Human Genetic Diseases

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  1. Hemophilia
    • X linked recessive 
    • loss of function in clotting factors
  2. Achondroplasia
    • Autosomal dominant
    • FGFR mutations, premature activation leads to skeletal abnormalities
    • limb shortening, brachydactyly, macrocephaly
  3. Fragile X
    • X linked (recessive?)
    • expansion in CGG in 5' UTR of FMR1 leads to methylation and silencing 
    • Characteristics include large ears, Speech delay, hand flapping, lack of eye contact, hyperactivity, mimicry
  4. Rett Syndrome
    • X linked dominant "only" in females
    • MECP2 mutation leads to incorrect gene silencing in neurons in the brain
    • Characteristics include late onset developmental delay, speech delay, ataxia
  5. Cystic Fibrosis
    • Autosomal Recessive
    • Loss of transport or function of CFTR chloride channel in epithelial cells
    • Characteristics: thick sticky mucous in narrow passageways (lung and pancreas most affected), incorrect/lack of development of Wolffian duct leads to infertility in many males, sweat glands also affected
    • Most common in Caucasian (especially Ashkenazi Jews), incredibly rare in Asians
  6. Sickle Cell Disease
    • Autosomal Recessive
    • Point mutation in HBB gene substitutes valine for the normal glutamate, sticky hydrophobic tail able to polymerize with other mutant beta chains in deoxygenated state
    • Characteristics: polymerization in deoxygenated state creates fibers which distend the normally round red blood cell, this leads to hemolysis (acute anemic crisis or acute aplastic crisis), vessel occlusion, ischemia infarcts and pain related to necrosis, jaundice, dehydration, strokes, pulmonary hypertension
    • Prevalence: highest in people of African, Mediterranean, Middle Eastern, and Indian descent, Allele frequency as high as 8-10% in 
    • African Americans and 25-30% in West Africa
    • Defined by presence of HbS (either homozygous or compound heterozygosity mutant)
    • Hydroxy Urea increases concentration of fetal hemoglobin
  7. Thalassemias
    • Autosomal Recessive
    • Reduced synthesis or stability of HBA or HBB from alpha globin (either of the 2 genes) or beta globin, imbalance of alpha and beta chains causes problems
    • Characteristics: alpha - total absence leads to hydrops fetalis, some alpha production leads to beta chain tetramers (HbH) which cause hemolysis; beta - b null babies normal at birth but symptoms in first two years including severe transfusion dependent anemia, b+ is compatible with life because some b chain still produced
    • Prevalence: alpha highest in Asian populations, some African descent, beta most common in Mediterranean, African, and Southeast Asian
  8. Marfan (Genetics)
    • Autosomal Dominant
    • FBN1, fibrillin 1,mutations disrupt microfibril formation in the extracellular matrix of connective tissues
    • Prevalence: 1 in 10-20,000
    • Inheritance risk: 50% from affected parent
  9. Marfan (Clinical)
    • Affects: heart, blood vessels, lungs, eyes, bones, and ligaments
    • Ghent Diagnostic Criteria: Four of 8 skeletal features; Ectopia lentis; Dilatation or dissection of the aorta; Dural ectasia; Dominant inheritance
  10. Ehlers-Danlos Syndrome
    • Autosomal Dominant
    • Mutations in Collagen production, processing, or alpha chains
    • Prevalence: 1 in 5000
    • Mostly affects skin and joints; hyperextensible and fragile skin and hypermobile joints
  11. Huntington Disease
    • Autosomal Dominant
    • CAG repeat expansion in huntingtin (htt) gene creates poly-Q expansion in protein
    • 25 or less repeats = normal
    • 26-35 repeats = expansion risk
    • 36-39 repeats = at risk (incomplete penetrance)
    • 40 or more repeats = will develop
    • 60 or more repeats = juvenile onset
    • Inheritance Risk: 50% from affected parent
