Complete Genetics for Medical Students

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GENETICS

• IMEC INC.
• Quick Learning
• Technique

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Punnetts Square
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Burkitts
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X-linked Recessive
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AUTOSOMAL RECESSIVE
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AUTOSOMAL DOMINANT
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Incomplete Penetrance
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MITOCHONDRIAL INHERITANCE FATHER
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Suppressor Genes

• Gene Chromosome Tumor
• Rb 13b Retinoblastoma
• BRCA-1/2 17q, 13q Breast/Ovarian
• P53 17p Most Human
  Cancers

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Common Congenital Malformations

• Heart defects (congenital rubella)
• Hypospadius
• Cleft lip with or without Cleft Palate
• Congenital Hip Dislocation
• Spina Bifida
• Anencephaly
• Pyloric Stenosis
• Note Anacephaly and Spina Bifida are associated
  with increased increased AFP
• Incidence increases without FOLATE INGESTION
  DURING PREGNANCY

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Congenital Heart Disease

• R-L SHUNT (3 Ts)
• Tetrology of Fallot
• Transposition of greater vessels
• Truncus Arteriosis
• Leads to progressive pulmonary hypertension
• L-R SHUNT
• VSD
• ASD
• PDA
• Note Frequency ( VSD ?ASD-?PDA )

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Eisenmengers Syndome

• Uncorrected VSD, ASD, PDA leads to progressive
  pulmonary hypertension. In an increased pulmonary
  resistance the shunt changes from (L?R)
  To (R?L)
• R?L causes late cyanosis (clubbing and
  polycythemia)

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TETROLOGY OF FALLOT

• Pulmonary Stenosis
• Right Ventricular Hypertrophy
• Over-riding Aorta
• Ventricular Septal Defect
• This is a (R?L) Shunt which leads to cyanosis
• This also causes a displacement of the
  infundibular septum

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Transposition of Greater Vesicles

• Aortic leaves RV (ANTERIORLY) and the
• Pulmonary Trunk leaves the
• LV (POSTERIORLY)
• THIS SEPERATES SYSTEMIC AND PULMONARY CIRCULATION
• NOT COMBATABLE WITH LIFE UNLESS VSD or PDA

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Coarction of Aorta

• Infantile Type- (pre-ductal) insertion proximal
  to ductus arterioiosis
• Adult Type (post-ductal)
• Associated with hypertension in upper arms and
  decreased B/P in Lower limbs

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Patent Ductus Arteriosis

• In the Fetal Period a (R?L) shunt is normal
• In neonatal period and decrease in lung
  resistance normally closes it, and the PDA
  becomes (L?R)
• The (L?R) shunt may be needed to sustain life
• PGE and a lower O2 tension may be used to
  maintain the PDA

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AUTOSOMAL TRISOMIES
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Downs SyndromeTrisomy 21 (1700)

• Most common chromosomal defect causing mental
  retardation
• Retardation, flat facial features, Simian crease,
  duodenal atresia, congenital heart defect (HEART
  CUSHIONS)
• Alzheimers disease in individuals gt 35 YO
• 95 Non-Disjunction
• 4 Robertsonian
• 1 Mosaicism

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Edwards SyndromeTrisomy 18

• Severe Mental Retardation
• Rocker Bottom Feet
• Low-set ears
• CLENCHED HANDS
• Death usually within one year

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Pataus SyndromeTrisomy 13

• Severe Mental Retardation
• MICROCEPHALY
• Abnormal Forebrain
• CLEFT LIP/PALATE
• Polydactyly
• Congenital Heart Disease
• Death ussually within one year

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GENETIC GENDER DISORDERS
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KLINEFELTERS SYNDROME(XXY) 1850

• Testicular Atrophy
• Eunuchoid Body Shape
• Tall, with long extremities
• Female Hair Distribution
• Presence of inactivated Barr Body (X) chromosome

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TURNERS SYNDROME(XO)13000

• Short Stature
• Ovarian Dysgenesis
• WEBBING OF NECK
• Coarction of aorta (pretectal)
• PRIMARY AMENORRHEA
• NO BARR BODY

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Double Y Males(XYY) 11000

• Phenotypically Normal
• Very Tall
• SEVERE ACNE
• Some Anti-Social Behavior Noted (1-2)
• Observed increased among inmates

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PSEUDOHERMAPHRODITSM

• Disagreement between phenotype
• (EXTERNAL GENITALIA)
• and
• Gonadal Sex
• (Testis /Ovaries)

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Female Pseudohermaphroditism

• OVARIES ARE PRESENT
• External Genitalia is Ambigiously Virilized
• May be due to exposure to exogenous androgens
  during pregnancy
• Or may be due to
• ADRENAL HYPERPLASIA during pregnancy

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MALE PSEUDOHERMAPHODITE

• TESTIS ARE PRESENT
• EXTERNAL GENITALIA FEMALE
• MOST COMMON (ANDROGEN INSENSITIVE)
• X-LINKED RECESSIVE in ANDROGEN RECEPTOR
• BLIND END VAGINA

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TRUE HERMAPHRODITE

• Both Ovary and Testicular Tissue is Present
• Ambigious Genitalia

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CRI-DU-CHAT SYNDROME

• Congential deletion of
• Short Arm of Chromosome 5
• High Pitched crying/mewing
• Microcephaly/ Epicanthial folds/ retardation

