Genetic mutations Notes

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Osmosis High-Yield Notes

This Osmosis High-Yield Note provides an overview of Genetic mutations essentials. All Osmosis Notes are clearly laid-out and contain striking images, tables, and diagrams to help visual learners understand complex topics quickly and efficiently. Find more information about Genetic mutations by visiting the associated Learn Page.
NOTES NOTES GENETIC MUTATIONS GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Permanent alterations of DNA sequence → clinically significant syndrome ▪ Germ cell mutations inherited ▪ Somatic cell mutations due to environmental factors (e.g. radiation) ▪ Physiologic, pathologic processes: evolution, immune system development, cancer Inheritance patterns ▪ Autosomal dominant: one genetic copy mutated ▪ Autosomal recessive: both genetic copies mutated ▪ X-linked (dominant/recessive): mutation in X chromosome; no transmission from father to son; individuals who are biologically male more frequently/severely affected ▪ Y-linked: mutation in Y chromosome; passed from father to son ▪ Codominant: two alleles affect same trait (e.g. ABO blood group) ▪ Mitochondrial: mutation in mitochondrial DNA; maternal inheritance CAUSES Error during DNA replication ▪ Point mutation within coding sequences: substitution of single base; may occur as transition (e.g. purine → purine)/ transversion (e.g. purine → pyrimidine) ▫ Silent: codes same amino acid, no phenotypic change ▫ Missense: codes different amino acid, may cause phenotypic change (e.g. sickle cell anemia) ▫ Nonsense: early stop codon, produces nonfunctional protein, may cause 162 OSMOSIS.ORG ▪ ▪ ▪ ▪ ▪ phenotypic change (e.g. adrenal gland hyperplasia) Point mutation within noncoding sequences: mutation of promoter/ enhancer sequences → reduced/abolished transcription Deletion: removal of bases Insertion: addition of bases ▫ Splice site mutation: altered splicing of mRNA ▫ Frameshift: shifted reading frame Trinucleotide-repeat mutation: ↑ trinucleotide repeats Disorders of imprinting: one gene copy silenced by methylation (e.g. Prader–Willis syndrome) TYPES Mendelian disorder ▪ Single gene mutation, large effects Chromosomal disorder ▪ Numerical: insertion/deletion of entire chromosome (e.g. trisomies, aneuploidies) ▪ Structural: change in genetic sequence Complex multigenic disorder (polymorphism) ▪ Genes increase risk of disease, no gene capable of causing disease on own (e.g. hypertension, diabetes mellitus) RISK FACTORS ▪ Parental genetic defect ▪ Exposure to radiation, carcinogens COMPLICATIONS ▪ Spontaneous abortion; severe organ defects (e.g. tetralogy of Fallot, renal dysplasia); visual/hearing disturbances;
Chapter 25 Genetic Mutations growth deficiency; intellectual disability; cancer SIGNS & SYMPTOMS ▪ Abnormal physical features ▪ Organ defect-related signs/symptoms LAB RESULTS ▪ Altered blood tests, hormones, liver enzymes OTHER DIAGNOSTICS ▪ History, physical examination ▪ Genetic tests TREATMENT DIAGNOSIS DIAGNOSTIC IMAGING X-ray, CT scan ▪ Evidence of organ defects (e.g. fibrous dysplasia, cardiac malformations) SURGERY ▪ Surgical repair of significant defects ALAGILLE SYNDROME (ALGS) osms.it/alagille-syndrome PATHOLOGY & CAUSES ▪ Autosomal dominant disorder → liver, skeletal, ocular, cardiac, renal