Patterns of Single Gene Inheritance Flashcards
compound heterozygote
both alleles are variants, but at different locations in the gene
hemizygous
variant gene is on X chromosome in male patient
allelic heterogeneity
different mutations at the same gene locus causing the same phenotype
phenotypic heterogeneity
different mutations in the same gene cause different phenotypes
locus heterogeneity
mutations in multiple genomic loci (distinct genes) produce same phenotype
inheritance patterns can be different
pleiotropy
single gene variants that affect multiple organ systems, produce diverse phenotypes, and show a variety of signs and symptoms
very common for these genes to be transcription factors
you see a patient in clinic that has a rare disease in which the function of an important enzyme is severely limited. from this information alone, what inheritance pattern do you suspect?
autosomal recessive - limit/eliminate gene activity, often affect enzymes, are rare
AR diseases typically seen in one generation and typically seen among siblings
you have a patient with a single gene disorder, yet their symptoms are widely dispersed through multiple organ systems, and they present with several phenotypes. What type of gene variant must this be?
pleiotropy - single gene producing a variety of effects in multiple organ systems
two parents who are heterogenous for an autosomal recessive disorder have a child. What is the risk of an unaffected child being a carrier?
in other words, of the children that don’t have the disease (3/4), how many are carriers?
2/3
Pt is a 4 yo F referred to pediatric clinic for evaluation of poor growth. PMH includes diarrhea, colic, cough, and upper respiratory infections. No pertinent FMx. Pt’s ht & wt is within 2nd percentile. PE reveals clubbing of digits. Sweat chloride level was 75 mmol/L (<40 mmol/L normal). What is your initial diagnosis?
cystic fibrosis
A couples comes into clinic seeking genetic counseling. The father has cystic fibrosis (AR) and the mother is not sure whether she is a carrier, but her sister has CF (not her parents). They want to know the chance their child will have cystic fibrosis. What will you tell them?
the mother’s sister has CF but unaffected parents so they are both obligate carriers.
the mother’s chance of being a carrier is therefore 2/3
If she were a carrier, there would be a 1/2 chance of passing the mutated allele to the child
so the child’s risk is (2/3)(1/2) = 1/3
name 2 factors that can affect the risk of inheritance for an AR disorder
- carrier frequency of the disease in a given population
- consanguinity increases the chance that both parents are carriers of the same mutant allele (as closer or closer than second cousins)
what is the most common single-gene inherited disease in the US
hemochromatosis - affects iron storage, results in excess iron in the body which can be toxic
AR, but phenotype varies by sex because women have a physiologic mechanism to get rid of iron (menstruation, pregnancy) so their phenotype is less severe
what about hemochromatosis makes it difficult to track in a pedigree?
hemochromatosis: affects iron storage, causing excess in the body (mutation in HFE)
AR disease, but difficult pedigree because phenotype varies by sex - women who can get pregnant or menstruate naturally lose iron, so their phenotype is less severe
what is the associated gene mutation of cystic fibrosis? what is its inheritance pattern?
cAMP-regulated chloride channel
autosomal recessive
what mutation is associated with sickle cell disease, and what is its inheritance pattern?
mutation in hemoglobin beta subunit
autosomal recessive
what mutation is associated with thalassemia?
mutation in alpha or beta globin gene of hemoglobin
autosomal recessive
Explain this:
A couple both have syndromic deafness, an AR disorder. They each have a sibling with the disease, but their parents do not. The couple has 5 children, none of which have syndromic deafness.
locus heterogeneity !
They each inherited 2 recessive genes that cause deafness, but there is a different gene mutation affecting each family. The different mutations cause the same phenotype
In clinic you see a pair of monozygotic twins, a male and a female. Both have an AD mutation in the LH (luteinizing hormone) receptor gene such that it is constitutively active. However, only the male shows symptoms, exhibiting early-onset puberty. Explain this
male is affected by male-limited precocious puberty
sex-limited phenotype
disorder is transmitted via affected males or unaffected females (AD, but only carriers)
why might disease-causing genotypes in AD disorders not be expressed as a phenotype?
incomplete penetrance: probability that a variant gene will have any phenotypic expression (all or none)
penetrance has to be factored into risk of phenotype (multiply penetrance by risk)
If an AD disorder has a penetrance of 80%, what is the probability that a child with two affected heterozygous parents will have the phenotype?
penetrance = 0.8
probability of inheriting dominant allele from two heterozygous parents = 3/4 or 0.75
risk of phenotype = (0.8)(0.75)
Explain this:
A male affected by an AD disorder has children with an unaffected woman. They have 4 children, 2 of whom are affected. One of the unaffected daughters has children of their own with an unaffected male. Two of their four children have the AD disorder.
the “unaffected” daughter must have incomplete penetrance to be able to pass it on
they have the genetic abnormality but for whatever reason did not develop the disease
variable expressivity
varying severity of the phenotype among individuals with the same disease-expressing genotype
ex: neurofibromatosis
contrast incomplete penetrance with variable expressivity
incomplete penetrance: same phenotype, but not all those with allele variant are affected. Use this number in genetic counseling
variable expressivity: variable phenotype, but all those with allele variant have SOME phenotype
