Inherited diseases - examples of mono- & polygenic diseases

Question 1

what is the difference between monogenic and polygenic diseases?

Answer 1

monogenic diseases are 100% genetic, polygenic/complex diseases are a combination of hereditary predisposition & environmental factors

Question 2

describe the autosomal dominant inheritance pattern

Answer 2

inheritance of one mutated allele is sufficient to develop disease, heterozygous parent: 50% risk of a child to inherit it

Question 3

describe the recessive dominant inheritance pattern

Answer 3

must inherit two copies of a disease allele to develop disease (heterozygotes are healthy carriers), if both parents are carriers, children have 25% risk to get disease, 50 % risk to become a carrier

Question 4

describe the x-linked recessive inheritance pattern

Answer 4

incidence much higher in men, heterozygous women usually aunaffected/healthy carriers, if father is sick, all daughters will be carriers (male to male transfer not possible)

Question 5

describe the x-linked dominant inheritance pattern

Answer 5

• when father is sick, all of his daughters will be affected, none of his sons
• when mother is sick, 50 % risk for both sexes

Question 6

describe the inheritance pattern of mitochondrial diseases (if in mtDNA)

Answer 6

maternally inherited, dilution effect in zygote (sperm cell contains way less mtDNA), mtDNA actively removed from sperm prior to fertilization, bottleneck effect

Question 7

name an example of a common monogenic autosomal recessive disease (most common genetic alteration and phenotype)

Answer 7

-cystic fibrosis: mutations in cystic fibrosis transmembrane conductance (CFTR) gene, chromosome 7, channel that controls H2O/Cl- flow in/out of cells -> thick mucus in lungs (reduces free air flow, lung infection risk..)

Question 8

name two examples of a common monogenic autosomal dominant disease (most common genetic alteration and phenotype)

Answer 8

• familial hypercholesterolemia (FH): mostly mutations in LDL receptor, defect in live uptake/degradation of LDL-cholesterol
• Huntington’s disease: neurodegenerative disease, choreik movements, cognitive decline, dementia, psychological disturbances; CAG repeat extension in exon 1 of HD gene (chromosome 4, huntingtin)

Question 9

variable expressivity

Answer 9

severity of disease varies among individuals with the same mutation

Question 10

reduced penetrance

Answer 10

less than 100% of individuals with specific mutation who will develop disease

Question 11

how genetically similar are dizygotic twins?

Answer 11

50% of alleles same, often share same environment in childhood, same intrauterine life

Question 12

how genetically similar are monozygotic twins?

Answer 12

share 100 % of their genes, same childhood environment, same intrauterine life

Question 13

concordance rate

Answer 13

if one twin has a disease, how often does the other (same sex) have the disease? when MZ twins have a higher concordance rate, it means a significant genetic contribution

Question 14

what does a concordance rate of less than 100% in MZ twins mean?

Answer 14

disease also influenced by environment

Question 15

what does a similar concordance rate in MZ/DZ twins mean?

Answer 15

genetics does not play a significant role in development of disease

Question 16

limitations of twin studies

Answer 16

• MZ twins not necessarily 100 % identical (DNA rearrangements in somatic cells, different x-chromosome inactivation, epigenetics..)
• environmental exposure may differ
• twins are more likely to participate if both have the disease (inflates concordance rates)

Question 17

what can we say from twin studies and what is not possible to say?

Answer 17

there may (not) be a genetic contribution, and how large, we can not say which and how many genes contribute and how genes and environment interact in the disease

Question 18

GWAS

Answer 18

genome-wide association studies: large case-control studies, look for DNA differences, common genetic variants (often co-inherited) that occur in different frequences between case&controls

Question 19

limits of GWAS

Answer 19

supplementary analysis necessary to identify causal gene hit (e.g. increased marker density in sequence region), mostly not applicable in individual level (individual combinations of risk alleles), points to a region, not a gene, multiple loci, degree of exposure to environmental triggers

Question 20

what is the population prevalence of familial hypercholesterolemia in Norway?

Answer 20

most common autosomal dominant disorder in Norway: 1:350 - 1:500

Question 21

penetrance

Answer 21

fraction of individuals carrying a specific mutation who will develop the disease

Question 22

define anticipation

Answer 22

onset of the disease is correlated with the number of CAG repeats that increases in successive generations (deviation from strict Mendelian inheritance) e.g. in Huntington’s disease