Bocian Mendelian Flashcards
Describe Autosomal dominant inheritance
Autosomal Dominant Inheritance
A. The gene for the disorder is found on an autosome (i.e., not on the X or the Y or in the
mitochondrial genome)
B. The phenotype is expressed in heterozygotes (usually) or in homozygotes
1. aa is not affected
2. Aa is affected
Marfan syndrome inheritance?
Autosomal Dominant
Neurofibromatosis inheritance
Autosomal Dominant
Describe Autosomal Recessive inheritance
Autosomal Recessive Inheritance A. The phenotype is expressed only in those who are homozygous for the mutation 1. AA is not affected 2. Aa is a carrier but still normal 3. aa is affected
Cystic Fibrosis Inheritance?
Autosomal Recessive
What is Codominant Inheritance?
Codominant Inheritance
A. Expression of each allele can be detected, even in the presence of the other
1. Example: ABO and MN blood groups. The system consists of three alleles A, B, and
O. Both A and B are dominant in relation to O, so blood group A can have the genotype
AA or AO. Blood group B can have the genotype BB or BO. However, neither A nor B
shows dominance over the other, so individuals with the genotype AB have the
phenotypic characteristics of both blood group A and blood group B.
What is Incomplete Dominant (Semidominant) or Incomplete Recessive Inheritance?
Expression of heterozygote (Aa) is different from both homozygous types (AA and aa)
and is intermediate between them
1. Example: Achondroplasia (AD) – homozygotes are much more severe than
heterozygotes; however, achondroplasia is considered to be a dominant disorder.
Achondroplasia inheritance?
Autosomal Dominant
Describe 3 general characteristics of autosomal dominant diseases
A. The normal gene product is usually a non-enzymatic structural protein
B. The normal gene product is required in normal amount and with normal function
C. Abnormal phenotypes result from a mutant gene that produces no protein, a reduced amount of protein, reduced or increased activity or function of the protein, an abnormal form of the protein which may be toxic to the cell or have a new function, protein expression at the wrong time or place, or occasionally an increased amount of the protein.
Ehlers-Danlos syndrome inheritance?
Autosomal Dominant
Describe 3 general characteristics of Autosomal Recessive Disorders
A. The gene product is usually an enzyme
B. Abnormal phenotypes result from absent or very low levels of the enzyme/protein
C. There is a margin of safety wide enough to allow normal function in heterozygotes
1. An individual can have only half the normal amount of enzyme and still have
normal amounts of substrate converted
Describe PKU heterozygotes
PKU heterozygotes (“carriers”) (Pp) have only half the normal amount of enzyme but are normal clinically because half the enzyme is still enough to do the job
Describe genetic heterogeneity
Genetically different disorders may appear clinically (phenotypically) identical, and
identical disorders may be due to different genes………..
What is allelic (mutational) heterogeneity?
Different mutations in the same gene causing
the same disorder
What is Locus (non-allelic) heterogeneity?
Mutations in different genes causing the same
disorder
What is phenotypic heterogeneity?
Different mutations in the same gene causing different disorders
What is allelic homogeneity?
For some disorders, all or nearly all affected individuals have the same mutation
Mutation in achondroplasia?
Allelic homogeneity
99% have mutation in the FGFR3 gene
Describe allelic heterogeneity in recessive and dominant disorders
- In recessive disorders, e.g., cystic fibrosis, different mutations at the same locus (compound heterozygote) can account for variable severity of the disorder
- For many dominant disorders, all or most affected families have unique (“private”) mutations
Severity of NF-1?
Allelic heterogeneity
Severity and/or expression may differ depending on the type of mutation or where in
the gene the mutation occurs
Describe adult PKD in the context of locus heterogeneity
Autosomal dominant (“adult”) polycystic kidney disease can be caused by either of two genes, PKD1 (85% of cases) or PKD2 (15% of cases)
Same phenotype
What is variable expressivity?
Expressivity relates to the degree to which an affected person manifests a particular
disorder
Phenotype in variable expressivity?
The phenotypic manifestations may differ among people who have the same genotype
What is intrafamilial and interfamilial variability?
Intrafamilial variability (variability within families) may reflect the action of modifying genes, but interfamilial variability (variability between/among families) is more likely to be due to allelic heterogeneity at a single locus.
Describe variable expression in the context of a family with a disease
Affected individuals, even in the same family, can have different manifestations of the condition
What is variable severity?
Affected individuals, even in the same family, can be mildly, moderately, or severely affected
What is a congenital disorder?
A congenital disorder is one that is present at birth; it may or may not have a genetic basis
What is a genetic disorder?
