Patterns of Inheritance III and IV

Question 1

describe X-linked SCID

Answer 1

• Caused by a defect in the γ-chain of the receptor for several different interleukins (IL2RG)
  
  • also called the γc-cytokine receptor, since interleukins are cytokines
• If T-cells lack this receptor they cannot mature
• In turn, this results in a deficiency of normal B-cell function

Question 2

describe X-linked dominant disorders

Answer 2

• More females affected than males
• Skipping of generations NOT common
• Preponderance of females compared to males
• No male to male transmission
• Affected male transmits the diseases to ALL HIS DAUGHTERS, but none of his sons would be affected

Question 3

describe inheritance Rett Syndrome

Answer 3

• Affects females more often than males (lethal in males)
  
  • Males die in utero or soon after birth
• Mother may have have manisfestations of the disease:
  
  • skewed X chromosome inactivation
  • disorder may be due to a germline mutation in the mother (mosaicism – confined to germline cell)

Question 4

describe incontinentia pigmenti

Answer 4

• Males with the disorder die in utero –> only females have it
• Manifests as rashes and blisters in early life
• Later, patches of hyperpigmentation “marble cake appearance” of skin
• Intellectual and learning disability (in some patients)
• Retinal detachment
• Variable expressivity in females: due to the phenomena of X-inactivation

Question 5

name the X-linked dominant disorder

Answer 5

• Vitamin D resistant Rickets (hypophosphatemic rickets)
• Retty Syndrome (lethal in males)
• Incontinentia pigmenti (lethal in males)

Question 6

go through the pedigree tree

Answer 6

Question 7

describe Y-linked inheritance

Answer 7

• Only males are affected
• Genes on Y are primarily genes involved in spermatogenesis and therefore, mutations usually cause sterility and not passed on
• Examples:
  
  • Various mutations in the SRY genes
  • H-Y histocompatability antigen
  • Hairy ears

Question 8

describe incomplete penetrance

Answer 8

• May be dependent on age, especially in adult onset diseases
• Called “age dependent penetrance”
• Huntington’s disease
• Familial breast cancer

Question 9

describe variable expression

Answer 9

• In individuals who have inherited the same mutant allele, some individuals are severely affected and others are mildly affected
• 3 reasons
  
  • random chance
  • other genetic factors
  • environmental exposure

Question 10

name an example of high penetrance but variable expression

Answer 10

• Neurofibromatosis type I (AD disorder)
• Some have cafe-au-lait spots, neurofibromas on the skin, bone deformities, learning disabilities
• Generally all patients with the mutant NF1 gene express at least some signs (VARIABLE expression) of the disorder (HIGH penetrance)

Question 11

name 2 examples of variable expression

Answer 11

• Iron overload disorder (hemochromatosis) (AR disorder) – more severe in males (females menstruate and lose iron)
• Xeroderma pigmentosum (AR) – more severe in individuals exposed more frequently to environmental UV radiation
• OI (AD) – Less severely affected, maybe blue sclerae in. More severely affected, maybe multiple fractures

Question 12

describe pleiotropy

Answer 12

• Disease causing mutation affects multiple organ system
• Marfan syndrome (autosomal dominant)
  
  • Mutation in the fibrillin-1 gene
• OI
  
  • mutation in the collagen gene

Question 13

describe locus heterogeneity

Answer 13

• Mutations at different loci that cause the same disease phenotype. Mutations of different genes cause the same disease phenotype
• OI: defect in collagen
  
  • Mutations at different locations but = same disease
• Others:
  
  • sensorineural hearing impairment
  • Retinitis pigmentosa
  • Charcot Marie Tooth disease
  • SCID (AR and X-linked)

Question 14

describe allelic heterogeneity

Answer 14

• Different kinds of mutations of the same gene cause the disease
• NF-1 is caused due to a mutation in the NF-1 gene
  
  • >1000 different mutations have been identified in the NF-1 gene
• Heterochromatosis also exhibits allelic heterogeneity due to different mutations of the HFE gene

Question 15

describe new mutations

Answer 15

• The mutation is transmitted from an unaffected parent to an affected offspring
• NO family history of the disease
• Hot spot for mutations:
  
  • NF1
  • FGFR3
  • DMD (Dystrophin gene): about 1/3 of patients have new mutation

Question 16

describe germline mosaicism

Answer 16

• Presence of 2 affected children is in favor of germline mosaicism (compare to new mutation, where there is a single child with a disorder and no family history of the disorder)
• When there is more than 1 occurece = germline mosaicism