    • Anticipation: expansions grow with each generation leading to earlier onset
    • Features: motor (chorea), cognitive (executive functions), and psychiatric symptoms
  12. Down Syndrome
    • Complete or partial trisomy of Chromosome 21
    • Clinical Features: up-slanting palpebral fissures, epicanthal folds, protruding tongue, brachycephalic, single palmar crease, small 5th finger, gap between 1st and 2nd toes, atrial and ventricular defects, common atrioventricular candal, patent ductus arteriosis
    • Newborn Identification: hypotonia, excess nuchal skin, and excessively sleepy
  13. Prader-Willis Syndrome
    • Paternal deletion of 15q11-q13 or maternal uniparental disomy
    • Clinical Features: Obese, hyperphagia, small hands and feet, short stature, mental retardation
  14. Angelman Syndrome
    • Loss of maternal UBE3A (usually a chromosomal deletion)
    • Clinical Features: short stature, mental retardation, unusual facial appearance
  15. Neurofibromatosis
    • Autosomal dominant
    • Loss of function of NF1 or NF2 tumor suppressor genes (GAPs that inactivate RAS)
    • Features: Cafe au Lait spots (at least 5), freckles darker in axillary and inguinal regions, lisch nodules, neurofibromas
  16. Patau Syndrome
    • Trisomy 13, usually (80%) maternal nondisjunction
    • 98% die in utero, poor postnatal survival
    • Features: brain, microphthalmia, hypotelorism or cyclopis, bilateral cleft lip and palate, extra digits, truncus arteriosus and tetralogy of Fallot
  17. Edwards Syndrome
    • Trisomy 18, 90% maternal nondisjunction
    • 95% die in utero
    • Features: small triangular face, hypoplastic mandible, small palpebral fissures, fist with second and fifth fingers overlapping 3rd and 4th, "rocker bottom" feet, incomplete abdominal closure (omphalocele), dysplastic cardiac valves, genitourinary abnormalities
  18. Cri du Chat Syndrome
    • Deletion of part of 5th chromosome, usually spontaneous mutation
    • Prevalence: 1 in 216,000
    • Features: malformed larynx, intellectual disability, delayed development, microcephaly, low birth weight, hypotonia, heart defect
    • Distinctive Facial Features: hypertelorism, low-set ears, small jaw and rounded face
  19. Wolf Hirschhorn
    • Deletion of part of 4th chromosome, usually spontaneous mutation
    • Features: Delayed growth and development, intellectual disability, seizures
    • Distinctive Facial Features: broad, flat nasal bridge and a high forehead (Greek warrior helmet)
  20. Turner Syndrome
    • 45,X usually paternal nondisjunction
    • Incidence: 1 in 5000
    • 98% spontaneously abort
    • Features: newborn edema of foot and hand, short stature, unusual facies, low posterior hair, broad chest with wide spaced nipples, webbed neck, ovaries degenerate, amenorrhea, kidney and heart abnormalities, usually normal intelligence
  21. Klinefelter Syndrome
    • 47,XXY
    • Incidence: 1 in 1000 males
    • Features: tall with long legs and arms at puberty, sexual immaturity, small testes, infertility, androgen deficiency --> decreased muscle tone poor libido and decreased bone mineralization, gynecomastia, poor verbal skills, dyslexia, and social dysfunction
  22. Jacobs Syndrome
    • 47,XYY, always of paternal meiosis II nondisjunction
    • Incidence: 1 in 1000 males
    • No physical phenotype except tall stature
    • Increased risk of behavior problems: attention deficit, hyperactivity, impulsiveness, and aggression, often lower IQ, no fertility problems
  23. Trisomy X
    • 47,XXX, 95% maternal meiosis I nondisjunction
    • Incidence: 1 in 1000 females
    • No phenotype abnormalities, usually undiagnosed, fertile with normal children
    • Tall stature, mild developmental and learning disabilities
    • Additional X chromosomes (4-5) rare (<1 in 100,000), have increasing intellectual disability and developmental delay, delayed speech and facial dysmorphism