A genetic disorder is one that is determined by genes; it may be present at birth or may have later onset
Describe late-onset genetic disorder
Range of age of development of phenotype. Can be later in life
What is pleiotropy?
The phenomenon in which a single gene is responsible for a number of distinct and
seemingly unrelated phenotypic effects - a single cause results in abnormalities in more
than one organ system in different parts of the embryo or in multiple structures that arise
at different times during embryologic development
What are sex-limited phenotypes?
Autosomally transmitted but expressed only in one sex
What are sex-influenced phenotypes?
Expressed in both sexes but with different frequencies
What is penetrance?
The percentage of people with a particular genotype who are actually affected clinically
What is reduced penetrance or non-penetrance?
Some individuals who have the
appropriate genotype fail to express it
a) May be misinterpreted as “skipping a generation”
Describe the characteristics of autosomal dominant inheritance. What is meant by vertical transmission?
Only one copy of the mutated gene is required for expression of the trait
The trait appears in each generation (vertical transmission)
What is meant by new mutation? How does this relate to autosomal dominant mutations?
An affected child may not necessarily have an affected parent
What is germ-line mosaicism? How does this explain an autosomal dominant disease “carrier”?
Both parents may be clinically normal, but one may have the mutation in only some of
the body’s cells—not enough to be clinically (i.e., obviously) affected
- But, if the mutation is in some of the germ cells, i.e. eggs or sperm, more than one
child may be affected
Describe autosomal dominant mutation in regards to variable expression.
Autosomal dominant traits may vary widely in their phenotypic expression and/or severity, even among affected individuals in the same family
Describe incomplete penetrance in the context of autosomal dominant inheritance
Some individuals who carry the mutation may not show any clinical abnormality
Describe delayed age of onset in an autosomal dominant inheritance
In some conditions, e.g. Huntington disease, affected individuals may not show
manifestations until a later age
Diagnosis may not occur until after they have reproduced, depriving them of some
important options for reproductive decision-making
Give some examples of a negative family history with an autosomal dominant disease
A. The patient represents a new mutation
B. A parent has germ-line mosaicism
C. A parent carries the mutation but with non-penetrance or very mild expression which was
not recognized
D. Genetic heterogeneity; the patient really has another, similar disorder with different
inheritance, e.g. autosomal recessive
E. Delayed age-of-onset disorder, and a parent had the mutation but died from another cause
before onset and recognition of the genetic disorder
F. Non-paternity
What to tell patient in an autosomal dominant disease
- Offspring are at a 50% risk to inherit the gene
- The condition may be more or less severe, or may have different manifestations in the
child
What to tell couple with child with autosomal dominant disease
- Recurrence risk will depend on whether disorder was inherited from a parent or arose
as a new mutation - Parents may need to be carefully examined and/or have special studies to determine if
one of them carries the gene
Characteristic of autosomal recessive inheritance? What is horizontal transmission?
The trait usually appears only in siblings and not in their parents, offspring, or other relatives (horizontal transmission)
Two copies of the mutation are required for expression of the trait
What is a compound heterozygote?
Compound heterozygote has a pair of genes with a different mutation in each copy (really is a type of homozygote – the term is used to distinguish this individual from one who has the same mutation in each copy of the gene)
What is a double heterozygote?
Double heterozygote carries mutations in two different genes
What are obligate carriers?
An individual who may be clinically unaffected but who must carry a gene mutation based on analysis of the family history; usually applies to disorders inherited in an autosomal recessive and X-linked recessive manner (but could also apply to someone with an autosomal dominant disorder and incomplete penetrance)
What is consanguinity? Risk?
- Genetic relatedness between individuals descended from at least one common
ancestor - They are more likely to carry identical alleles inherited from this common ancestor
- Both could transmit an identical allele to their offspring, who would then be
homozygous for that allele and, therefore, affected - A consanguineous couple have an increased risk that their offspring will be affected
with a recessive disorder; the magnitude of the risk depends on where in the family the
common ancestor is - The more rare the disorder, the more likely that the parents are consanguineous
Genetic heterogeneity and clinical manifestation of disease?
Some genetically different disorders may appear clinically identical
What is pseudodominance?
Either consanguinity or a high gene frequency in the population may make a recessive pedigree falsely appear dominant
What determines gender in humans?
Either consanguinity or a high gene frequency in the population may make a recessive pedigree falsely appear dominant
The majority of genes on X chromosome?
The majority of genes on the X have nothing to do with sexualcharacteristics.
What is the Lyon hypothesis?
Single active X hypothesis
all but one X chromosome in each cell to be almost entirely turned off (inactivated). (The “almost” is very important – there are some genes on the X that
escape inactivation.)
