Topic 3: patterns of inheritance

Question 1

What is a gene in terms of DNA?

Answer 1

An open reading frame (ORF) with start (ATG) and stop codons (TAG, TAA, TGA), encoding a protein with 100 or more amino acids. ORF is often preceded by a promoter.

Question 2

What is the process from DNA to protein?

Answer 2

DNA is transcribed to RNA, which travels to ribosomes that assemble amino acid sequences to form proteins.

Question 3

What are exons and introns in DNA?

Answer 3

Alternating segments where introns are spliced out via the spliceosome before RNA is translated into protein.

Question 4

What are mutations?

Answer 4

Genetic variations defined as changes in the genetic material, which can be heritable or not. Most occur spontaneously through errors in DNA replication and repair.

Question 5

What are polymorphisms?

Answer 5

Germline sequence variants with no obvious effects on phenotypes.

Question 6

What are the types of mutations?

Answer 6

Silent: same amino acid

Missense mutation: single altered amino acid affecting protein function or stability

Nonsense mutation: stop codon inserted, leading to loss of function

Insertion/deletion: disrupts the reading frame, causing a frameshift.

Question 7

What is nonsense mediated RNA decay?

Answer 7

A process that destroys RNA molecules before translation if an error is detected, preventing faulty protein production.

Question 8

What are splice site alterations and their effects?

Answer 8

Alterations that weaken or abolish the native splice site, causing exon skipping. Type I: 3’ Acceptor alterations cause skipping of the following exon. Type IV: Synonymous mutations may lead to splicing defects (e.g., cryptic splice site).

Question 9

What is the difference between loss of function and gain of function mutations?

Answer 9

Loss of function: Reduces gene activity or product production.

Gain of function: Causes normal gene product to be expressed inappropriately or acquire a new abnormal function. Example: Sickle cell disease.

Question 10

Who is the proband in a pedigree analysis?

Answer 10

The person coming in for counseling. Start with the proband and work around them, gathering relationships for at least 3 generations.

Question 11

What ancestry/history information should be collected in a pedigree analysis?

Answer 11

Origin, diseases (cancers, intellectual disabilities, autism, vision or hearing impairment, movement disorders, etc.). Some illnesses may be related, others coincidental.

Question 12

What is pattern recognition in pedigree analysis?

Answer 12

Awareness of specific syndromes and recognition of inheritance patterns to identify at-risk families.

Question 13

What example points to Fragile X syndrome in pattern recognition?

Answer 13

Child (boy) with developmental delay and autistic features, mother with premature ovarian failure, and grandfather with tremor/ataxia.

Question 14

What complexities can influence pedigrees?

Answer 14

Pleiotropy, genetic (locus) heterogeneity, allelic heterogeneity, penetrance, variable expressivity, consanguinity.

Question 15

What is autosomal dominant inheritance pattern?

Answer 15

Males and females affected equally, male-to-male transmission, disease in every generation.

Example: Marfan syndrome.

Question 16

What is reduced penetrance in autosomal dominant inheritance?

Answer 16

When a generation is skipped, it may be due to reduced penetrance where individuals have the gene but do not develop the disease.

Question 17

What is pleiotropy?

Answer 17

A single gene causing multiple effects in different organs or systems.

Example: Marfan syndrome.

Question 18

What is variable expressivity?

Answer 18

The same genetic mutation causing varying degrees of severity in different individuals.

Example: Marfan syndrome.

Question 19

What is de novo mutation?

Answer 19

A new mutation that occurs spontaneously, not inherited from parents.

25% of Marfan syndrome mutations are de novo.

Question 20

What is penetrance?

Answer 20

A yes or no phenomenon. If everyone with the genotype presents with symptoms, it is fully penetrant. Reduced penetrance occurs when not all individuals with the genotype show symptoms.

Question 21

How is penetrance expressed?

Answer 21

As a percentage – the proportion of individuals with the genotype who exhibit the expected clinical symptoms by a certain age.

Question 22

What factors are linked to penetrance?

Answer 22

Age, sex, environment, epigenetic modifiers, and modifier genes.

Question 23

what gene is affect in Marfan Syndrome?

Answer 23

FBN1

Question 24

what are mendelian inheritance patterns?

Answer 24

• autosomal domninant
• autosomal recessive
• X-linked recessive
• x-linked dominant
• y-linked inheritance

Question 25

What is the inheritance pattern of autosomal recessive disorders?

Answer 25

If both parents are carriers, there is a 25% chance of the disease, 50% chance to become a carrier (2/3 chance to be a carrier), with males and females equally affected.

Question 26

What is compound heterozygous?

Answer 26

A different pathogenic variant on each allele.

Question 27

What is homozygous in the context of genetic variants?

Answer 27

The same pathogenic variant on both alleles.

