affected) (both parents’ genes are defective, but they aren’t personally affected, often from consanguineous marriage) 1. Huntington Disease 1. Cystic fibrosis 1. Duchenne muscular dystrophy 2. Myotonic dystrophy 2. Phenylketonuria (PKU) 2. Hemophilia A & B 3. Marfan syndrome 3. Galactosemia (cataracts) 3. Glucose-6-phosphate dehydrogenase deficiency 4. Ehlers-Danlos (stretchy skin) 4. ⍺₁-antitrypsin deficiency (G6PD) 5. Familial hypercholesterolemia 4. Agammaglobulinemia 5. Glycogen storage diseases 6. Chromosome 22q11.2 deletion syndrome 5. Wiskott-Aldrich syndrome 6. Ehlers-Danlos (others) 6. Fragile X syndrome 7. Tay- Sachs 8. Thalassemia Chromosomal Disorders Chromosome 22q11 Turner syndrome Klinefelter syndrome Down Syndrome Prader-Willi syndrome Angelman syndrome Monosomy X: 45X Males have an extra X (47, Trisomy 21 Maternal uniparental disomy Paternal uniparental disomy Deletion of a small piece of XXY) (Three of 21 chromosomes) of chromosome 15; deletion of chromosome 15; deletion chromosome 22 at region 11, 2nd X is altered/missing of band q12 on paternal of q12 on maternal Robertsonian translocation of including the DiGeorge More estrogen and low chromosome 15 chromosome the long arm of chromosome chromosomal region (DGCR). Failure to develop normal testerone = soft body and 21 to another chromosome secondary sex characteristic boobies (e.g., 22 or 14). (DiGeorge syndrome and Male infertility and low sperm Velocardiofacial syndrome)  X-LINKED RECESSIVE DISORDERS X-linked recessive disorders are caused by mutations in genes on the X chromosome. Example: G6PD Deficiency (affects blood cells): Common in males; carrier females may show mild symptoms depending on X-chromosome inactivation. Characteristics: Females Males Males: Affected if they inherit a Females have two X chromosomes, so they usually do not express the full Males have only one X chromosome and mutant gene on their single X phenotype of an X-linked recessive disorder because the normal allele on are hemizygous for X-linked genes, so they chromosome. They cannot pass the the second X chromosome compensates for the mutant one. will express the disorder if they inherit the disorder to sons, but all daughters Heterozygous females (carriers) have a 50% chance of passing the mutant mutant gene. become carriers. gene to their sons, who may be affected, and a 50% chance of passing the An affected male does not transmit the Females: Usually carriers and less carrier status to their daughters. disorder to his sons (who inherit his Y affected due to a second normal X Due to random X-chromosome inactivation (lyonization), some cells in chromosome), but all his daughters will chromosome, but can show mild heterozygous females may inactivate the normal X chromosome, leading be carriers (since they inherit his X symptoms due to random to partial expression of the disorder. chromosome with the mutant gene). inactivation of one X chromosome Usually do not express the disorder fully due to the presence of a second, Always express the disorder if they inherit the (lyonization). normal allele. However, they can exhibit mild symptoms if some of their mutant gene, since they lack a second X cells inactivate the normal X chromosome. chromosome to provide a normal copy of the gene. Genetic Mutations Trinucleotide-Repeat Mutations Accumulation of aggregated mutant proteins in large intranuclear inclusions Fragile X Syndrome Myotonic Dystrophy Huntington Disease Loss of gene function (transcription silencing) Gene: DMPK (myotonic dystrophy protein kinase) Toxic gain of function by altered protein RNA-mediated toxicity (tremor/ataxia) [CTG] Gene: HTT Gene: FMRI (FRAXA) [CAG] [CGG] Anticipation – # of repeated DNA sequences (trinucleotide repeats) tends to increase when the gene is passed from one generation to the next. Enzyme Deficiencies Tay-Sachs Disease Marfan Syndrome Familial Hypercholesterolemia Deficiency of hexosaminidase A - excessive accumulation of Mutations in FBN1 - defect in fibrillin-1 (extracellular Mutations in the LDLR (85%) gene. certain fats (gangliosides) in the brain and nerve cells glycoprotein essential for connective tissue) APOB (5-10%) PCSK9 (1-2%) - Leads to progressive dysfunction of the CNS Defect in fibrillin-1 → abnormal activation of TGF-β Elevated low-density lipoprotein cholesterol (LDL-C) - (lysosomal storage disease) atherosclerotic plaque deposition in the coronary arteries and - Failure to breakdown GM2-ganglioside - abnormal (tissue overgrowth and instability in CV system) proximal aorta accumulation in brain and nerve cells  FRAGILE X SYNDROME (Monosmy X) Genetic mutation: Cognitive impairment [CGG] repeat expansion in familial mental retardation 1 (FMR1), causing deficiency of the FRMP protein that leads to abnormal synapse development Mutations on the X chromosome (from mom) Clinical Presentation: Tremor/ataxia (fragile x-associated) Primary ovarian failure (in granulosa cells and ovarian stromal cells) due to toxic gain of function by the abnormal FMR1 mRNA Epilepsy Aggressive behavior Autism spectrum disorder/ADHD Affects MALES Phenylketonuria: Learn about the enzyme deficiency responsible for phenylketonuria and its genetic