Why is Turner phenotype not too different from normal?
patients missing an entire X chromosome (i.e., Turner syndrome) or those with an entire extra X chromosome (e.g., XXY or XXX individuals) are
not very different overall from normal individuals because all but one X chromosome is inactivated.
What is XIST?
There is a gene called XIST (X-inactivation-specific transcript) on the X chromosome (at Xq13.2) that is the master regulatory switch locus for Xinactivation.
Describe 6 major characteristics of X-linked recessive inheritance
- Males are affected
- Heterozygous (carrier) females are (usually) clinically normal or show only mild
clinical expression - All sons of affected males are normal
a) A son inherits his fathers’ Y chromosome, not his X, so he won’t inherit the
mutation - All daughters of affected males are carriers
a) Daughters inherit their fathers’ X chromosome; since it has the recessive
mutation, they will all be carriers and (usually) unaffected - Half the sons of a heterozygous female are affected
a) Women have two X’s; since their sons get either one or the other X, half will be
affected and half normal - Half the daughters of a heterozygous female are carriers
a) The trait may be passed through a series of carrier females
b) Affected males are always related through females
What is skewed X-inactivation?
X-inactivation doesn’t occur at the 2-cell stage – it occurs after the early cleavage stage; therefore, there are multiple cells present, each of which
randomly inactivates one of the X’s
What is the distribution of X inactivation? Consequences?
think of Xinactivation the female population as a bell-shaped curve
Therefore, some carrier females may express the disorder because of skewed Xinactivation,
in which the majority of cells have the normal X inactivated and the X with the mutation active – therefore, there is much less of the normal product of that gene than there would be if the normal X were active in at least half the cells.
Diseases that are X linked but women may still have?
some women might have a low-enough level of clotting factor VIII to give them symptoms of hemophilia A, or some women might
have symptoms of Duchenne muscular dystrophy (both of these are classical X-linked recessive disorders in which males are affected and females are unaffected (usually) carriers
Describe sex chromosome abnormalities in women
Sex chromosome abnormalities may cause a carrier female to express the disorder
(1) 45,X women (Turner syndrome) may manifest X-linked recessive disorders
(2) A man with 47,XXY (Klinefelter syndrome) may carry an X-linked recessive disorder but not express it
Describe homozyogosity of a mutant X linked gene in an affected female
Homozygosity for the mutant gene in an affected female will result in expression of the disorder in the female
(1) XX carrier sister of XY man with hemophilia-A meets another XY man with hemophilia-A in the waiting room of the hemophilia clinic……if they have children, a daughter could inherit the X with the mutation from each of them and have hemophilia (XX x XY -> XX)
New sex linked mutation?
Not every affected male necessarily has a carrier mother
~1/3 of males with X-linked recessive disorders have new mutations
Describe Germ-line mosaicism and X-linked disease
In general, in X-linked recessive disorders, ~2/3 of cases are inherited from a carrier mother and ~1/3 of cases are new mutations.
A proportion of these mothers are mosaics
So, if the mother of a boy with a Duchenne muscular dystrophy mutation tests negative for the mutation in her blood, she still has a ~15% chance of carrying the mutation in her germline (empiric risk) and could have another affected
son or carrier daughter.
What is Fragile X syndrome inheritance?
X linked recessive
The most common inherited cause of intellectual disabilities
What is the most common inherited cause of intellectual disability?
Fragile X syndrome
Can Fragile X occur in females?
YES (remember skewed X inactivation)
Describe Fragile X in males and females with a full mutation
Nearly all males with a full mutation are affected (usually moderately)
Half of females with a full mutation are affected (usually mildly)
Mutation in Fragile X?
Fragile X is due to unstable DNA tri-nucleotide repeat sequences
Unstable DNA tracts of tandemly-repeated 3-base-pair units increase in length (allelic expansion) and cause methylation and loss of gene function
Describe repeat classification in Fragile X
Normal gene: 5 - 44 copies of the CGG repeat
(1) Phenotypically normal
Intermediate: 45 – 54 repeats
(1) Phenotypically normal; might expand into a premutation but not into a full mutation
Pre-mutation (“carrier”): 55 – 200 repeats
(1) Can occur in females or in males
Full mutation: >200 repeats
(1) Are methylated and silenced
When can pre-mutations expand to full mutations in Fragile X?
Pre-mutations expand to full mutations only when passed on by females
Characteristics of X-linked dominant inheritance. 2 Trends. How common?
Affected males have all daughters affected and all sons normal
Affected females transmit the condition to half of their children of either gender
a) Affected females are twice as common than affected males
b) Affected males are more severe than affected females
Y-linked (Holandric) inheritance? What is associated with it?
The only trait that is consistently associated with the Y chromosome is maleness
Is it ok to refer to an affected patient as a mutant?
No