defects ▪ AKA arteriohepatic dysplasia, Alagille– Watson syndrome ▪ Variable penetrance; severity related to size of deletion ▪ Sometimes associated with somatic/ germline mosaicism ▪ Individuals susceptible to additional mutations CAUSES ▪ Mutation/deletion related to notch signalling pathway (involved in angiogenesis, cell proliferation, differentiation) ▫ 95% involve JAG1 gene (chromosome 20p12) ▫ NOTCH2 gene (chromosome 1p.13); related to renal malformations ▪ Results in absence of intrahepatic bile ducts → ↑ risk of progressive liver disease → chronically elevated bilirubin, cholesterol COMPLICATIONS ▪ ▪ ▪ ▪ Malabsorption Pancreatic insufficiency Abnormal vertebral segmentation Vascular anomalies (e.g. basilar artery aneurysm; ↑ risk of intracranial bleeding) Liver ▪ Chronic cholestasis (95%), cirrhosis, liver failure Cardiac ▪ Peripheral pulmonary artery stenosis, tetralogy of Fallot Ocular ▪ Shallow anterior chamber, keratoconus, embryotoxon (prominent Schwalbe’s ring), Axenfeld anomaly (embryotoxon + attached iris strands), pigmentary retinopathy, cataracts Renal ▪ Dysplasia, renal tubular acidosis OSMOSIS.ORG 163
SIGNS & SYMPTOMS ▪ Intellectual disability, learning difficulties ▪ Hepatosplenomegaly Cholestasis ▪ Jaundice, pruritus, xanthomas (cholesterol deposits in skin) Facial features ▪ Triangular face, prominent forehead, hypertelorism (widely-spaced eyes), deepset eyes, upslanting eyelids, long nose with bulbous tip, large ears, prominent mandible, pointed chin; more prominent with age Growth deficiency ▪ Short stature DIAGNOSIS DIAGNOSTIC IMAGING Spinal X-ray ▪ Butterfly-shaped vertebrae, hemivertebrae, spina bifida occulta LAB RESULTS ▪ ↑ bilirubin (total, conjugated), ↑ liver enzymes, ↑ cholesterol ▪ Liver biopsy: intrahepatic bile duct paucity, portal inflammation OTHER DIAGNOSTICS ▪ History, clinical examination ▪ Genetic tests TREATMENT MEDICATIONS ▪ Choleretic agents: ursodeoxycholic acid + cholestyramine/rifampin/naltrexone SURGERY ▪ Biliary diversion/liver transplantation ▪ Heart defect surgical repair OTHER INTERVENTIONS ▪ Nutritional support Abdominal ultrasound ▪ Kidneys: small, echogenic, presence of cysts, ureteropelvic obstruction MCCUNE–ALBRIGHT SYNDROME osms.it/mccune-albright_syndrome PATHOLOGY & CAUSES ▪ Genetic disorder characterized by fibrous dysplasia (FD), endocrinopathy, unilateral café-au-lait skin spots ▪ Occurs most commonly in skull base/ proximal femur; most lesions appear < age 15 ▪ External beam radiotherapy: ↑ risk of malignant transformation ▪ More common among individuals who are biologically female 164 OSMOSIS.ORG ▪ Post zygotic mutation in GNAS1 gene (20q.13.1-13.2) ▫ Encodes Gs alpha protein → G protein/ cAMP/adenylate cyclase signaling pathway ▪ Somatic mosaicism: some somatic cells mutated COMPLICATIONS ▪ Pathologic fractures; osteosarcoma; osteomalacia; visual/hearing disturbances (due to nerve compression); severe pain; scoliosis; ovarian cysts; acromegaly,