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Fragile X Syndrome

• 2nd Most Common Genetic Mental Retardation
• Methylated FMR 1 Gene (triplet CGGn )
• Associated with Macro-Orchidism
• BIG BALLS
• Long Face
• Large Ears
• Autism

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Duchennes Muscular Dystrophy

• Duchennes is X-Linked recessive (MALES) due to
  dystrophin deletion.
• Weakness begins in the pelvic girdle
• Pseudo-hypertrophy of calf muscles
• Requires assistance of upper extremities to stand
• Cardiac myopathy
• Diagnosis is Muscle Biopsy and CPK-MM

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Beckers Muscular Dystrophy

• Beckers is due to a dystrophin gene mutation?not
  deletion
• Less severe than Duchennes

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CYSTIC FIBROSIS

• AUTOSOMAL RECESSIVE defect in CFTR gene of
  chromosome 7.
• Defective Cl- channels
• Thick mucous in lungs, pancreas liver
• Bronchiestasis
• Steatorrhea
• Recurrent Pulmonary Infections
• Pseudomonas
• Staphylococcus aureus
• Infertility in males
• Fat Soluble vitamin defeciency (A, D, E, K)
• Most common lethal genetic in Caucasians

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AUTOSOMAL DOMINANT DISEASES
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Adult Polycystic Kidney Disease

• ALWAYS BILATERAL
• Massive Enlargement of Kidneys due to large cysts

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FAMILIAL HYPERCHOLESTEROLEMIA(TYPE II)

• Elevated LDL owing to defective or ABSENT LDL
  RECEPTOR
• Heterozygotes (1/500) have Cholesterol 300mg/dl
• Homozygotes (very rare) have Cholesterol greater
  gt 700mg/dl
• SEVERE ATHEROTIC DISEASE, TENDONOUS XANTOMAS
  (CLASSIC ACHILLIS) TENDON.
• MI MAY DEVELOP BEFORE 20 YO

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Marfans Syndrome

• Fibrillin Gene Mutation-?connective tissue
  disorder
• Skeletal abnormalities tall with long
  extremities, hyper-extensive joints, and long
  tapering fingers and toes
• Cardiovascular Cystic medial necrosis of aorta?
  dissecting aortic aneursym
• Floppy Mitral Valve Prolapse
• Ocular subluxation of lenses

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Von Recklinghausens Disease(Chromosome 17)

• Iris Hemartomas (Lisch Nodules)
• Neural Tumors
• Café-au-lait spots
• Skeletal disorders (scoliosis)
• Increased tumor susceptability
• One long arm of Chromosome 17

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Von Hipple Lindau Disease(Chromosome 3)

• Hemangioblastoma of Retina/Cerebellum/medulla
• About ½ of affected individuals Develop Multiple
  Renal Cell Carcinomas and other tumors
• Associated with deletion of VHL gene
• VHL is a Tumor Suppressor on Chromosome 3 (3p)

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Huntingtons Disease(Chromosome 4)Triplet
repeat disorder

• Progressive dementia
• Chorioform movements
• Caudate atrophy
• Decreased level of GABA and Acetylcholine in the
  brain
• Manifest at age between 20-50

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Familial Adenomatous Polyposis(Chromosome 5)

• Colon becomes covered with adenomatous polyps
• Autosomal-dominant characteristic
• POSITIVELY WILL GET COLON CANCER (100 without
  resection)

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ROBERTSONIAN TRANSLOCATION
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Hereditary Spherocytosis

• INCREASED MCHC
• Spheroid erythrocyte
• Hemolytic anemia
• Splenectomy is curative

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Neurofibromatosis

• Autosomal dominant
• Increased Tumor Susceptibility
• Multiple CaféAu Lait Spots

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OTHERS
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Osteogenic Imperfecta

• Increased susceptibility to fractures
• Connective tissue fragility
• 110000 births
• Phenotypically and genetically heterogenous

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Autosomal Recessive Disorder (list)

• Cystic Fibrosis
• Albinism
• Alpha-1-antitrypsin deficiency
• Phenylketonuria
• Thallasemias
• Sickle Cell
• Glycogen Storage Diseases
• Mucupolysacchridosis (except Hunters)
• Sphingolipidosis (except Fabrys)
• Infant Polycystic Kidney DX
• Hemochromatosis

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X-Linked Disorders

• Fragile X
• Duchennes Muscular Dystophy
• Hemophilia A B
• Fabrys
• G6PD deficiency
• Hunters Syndrome
• Ocular Albinism
• Lesch-Nyhan Syndrome
• Brutons
• Agammaglobulinemia
• Wiskott-Aldrich Syndrome

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Neural Tube Defects

• Associated with low folic acid intake during
  pregnancy
• Elevation of AFP in Amniotic Fluid
• Spina Bifida occulta Failure of bony Spinal
  Canal to closeNo structural herniation Tufts
  of Hair
• Menengiocele Meninges Herniate through spinal
  cal defect
• Menengiomylocele meninges and spinal chord
  herniate through spinal canal defect

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Fetal Alcohol Syndrome

• Number One cause of Congenital Malformations in
  the US
• Highest Risk _at_ (3-8 weeks)
• Retardation
• Limb dislocations
• Heart and lung fistulas
• MICROCEPHALY

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