CBCL2: Complex (Non-Mendelian) Disorders Flashcards
What is non-Mendelian inheritance?
there is no straight inheritance pattern - it may skip generations or have multiple genetic and environmental factors
recall: pure Mendelian inheritance = clear inheritance pattern (autosomal dominant, recessive, X-linked, etc)
What is the difference between monogenic, multifactorial, polygenic and multigeic disorders?
monogenic: one gene influences the trait
polygenic = multigennic: multiple genes influence the trait
multifactorial: multiple genes + environment influences the trait…“the type of non-Mendelian inheritance shown by traits that are determined by a combination of multiple factors”
What are modifier genes? Give an example.
modifier genes are genes that do not cause the disease, but contribute to disease risk. an example is the APOE gene and how it contributes to Alzheimer’s Disease. APOE does not cause Alzheimer’s, but the mutation e4/e4 increases the risk for Alzheimer’s while mutations in the genes APP, PSEN1 and PSEN2 directly cause early-onset Alzheimer’s in an autosomal dominant fashion
Explain threshold and recurrence risk - how are they different?
recurrence risk is when an individual has a disease and the other members in their family is now more likely to get the disease
threshold is the value in which the disease state is reached - it is more continuous and many factors can contribute to reaching (or not reaching) the threshold value
What is the difference between Mendelian, familial and sporadic inherited diseases?
Mendelian: mostly genetic; single-gene mutation/effect with minimal environmental influences
familial: combination of genetic and environmental; complex/multifactorial
sporadic: mostly environmental, de novo mutations; appears stochastic but has some genetic influence
Describe the inheritance of complex diseases.
complex diseases are due to the inheritance of common variants or low-frequency variants
alone, these mutations do not cause disease…is really a continuum of genetic factors
how do most cancers develop?
sporadic mutations -> no inherited component
acquire somatic mutations
however, the types of inherited cancer can show pathogenesis of the cancer and provide insight into the disease
what is the two-hit hypothesis?
start off with one bad allele and one good allele…then in life, the good allele becomes bad and disease results
this is the most common mechanism in genetic diseases
Familial Hypercholesterolemia (gene, environment, pathogenesis)
genetic: mutation in low-density lipoprotein receptor (LDLR); autosomal dominant (dominant negative) disorder of cholesterol and lipid metabolism; founder effects
heterozygous: early to middle adulthood onset
homozygous: childhood onset
environmental modifiers: diet mostly, but are other genetic and environmental factors
pathogenesis: cause accumulation of plasma LDL by increasing production of LDL from intermediate-density lipoproteins and decreasing hepatic clearance of LDL
Long QT (gene, environment, pathogenesis)
genetic: autosomal dominant or recessive; locus heterogeneity (at least 5 known cardiac ion channel genes and different mutant alleles in the same locus can result in 2 distinct diseases), incomplete penetrance (not a lot of new de novo mutations), genetic susceptibility to medications
pathogenesis: caused by defects in cardiac ion channels that affects repolarization
penetrance: aggravated by lifestyle - anything that messes up the heart will make this disease worse
two main types: Romano-Ward syndrome (dominant?) and Jervell and Lange-Nielsen syndrome (recessive)
most cases are cause of LOF mutations in genes that encode subunits or regulatory proteins for K channels….genes whose names begin with “KCN”; other mutation is GOF in Na channel gene: SCN5A
Insulin Dependent Diabetes Mellitus
T1D - 90% of IDDM occurs without a strong family history of diabetes -> appears to not be genetic, but the gene that may be associated is the HLA gene
multifactorial: polygenic + environmental trigger (viruses or early exposure to bovine albumin) -> usually results from a genetic susceptibility and subsequent environmental insult
progression to T1D involves more than the development of autoantibodies (less than 1% of the general population develops diabetes although 10% have islet autoantibodies
Non-Insulin Dependent Diabetes Mellitus
T2D -> appears to be strongly genetic
mutations: PPARG, HNF4A, and/or GCK
polygenic, environmental modifiers
Native Americans, African Americans and Mexican Americans
insulin desentization/not enough insulin is being produced