Question 28

Why do most patients with autosomal recessive disorders not have affected relatives?

Answer 28

Due to the carrier frequency. ## Footnote Example: Incidence of phenylketonuria (PKU) is 1/12,000 in North America, with a carrier frequency of 1/55.

Question 29

What is uniparental disomy?

Answer 29

Two alleles come from the same parent. Types include isodisomy (identical sister chromatids) and heterodisomy (both homologues from one parent).

Question 30

What is an example of an X-linked recessive disorder?

Answer 30

Duchenne muscular dystrophy (DMD), which is fully penetrant in boys ~4 yrs old and is considered to be lethal from a mendelian viewpoint

Question 31

What are the symptoms of Duchenne muscular dystrophy?

Answer 31

Progressive muscle weakness, difficulty climbing stairs, 'Coke' colored urine after exercise, Gower sign, and elevated creatine kinase levels.

Question 32

What is X chromosome inactivation (XCI)?

Answer 32

In each female somatic cell, one X chromosome is randomly inactivated early in development to equalize X chromosome gene expression between males and females.

Question 33

What is skewed X chromosome inactivation (XCI)?

Answer 33

When the inactivation of one X chromosome is favored over the other. The ratio is considered skewed if it is ≥65:35.

Question 34

What is the inheritance pattern of X-linked dominant disorders?

Answer 34

No direct male-to-male transmission. Males and females affected, more affected females than males, females usually less severely affected. Affected males transmit to all daughters, none to sons.

Question 35

What is y-linked inheritance?

Answer 35

Never occurs in females and occurs in all male descendants of an affected male. ## Footnote Examples include SRY gene, TDF, TSPY, and gene for excessive hair on the ear pinna.

Question 36

Front: What are multifactorial inheritance patterns affected by? .

Answer 36

Back: Affected by several genetic factors and environmental factors. Recurrence risk is higher with multiple affected family members, severe disease expression in the proband, and if the proband is of the less commonly affected gender

Question 37

Front: How can empirical recurrence risk in complex disorders be estimated?

Answer 37

Back: Using family population studies, estimation programs, and genome-wide association studies (GWASs) of single nucleotide polymorphisms (SNPs).

Question 38

What are repeat expansion disorders?

Answer 38

Disorders arising from normally existing polymorphic repeats. Expansions are unstable, causing more severe and earlier onset diseases in successive generations, with clinical anticipation and highly variable phenotypes.

Question 39

What are the three classes of repeat expansions?

Answer 39

CAG repeats: Huntington's disease. CGG repeats: FMR1-related disorders (Fragile X). CUG repeats: myotonic dystrophy

Question 40

where on the the genome does Huntington's disease occurs and how is it inherited?

Answer 40

* Occurs in the 5’ end of the Huntington disease gene * Paternal meiosis accounts for the increased risk of early-onset Huntington disease, occasionally in childhood or adolescence, when the gene is transmitted by the father * due to chromosome “slipping”

Question 41

how many CGG repeats cause fragile X, and which gene is affected?

Answer 41

the FMR1 gene on chromosome X: * >200 repeats: Fragile X * 55-200 repeats: fragile X tremor/ataxia or fragile X-associated primary ovarian insufficiency * 45-54 repeats: may expand to pre-mutation * 5-44 repeats: normal

Question 42

What is genomic imprinting?

Answer 42

The differential expression of genes depending on whether they are inherited from the mother or father, regulated by DNA methylation.

Question 43

What is Prader-Willi Syndrome (PWS) and its causes?

Answer 43

An endocrine and neurological disorder caused by loss of SNRPN gene via: paternal deletion (60-70%), maternal uniparental disomy (29-39%), or imprinting defect of ICR (imprinting control region)

Question 44

What is Angelman Syndrome (AS) and its causes?

Answer 44

A neurological disorder caused by lack of UBE3A gene via: maternal deletion (65-75%), paternal uniparental disomy (3-7%), pathogenic variant of UBE3A on maternal gene (5-11%), or imprinting defect (3%).

Question 45

where is the imprinting control region?

Answer 45

15q11.2-q13 (also called the PWS/AS region)

Question 46

what are the differentially expressed/controlled genes on the ICR (or the PWS/AS region)?

Answer 46

The 5’ end of the ICR is methylated on the maternal side. 1 UBE3A gene (maternal) and 1 SNRPN gene expressed (paternal)

Question 47

What are mitochondrial diseases and their inheritance pattern?

Answer 47

Disorders caused by pathogenic variants in mitochondrial DNA, inherited only from mothers, affecting all children with varying severity. Most susceptible organs are CNS, skeletal muscle, and heart

Question 48

What is a genetic bottleneck in mitochondrial diseases?

Answer 48

A process where a person can inherit the same number of abnormal mitochondria but have different outcomes due to random selection of mitochondria.