Chapter 25 Genetic Mutations gigantism; Mazabraud syndrome (fibrous dysplasia + intra/juxtamuscular myxoma); liver disease; higher risk of thyroid, testicular, breast cancer LAB RESULTS SIGNS & SYMPTOMS GH excess ▪ ↑ GH, ↑ prolactin Clinical triad ▪ Bone fibrous dysplasia ▫ Limp, pain, dysmorphism ▪ Hyperfunctioning endocrinopathy ▫ Hyperthyroidism: change in appetite, insomnia, fatigue, palpitations ▫ Cushing’s syndrome: moon facies, plethora, hirsutism ▫ Growth hormone (GH) excess: enlarged facial/body features, excessive sweating, thickened skin ▫ Renal phosphate wasting: usually asymptomatic; weakness, pain, altered mental status ▫ Precocious puberty: early vaginal bleeding, breast development in individuals who are biologically female; early testicular/penile enlargement, scrotal rugae, body odor, pubic/axillary hair, sexual behaviour in individuals who are biologically male ▪ Café-au-lait skin spots ▫ Brown macules, irregular borders (“coast of Maine”); mostly on lower back, buttocks DIAGNOSIS DIAGNOSTIC IMAGING X-ray, radionuclide bone scan ▪ Long bones: expansile, lytic lesions; endosteal scalloping (focal resorption of cortex inner layer), cortex thinning, “ground-glass” appearance of medulla; epiphysis usually spared ▫ Proximal femur: “shepherd’s crook” malformation ▪ Skull: sclerotic lesions, “ground-glass” appearance, cyst-like lesions Hyperthyroidism ▪ ↓ thyroid stimulating hormone (TSH), ↑ triiodothyronine (T3) Cushing’s syndrome ▪ ↑ 24-hour urinary free cortisol Renal phosphate wasting ▪ ↑ urinary phosphate, ↓ serum phosphate Precocious puberty ▪ ↑ testosterone/estradiol, ↓ luteinizing hormone (LH), ↓ follicle-stimulating hormone (FSH) Bone tissue biopsy ▪ Absence of lamelation pattern, “Chinese writing” pattern, areas of unmineralized osteoid OTHER DIAGNOSTICS ▪ History, physical examination ▪ Genetic tests (e.g. polymerase chain reaction, next-generation sequencing) TREATMENT MEDICATIONS ▪ Bisphosphonate treatment for pain management (no effect on disease progression) ▪ Medication for endocrine disorders (e.g. gonadotropin releasing hormone analogues, tamoxifen, thionamides) SURGERY ▪ Surgical management of fibrous dysplasia (e.g. intramedullary devices, bone grafting) OTHER INTERVENTIONS ▪ Physical exercise (e.g. cycling, swimming) ▫ ↑ bone support → ↓ fracture risk Thyroid ultrasound ▪ Presence of cystic areas OSMOSIS.ORG 165
PRIMARY CILIARY DYSKINESIA osms.it/primary-ciliary-dyskinesia PATHOLOGY & CAUSES ▪ Congenital disease; defect in cilia motility → impaired mucociliary clearance, decreased fertility ▪ AKA immotile-cilia syndrome ▪ Affects cilia of respiratory tract, fallopian tubes, sperm flagella ▪ Inheritance pattern: autosomal recessive CAUSES ▪ Defect in proteins of cilia structure → absent/altered motion (e.g. clockwise rotation) ▪ Genetic mutations ▫ DNAH5, DNAI1: encode axonemal outer dynein arms ▫ RSPH4A, RSPH9: encode radial spokes COMPLICATIONS ▪ Chronic sinusitis; Kartagener’s syndrome (situs inversus, chronic sinusitis, and bronchiectasis); hydrocephalus; transposition of great vessels; epispadias; pectus excavatum; chronic secretory otitis media; conductive hearing loss SIGNS & SYMPTOMS ▪ Recurrent upper/lower respiratory tract infections: chronic cough, mucopurulent sputum; symptoms increase during course of day ▪ Newborns: present with mild respiratory distress (tachypnea, mild hypoxemia) ▪ Bronchiectasis: crackles, wheezes ▫ Exacerbation: dark sputum, dyspnea, pleuritic pain ▪ Rhinosinusitis: runny nose, constant congestion, nasal polyps, altered sense of smell ▪ Fatigue, headaches 166 OSMOSIS.ORG ▪ Infertility ▪ ↓ aerobic fitness DIAGNOSIS DIAGNOSTIC IMAGING Chest X-ray, CT scan ▪ Pulmonary hyperinflation, peribronchial