implications. Autosomal recessive disorder Severe deficiency of the enzyme phenylalanine hydroxylase (PAH) leading to hyperphenylalaninemia o Mutations in both PAH (on chromosome 12) alleles to develop disease – inability to convert phenylamine into tyrosine o Restricting phenylalanine intake early in life to avoid intellectual disability 1/3 of kids cannot walk Usually by 6 months, severe intellectual disability becomes evident 2/3 cannot talk Maternal PKU occurs when women with phenylketonuria (PKU) have high levels of phenylalanine due to stopping dietary Seizures restrictions in adulthood. Decreased pigmentation of hair Effects on Children: 75-90% risk of intellectual disability and microcephaly; 15% risk of congenital heart disease, even if the child and skin is a heterozygote. MUSTY ODOR Cause: Teratogenic effects of high phenylalanine or its metabolites crossing the placenta. Eczema Prevention: Strict dietary phenylalanine restriction before conception and throughout pregnancy to prevent fetal anomalies. Necrotizing Enterocolitis: Study the risk factors and clinical course of necrotizing enterocolitis. Risk Factors: Higher risk in more premature and lower birth weight infants (especially 20 globulin (RhIg) containing anti-D antibodies Turner syndrome – abnormalities of lymphatic mg/dL in infants and low in drainage from the neck à postnucal fluid premature infants) accumulation (cystic hygromas) 3. Fetal anemia: Homozygous a-thalassemia – deletion of all four a-globin genes Fetal red cells may reach the maternal circulation during the last trimester of pregnancy, when the cytotrophoblast is no longer present as a barrier, or during childbirth itself. The mother thus becomes sensitized to the foreign antigen. The initial exposure to Rh antigen evokes the formation of IgM antibodies that unlike IgG antibodies, do not cross the placenta. Thus, Rh disease is uncommon with the first pregnancy. Exposure during a subsequent pregnancy generally leads to a brisk IgG antibody response and the risk of immune hydrops. Cystic Fibrosis: Review the genetic defect in cystic fibrosis and its clinical manifestations. Genetic Defect: Autosomal Recessive Disorder: Caused by mutations in the CFTR gene on chromosome 7q31.2. Primary Defect: Abnormal chloride and bicarbonate ion transport due to dysfunctional CFTR protein. Regulation of Multiple Ion Channels: CFTR mutations affect other ion channels, such as the epithelial sodium channel (ENaC) and potassium channels. Mutation in CFTR (cystic fibrosis transmembrane conductance regulator) o Loss of CFTR à decrease reabsorption of sodium chloride and production of hypertonic sweat o Changes in ion distribution result in increased passive water reabsorption from the lumen, lowering the water content of the surface fluid layer coating mucosal cells o Respiratory and intestinal complications is due to isotonic but low-volume fluid layer o CFTR regulates the transport of bicarbonate ions Pathophysiology: Sweat Glands: Mutations lead to decreased ENaC activity, causing hypertonic sweat with high sodium chloride, explaining the “salty” sweat observed in affected infants. Respiratory and Gastrointestinal Tracts: o Respiratory: Defective chloride and water transport results in thick, dehydrated mucus, leading to mucociliary dysfunction, airway obstruction, and recurrent infections. o Gastrointestinal: Abnormal bicarbonate transport leads to acidic secretions, promoting mucin precipitation, ductal plugging, and bacterial colonization. Pancreatic and Hepatic: Pancreatic insufficiency results from duct obstruction, while hepatic cirrhosis may occur due to bile duct obstruction. Clinical manifestations: Sinopulmonary – CF pathogens (staphylococcus aureus, Hemophilus influenzae, mucoid and nonmucoid pseudomonas aeruginosa) o Chronic cough and sputum production o Persistent chest radiograph abnormalities o Airway obstruction – wheezing and air trapping o Nasal polyps o Obstructive pulmonary disease o Cor pulmonale o CLUBBING GI and nutritional – o Intestinal: meconium ileus, distal intestinal obstruction syndrome, rectal prolapse o Pancreatic: insufficiency, acute and chronic pancreatitis § Associated with protein and fat malabsorption and increased fecal loss o Hepatic: biliary cirrhosis or multilobular cirrhosis, prolonged neonatal jaundice o Nutritional: FTT, hypoproteinemia, edema, complications secondary to fat-soluble vitamin deficiency Salt-loss syndrome – acute salt depletion, chronic metabolic alkalosis Male urogenital abnormalities – obstructive azoospermia (congenital bilateral absence of vas deferens) Hemangiomas: Understand the clinical course and typical progression of hemangiomas in infants. Flat, larger lesions (vascular ectasias) – port-wine stains (stay longer on body) Located on skin; particularly on the face and scalp where it is flat to elevated, irregular, red-blue masses Can enlarge when the child grows, spontaneously regresses Can be from hereditary disorder von Hippel-Landau disease A subset of CNS cavernous hemangiomas can occur in the familial setting; these families harbor mutations in one of three genes: o KRIT1, CCM2, or PDCD10 Risk factors: prematurity, placental complications, females