genet 302 lec 8 & 9
What is the purpose of a pedigree chart?
To track inheritance of traits through generations using standardized symbols.
What do the basic pedigree symbols mean?
Square = male
Circle = female
Filled symbol = affected
Empty symbol = unaffected
Diagonal slash = deceased
How are multiple individuals represented?
If number known → write number inside symbol
If number unknown → write “n” inside symbol
What are the key pedigree lines?
Relationship line → connects partners
Line of descent → from parents to children
Sibship line → connects siblings
Individual line → vertical line from sibship to person
What are pedigree formatting rules?
Male on left, female on right (if possible)
Siblings listed left → right in birth order (oldest to youngest)
How are identical (monozygotic) twins represented?
Two offspring from same point with a horizontal connecting line between them.
How are non-identical (dizygotic) twins represented?
Two offspring from same point without connecting line.
What is the most probable outcome of dizygotic twins?
All combinations (two girls, two boys, one of each) are equally likely.
What is the genotype for DiGeorge syndrome?
46,XX,del(22)(q11q11)
or
46,XY,del(22)(q11q11)
Is the 22q11 deletion terminal or interstitial?
Small interstitial deletion (internal segment removed).
Common phenotypes of DiGeorge syndrome?
Learning/behavioural problems
Characteristic facial features
Congenital heart defects
Cleft palate
How is a 22q11 deletion confirmed cytogenetically?
Using FISH probes:
22q11 (test probe)
22q13 (control probe)
Missing 22q11 signal confirms deletion.
Major inheritance patterns to recognize in pedigrees?
Autosomal dominant
Autosomal recessive
X-linked dominant
X-linked recessive
Mitochondrial
What inheritance pattern is DiGeorge syndrome typically?
Autosomal dominant (though often due to new mutation).
What is pleiotropy?
When one mutation causes multiple different phenotypes.
Does DiGeorge syndrome show pleiotropy?
Yes — affects heart, face, learning ability, palate, etc.
What is penetrance?
% of individuals with a mutant genotype who show the mutant phenotype.
Difference between complete and incomplete penetrance?
Complete (100%) → all with mutation show phenotype
Incomplete (<100%) → some with mutation do not show phenotype
What is expressivity?
The severity or variation of phenotype among individuals with the same mutation.
Difference between narrow and broad expressivity?
Narrow → similar severity
Broad → wide variation in severity
How are penetrance and expressivity different?
Penetrance = whether phenotype appears
Expressivity = how severe/variable it appears
Can a trait have complete penetrance but broad expressivity?
Yes — everyone shows the phenotype, but severity varies.
Can a trait have incomplete penetrance but narrow expressivity?
Yes — only some individuals show phenotype, but those who do are similar in severity.
What must you be able to do for pedigree probability questions?
Determine inheritance pattern
Calculate recurrence risk
Identify carriers (if applicable)
Apply Mendelian ratios
What is OMIM and what is it used for?
OMIM (Online Mendelian Inheritance in Man) is a database of human genes and genetic phenotypes.
What organization approves official human gene symbols?
HGNC (HUGO Gene Nomenclature Committee).
What does the HBB gene encode?
The β-globin polypeptide (hemoglobin beta chain).
What does cytogenetic location 11p15.4 mean?
Chromosome 11
Short arm (p)
Region 1
Band 5
Sub-band 4
What does genomic coordinate 11:5,225,464–5,227,071 describe?
Exact base pair positions on chromosome 11.
What OMIM symbol indicates a phenotype entry?
a:%20%E2%80%9C%23%E2%80%9D%20before%20number%20(e.g.,%20%23603903%20=%20Sickle%20cell%20disease).
Define neutral mutation (model organisms)
No change in protein amount or activity.
Define hypomorphic mutation.
Reduced protein amount or activity (partial loss of function).
Define amorphic mutation.
Complete loss of protein function (null).
How are human variants classified clinically?
Pathogenic
Likely pathogenic
Variant of uncertain significance (VUS)
Likely benign
Benign
What does A⁺/A⁺ mean?
Homozygous wild-type.
What does A⁺/Am1 mean?
Heterozygous for one mutant allele (monoallelic mutation in humans).
What does Am1/Am1 mean?
Homozygous mutant (biallelic mutation).
What does Am1/Am2 represent?
Compound heterozygous (two different mutant alleles).
In human mutation nomenclature, what does “c.” mean?
Coding DNA position numbering (based on cDNA sequence).
What does c.26G>A mean?
At coding position 26, G was replaced by A.
What type of mutation is GC → AT?
Base pair substitution.
What does c.26del mean?
Deletion of nucleotide at coding position 26.
What does c.26_27insCC mean?
Insertion of CC between positions 26 and 27.
What are indels?
Insertions or deletions of one or more base pairs.
What does c.26delinsAA mean?
One event where original base(s) are deleted and replaced with AA.
Why is deletion-insertion considered one event?
It replaces sequence in a single mutational event (not two separate events).
What mutations can CRISPR cause?
Substitutions
Insertions
Deletions
Deletion-insertions
If codon 44 = UGC, what amino acid is encoded?
Cysteine (Cys).
What does CYS44TRP mean?
Amino acid at position 44 changed from cysteine to tryptophan.
(Type: missense mutation)
What does CYS44DEL mean?
Deletion of cysteine at amino acid 44.
What does CYS44TER mean?
Amino acid 44 changed to a stop codon.
(Type: nonsense mutation)
Which mutation is nonsense: UGC→UGG, UGC deleted, or UGC→UGA?
UGC→UGA (creates stop codon).
Difference between missense and nonsense mutations?
Missense → amino acid change
Nonsense → premature stop codon
Difference between homozygous mutant and compound heterozygous?
Homozygous → same mutation on both alleles
Compound heterozygous → two different mutations