thickening, atelectasis, bronchiectasis; situs inversus LAB RESULTS ▪ Reduced/absent nasal nitric oxide (also present in some cases of cystic fibrosis) Cell culture ▪ Inferior concha epithelium: tissue culture → cilia shed → emergence of new, immotile cilia → diagnosis confirmation OTHER DIAGNOSTICS ▪ Spirometry: obstructive pattern ▪ Genetic tests Ciliary motion, ultrastructure ▪ High speed video microscopy analysis (HSVA): live examination of respiratory epithelial cells; after air-liquid interface/ cooling → assessment of motion pattern, beat frequency ▪ Transmission electron microscopy (TEM): observation of ciliary ultrastructure defects TREATMENT MEDICATIONS ▪ Bronchiectasis ▪ Antibiotics, airway hydration (e.g. nebulized hypertonic saline), mucolytic agents Chronic rhinitis ▪ Nasal saline lavage + intranasal glucocorticoids
Chapter 25 Genetic Mutations SURGERY Chronic rhinitis ▪ Polyp removal OTHER INTERVENTIONS ▪ Smoking cessation ▪ Pneumococcus, influenza vaccination Bronchiectasis ▪ Daily chest physiotherapy TREACHER COLLINS SYNDROME osms.it/treacher-collins-syndrome PATHOLOGY & CAUSES ▪ Severe genetic disorder of craniofacial development ▪ AKA mandibulofacial dysostosis, Franceschetti–Zwahlen–Klein syndrome ▪ Inheritance pattern: autosomal dominant, variable penetrance; 60% spontaneous CAUSES ▪ TCOF1 gene mutation (chromosome 5q32) → treacle protein (ribosome biogenesis regulator) insufficiency → neuroepithelial cell apoptosis → ↓ neural crest cells → first, second branchial arch anomalies → cranioskeletal hypoplasia ▪ Other genetic mutations: POLR1C (6q21.2), POLR1D (13q12.2); involved in ribosome biogenesis COMPLICATIONS ▪ Perinatal death; bilateral conductive hearing loss; speech problems; airway compromise; feeding difficulties; visual loss; brachycephaly; choanal atresia; congenital heart defects; intellectual disability; renal malformation SIGNS & SYMPTOMS ▪ Facial bone hypoplasia (esp. mandible, zygomatic bone): retrognathia, sunken cheeks ▪ Facial asymmetry ▪ Projection of scalp hair to lateral cheek ▪ Dental: high/arched/cleft palate; malocclusion, tooth agenesis, enamel opacities ▪ Ocular: downslanting eyelids, lower eyelid coloboma, paucity of eyelashes medial to notch, hypertelorism (widely spaced eyes) ▪ Malformation of external ear, external auditory canals, middle ear ossicles DIAGNOSIS DIAGNOSTIC IMAGING Cranial X-ray, orthopantomogram, CT scan ▪ Facial bone hypoplasia, altered middle ear ossicles, external auditory canal stenosis OTHER DIAGNOSTICS ▪ History, clinical examination ▪ Prenatal: amniocentesis, chorionic villus sampling OSMOSIS.ORG 167
TREATMENT SURGERY ▪ Reconstructive surgery ▪ Tracheostomy (severe airway obstruction at birth) ▪ Glossopexy (tongue-lip adhesion) ▪ Corrective surgery for cleft lip/palate/ choanal atresia ▪ Gastrostomy tube placement OTHER INTERVENTIONS ▪ Supportive treatments (e.g. hearing aid, speech therapy) 168 OSMOSIS.ORG Figure 25.1 The face of a female child with Treacher Collins syndrome.

Osmosis High-Yield Notes

This Osmosis High-Yield Note provides an overview of Genetic mutations essentials. All Osmosis Notes are clearly laid-out and contain striking images, tables, and diagrams to help visual learners understand complex topics quickly and efficiently. Find more information about Genetic mutations by visiting the associated Learn Page.