Inheritance patterns

Question 1

Explain Mendelian modes of Inheritance

Answer 1

-Autosomal dominant= X-linked dominant
Autosomal recessive= X linked recessive and Y-linked

Key feature of Mendelian disorders: they are monogenic = one mutation
in one gene is sufficient to cause the disease; they are rare
Different from non-Mendelian disorders which are multifactorial = many
variants in many genes combine to increase risk of disorder, usually with
environmental component as well

Question 2

Explain autosomal dominant

Answer 2

● Manifest with heterozygous
genotype
● Both sexes affected
● Male to female and female to
male transmission
● Often an affected parent
● 50% risk to offspring of affected
parent
● Multiple generations affected

Question 3

Explain homozygosity and heterozygosity

Answer 3

Chromosome pair:
homologous chromosomes
with genes at the same loci

● The allele at that locus may be
the same (homozygous) or
different (heterozygous)

Question 4

Explain autosomal recessive

Answer 4

Manifest in homozygous or compound
heterozygous form
● Carriers (single heterozygous) not affected
● Both sexes affected
● Male to female and female to male
transmission
● Usually one generation affected
● 25% risk to offspring of two carriers
● May suggest consanguinity (some rare
recessive conditions much more common in consanguineous/endogamous populations)

● Trait often found in clusters of siblings
of healthy parents
● All offspring of affected individuals are
obligate carriers (they have to be
heterozygous for one mutation)
● Carrier probability =2/3 for unaffected
siblings of affected person

Question 5

Discuss homozygous or compound heterozygous?

Answer 5

Homozygous:
-2 mutations in the same gene
-2 identical mutations
-cystic fibrosis
-delF508

Compound heterozygous:
-2 mutations in the same gene
-mutations are different
-one on each parental allele
-cystic fibrosis
-delIF508 and G542X

Question 6

Explain X linked inheritance

Answer 6

Genetic females have two X
chromosomes
● Two copies of X-linked
genes
● Can be homozygous or
heterozgous
● Genetic males have one X
and a Y
● Only a single copy of X-
linked genes
● Hemizygous

Question 7

Explain how X linked inheritance can be recessive or dominant

Answer 7

X-linked inheritance can
be:
● Recessive
● Females are carriers and
unaffected
● No male to male transmission

● Dominant
● Females are affected
● Males more severely
affected/lethal

Question 8

Explain features of X-linked inheritance

Answer 8

● X-linked genes never passed from father to son.
● All daughters of affected males are obligate carriers (if recessive;
affected if dominant)
● Children of heterozygous females have a 50% chance of inheriting
mutant allele.
● Skewed X-inactivation: generally random but ~10% of females have
uneven or skewed X-inactivation.
● Manifesting carriers: some females have some symptoms in X-
linked recessive conditions e.g. cardiomyopathy in DMD.

Question 9

Explain Y linked inheritance

Answer 9

Always and only passed from fathers to sons
● Y-linked traits include hypertrichosis, Y-chromosome infertility,
Swyer syndrome

Question 10

Explain complications of Mendelian inheritance

Answer 10

● Incomplete/reduced penetrance: some people have the mutation but
do not have the disease
● Variable expressivity: variation in severity/symptoms of disorder
between individuals with the same mutation
De novo mutation rate: not all affected individuals have an affected
parent; often depends on severity of disorder; varies greatly between
conditions
● Mosaicism: mutation only present in a proportion of cells
● Anticipation: worsening of disease severity in successive disorders,
e.g. expansion disorders

Question 11

Explain incomplete/reduced penetrance

Answer 11

Percentage of individuals who have the disease genotype AND
develop symptoms of the disorder
● Age-related penetrance (many cancers, Huntington’s disease,
polycystic kidney disease)

Question 12

Explain variable expressivity

Answer 12

Variation in severity/symptoms of
disorder between individuals with same
genotype

Question 13

What mutations (variants) typically cause Mendelian disorders

Answer 13

Mutation: a change in the genomic material
● A pathogenic mutation (pathogenic variant) results in an alteration of
the function of the gene product and causes a disease phenotype
● Remember – these types of major effect mutations are rare
● What types of mutations are there?

Question 14

Explain Mutations/variants

Answer 14

Types:
● Substitutions (point mutation)
● Deletions
● Insertions
● Found in:
● Coding DNA
● Non-coding DNA (such as promoters, introns, etc)

Question 15

Explain Synonymous variants

Answer 15

-silent mutation (nucleotide change—-> without amino acid change: synonymous substitution)

Question 16

Explain the impact of missense variant

Answer 16

Hard to predict
● Physicochemical similarity between the two amino acids
● Functional role of the specific domain of the protein
● Phylogenetic conservation of original amino acid amongst
diverse species

Question 17

Explain the impact of a nonsense variant

Answer 17

Truncated protein
● No protein
● If mRNA transcript is destroyed by nonsense-mediated decay

Question 18

Explain the impact of splice variants

Answer 18

● Incorporation of intron in mature mRNA transcript and
therefore used in translation
● Exon skipping
● Truncated protein

Question 19

Explain impact of frameshift variants

Answer 19

● Completely different chain of amino acids in protein
● Often premature stop codon as well and premature
truncation

Question 20

Discuss connecting variant genotypes to inheritance patterns

Answer 20

● If having one healthy allele produces sufficient protein for the individual
to be healthy, then this would present in a family as a recessive
disease (i.e. heterozygotes are healthy carriers, homozygotes are
affected)
● But if someone with just one healthy allele is affected then this would
present in a family as a dominant disease (i.e. heterozygotes are
affected)
● Which it is, depends partly on the protein, partly on the specific impact
of the variant on the protein

Question 21

Give a brief summary

Answer 21

Mendelian modes of inheritance = autosomal dominant/recessive and
sex-linked
● Use pedigrees to draw conclusions about mode of inheritance
● Mendelian disorders are monogenic and rare
● Usually caused by rare sequence variants with large impact on protein
● Most likely to be pathogenic are nonsense, frameshift and splice site
variants
● But missense variants often pathogenic as well