Genetics in Clinical Practice

Question 1

Definition of mutation

Answer 1

Pathogenic alteration in the gene affecting the structure or function of a protein

Question 2

Definition of hemizygous

Answer 2

Presence of only 1 copy of chromosome or gene (X chromosome in males)

Question 3

Definition of phenotypic heterogeneity

Answer 3

Many phenotypes arise from 1 variant

Question 4

Definition of genetic heterogeneity

Answer 4

Many variants => 1 phenotype

Question 5

Definition of variable (reduced) penetrance

Answer 5

Proportion of carriers who show within and between families

Question 6

Definition of variable expression

Answer 6

Extent of clinical manifestation can vary within and between families

Question 7

Definition of germline mosaicism

Answer 7

Parent carries a small proportion of gametes that harbour the same mutation

Question 8

Definition of compound heterozygosity

Answer 8

Different mutant recessive alleles in same gene at same locus => disease

Question 9

What are Mendel’s 2 laws of inheritance

Answer 9

Law of segregation
-everyone has 2 alleles of each characteristic but only 1 is passed on

Law of independent assortment

• genes at different loci segregate independently
• does not apply if 2 loci are closely linked

Question 10

What are the 3 main types of Mendelian disorder

Answer 10

Autosomal dominant
Autosomal recessive
Sex linked

MUTATION IS IN 1 GENE

Question 11

Describe

• phenotypic heterogeneity
• genetic heterogeneity

Answer 11

Phenotypic heterogeneity
-many phenotypes arise from 1 variant

Genetic heterogeneity
-many variants => 1 phenotype

Question 12

Describe the pedigree symbols for

• male and female
• marriage (consanguinous, many, unrelated)
• deceased
• affected with disorder/carrier
• couple with children/pregnant with unknown gender

Answer 12

🔲🔘
🔲-🔘  🔲=🔘  🔲/🔘-🔲
🔲with a line through it
⬛️  ⏺
child has P in🔷

Question 13

What are the 2 types of phenotypic expression possible in autosomal dominant conditions

Answer 13

Variable (reduced) penetrance

• proportion of carriers who show phenotypic signs of condition
• Not all individuals who inherit a dominant mutation express it

Variable expression
-extent of clinical manifestation can vary within and between families

Question 14

Describe the 2 ways in which autosomal dominant conditions can arise

How can you test for one of these methods

Answer 14

Can be inherited or de novo

Parent carries a small proportion of gametes that harbour the same mutation => inherited

Question 15

What are the risks associated with cosanguinity

Answer 15

Increased risk of recessive diseases in offspring

Probability of an unaffected child being a carrier => 2 in 3 (not limited to consanguinity)

Question 16

Describe compound heterozygosity

Answer 16

Different mutant recessive alleles in same gene at same locus => disease

Question 17

Describe how X inactivation affects the expression of X linked dominant and recessive disorders

Answer 17

Non random inactivation leading to chance expression in certain tissues

Affected females show mosaic pattern of involvement

Question 18

What is involved in the 2 branches of a genetic diagnosis

• clinical
• genetic tests

Answer 18

Clinical
-clinical dysmorphic features

Genetic tests

• chromosome analysis
• FISH
• Array CGH
• Single gene testing
• NGS
• Methylation analysis

Question 19

What is the function of a genetic diagnosis

Answer 19

Confirms diagnosis
Decreases need for other tests
Aids prognostication and recurrence risk, not predicitve
Reproductive choices/prenatal diagnosis

Question 20

What is the function of single gene testing

Answer 20

For diagnosis/confirmation of genetic disorders

• prenatal diagnosis
• preimplantation genetic diagnosis
• carrier/presymptomatic at risk relatives

Question 21

What are the 2 equations used in the Hardy Weinburg Principle

Answer 21

Allele frequencies p+q=1

Genotype frequencies p^2 + 2pq + q^2 =1

Question 22

How would you calculate the risk of expressing an autosomal dominant phenotype in a child

Answer 22

Probability of inheriting mutant allele x penetrance

Question 23

How would you calculate the risk of having a child affected by an X linked recessive disease

Answer 23

Carrier risk of mother x probability risk of passing on gene (0.5) x gender of child

Question 24

How would you calculate the risk of passing on an autosomal recessive disease

Answer 24

Carrier risk in 1 parent x carrier risk in unaffected other parent x probability of offspring being homozygous recessive