  24. Retinoblastoma
    • Autosomal dominant predisposition
    • loss of function of Rb (tumor suppressor gene)
    • Incidence: 1 in 20,000
    • Features: childhood retinal cancer, bilateral always hereditary, leukocoria (white eye), strabismus (poorly aligned eyes)
  25. Li Fraumeni
    • Autosomal Dominant Predisposition
    • Loss of function in p53 (guardian of the genome)
    • Features: high incidence of "sporadic" cancers due to high frequency of mutations and failure to arrest the cell cycle
  26. Breast Cancer
    • Autosomal dominant predisposition
    • Mutations in BRCA1 or BRCA2 most common hereditary, loss of homology dependent double-strand break repair
    • Prevalence: high (1/40) in Ashkenazi Jews, high in Caucasians, low in African-Americans
    • Associated Cancers: Ovarian (more with BRCA1) and Prostate
  27. APC colon cancer
    • Adenomatous Polyposis Coli
    • APC protein associates with beta-catenin leading to its degradation, tumor suppressor gene, frameshift mutation leads to loss of function
    • Overgrowth creates polyps with can become cancerous (familial adenomatous polyposis)
  28. Neural Tube Defects: spina bifida, anencephaly, craniorachischisis
    • 1 in 1000 live births
    • tube/vertebral arch closure fails in 1st month of development
    • exposure to amniotic fluid damages spinal cord
    • most commonly due to defects in planar cell polarity genes or a folate deficiency
  29. Hypospadias
    • 1 in 200-300 live births
    • misplaced (ventral) urethral opening at 8-14 weeks
    • Defects: Shh/Gli (in VACTERL), Hoxa13 (in Hand-Foot-Genital), or DES exposure (affects Wnt & Hox)
  30. Clubfoot
    • 1 in 400-1,000 live births
    • foot turned inward and downward; usually short tendons and short bones and muscles
    • Defects: Pitx1, Tbx4, & others, increased risk with maternal smoking
  31. Polydactyly
    • 1-2 in 1000
    • Extra digits; Pre axial (thumb) or post axial (little finger)
    • Defects: Gli3 or Valproate exposure
    • Can be a sign of: VACTERL, Pallister-Hall, Bardet-Biedl
  32. Syndactyly
    • 1 in 2,000-3,000
    • Fused digits at 2-3 months development
    • Defects: Hoxd13, d10, or a11
    • Can be a sign of: Holt-Oram (Tbx5 mutation) or Apert (FGFR2 mutation)
  33. Brachydactyly
    • Rare disruption in cartilage formation
    • Short digits
    • Defects: Hoxa/d13, IHH, or BMPR1B
    • Can be a sign of: Turner's or Brachydactyly MR Syndromes
  34. Thalidomide Embryopathy
    • Anti-angiogenic leads to decreased FGF in apical ectodermal ridge
    • Developmental time frame: 20-36 days
    • Characteristics: phocomelia (proximal limb elements absent) or amelia (limb absence), may include eye/ear, CNS, skeletal, and visceral problems
  35. Esophageal Atresia & Tracheo-Esophageal Fistula
    • 1 in 3500
    • Definition: discontinuous esophagus with or without connection between trachea and distal esophagus, polyhydramnios at 26 days
    • Rare genetic defects: Shh, Gli3, FoxF1, Wnt, BMP, Noggin, Nkx2.1
    • Can be part of: notochord defect, VACTERL, Down's, CHARGE, Franconi Anemia, delta-22q11
  36. Anorectal Malformations
    • 1 in 2500-3000
    • Definition: connections between anal/rectal canal and UGS, imperforate anus, persistent cloaca (2nd month)
    • Defects: Shh (severe) or Gli2/Gli3 (less severe)
    • Can be part of: Pallister-Hall, delta-13q, Trisomies, CDX1 (downstream target of wnt)
  37. Mullerian Duct Abnormalities
    • 1 in 2,000 to 10,000
    • Defects in formation of oviducts, uterus, cervix, and vagina or defects in fusion (bicornate/septate uterus or duplex cervix
    • Causes: Hoxa10 or Hoxa13 or DES exposure
  38. Hand-Foot-Genital Syndrome
    • Rare
    • Autosomal dominant mutation in Hoxa13
    • Distal limbs --> 1st digit brachydactyly
    • Genital --> hypospadias (male) or Mullerian duct fusion abnormality (female)
    • Urinary --> abnormalities of ureters and junction with bladder or kidney
  39. Pallister-Hall
    • Rare
    • Autosomal dominant mutation in Gli3
    • Defects: bifed epiglottis, hypospadias (male or Mullerian duct atresia (female), anorectal malformations, renal abnormalities, hypothalamic mass, hypo-pituitary, and synpolydactyly
  40. VACTERL Association
    • 1 in 10,000 to 40,000
    • Mutations/Exposures: FoxF1, Hoxd13, or maternal diabetes/alcohol
    • Defects: Vertebral, Anorectal, Cardiovascular, T(ef) & E(a), Renal dysplasia, Limb Defects (radial defects and polydactyly)
  41. Persistent Truncus Arteriosus
    • lack of separation of aortic and pulmonary trunks
    • Defect: cardiac cushions or neural crest
  42. Transposition of the Great Vessels
    • Reversal of aorta and pulmonary trunk
    • Defect: failure of truncal cushions and septa to spiral, abnormal rotation of the atria
  43. Ventricular Septal Defect
    • Incidence >1 in 1000 live births
    • Usually incomplete membraneous IV septum
    • Causes: deficient development of conal cushions, failure of fusion of membraneous and muscular septa, failue of AV cushion development and/or fusion, insufficient development of muscular septum
  44. Tetralogy of Fallot
    • 1. Pulmonary stenosis
    • 2. Overriding aorta
    • 3. Ventricular septal defect
    • 4. Hypertrophy of the right ventricle
    • Underlying Cause: misalignment of aorticopulmonary septum --> small pulmonary outflow tract and large aortic outflow; right ventricle hypertrophy due to extra work to pump blood to lungs
  45. Holt-Oram Syndrome
    • TBX5 mutations affect early limb induction and primary heart field (left ventricle and IV septum)
    • Usually show atrial septal defects, conduction defects, and limb abnormalities
  46. DiGeorge's/Velocardiofacial Syndrome
    • 22q11 deletion including TBX1 gene
    • Defect: 3rd and 4th pouch derivatives fail to develop
    • Abnormalities: heart outflow tract (persistent truncus, aortic arch abnormalities, ventricular septal defects, shortened outflow tract) and craniofacial defects (facial dysmorphia, cleft palate), learning difficulties, psychiatric problems, kidney abnormalities, hypoplasia of thyroid and parathyroid glands, hypoplasia of the thymus (frequent infections)
  47. Treacher Collins Syndrome
    • Defect: neural crest contribution to 1st branchial arch
    • Mutations: TCOF1, nuclear protein for rRNA transcription; loss of function leads to extensive cranial neural crest cell death
    • Features: mandibular hypoplasia, malformations of external and middle ears, cleft or high palate, tooth problems, lower eyelid defects
  48. Holoprosencephaly
    • developmental defect of the forebrain; underdevelopment of the brain, palate, nose, and eyes (midface)
    • Possible Causes: point mutations in Shh, BMP, FGF, and Nodal, ethanol or altered RA level exposures
  49. Fetal Alcohol Spectrum Disorders
    • Very similar to holoprosencephaly
    • Craniofacial abnormalities: midface hypoplasia, short palpebral fissures, epicanthal folds, thin upper lip, microophthalmia, microtia, cleft lip and palate, cortical dysgenesis, mental retardation, cardiac septal defects, clinodactyly of 5th finger
    • Possible Causes: impaired migration of prechordal mesoderm cells, loss of Shh, reduced RA levels
  50. Retinoic Acid Embryopathy
    • Very similar to holoprosencephaly
    • Abnormalities: midface underdevelopment, micrognathia and palate defects, craniosynostosis, microphthalmia, microtia, thymus defects, microcephaly, neural tube defects, mental retardation, cardiac septal defects, limb defects
    • Possible Causes: Accutane leads to excess retinoids, arrests cranial crest migration and proliferation
Card Set:
Human Genetic Diseases
2015-11-01 18:54:33
Genetics Disease Inheritance

Diseases presented in human genetics
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