Non-Mendelian Inheritance

Question 1

Anticipation

Answer 1

triple repeat disorders

Question 2

Mosaicism

Answer 2

more than one cell type contained in an individual

Question 3

uniparental disomy

Answer 3

individual inherits both alleles or homologous chromosomes from one parent

Question 4

Genomic imprinting

Answer 4

expression of phenotype depends on the parent of origin

Question 5

mitochondrial

Answer 5

inheritance is from the mother

Question 6

Myotonic dystrophy shows what genetic phenomenons? What is its inheritance and triple repeat codon?

Answer 6

anticipation, penetrance, triple repeat, pleiotropic
Autosomal dominant 19q13.32
CTG repeats

Normal alleles - 5-34 CTG repeats
Premutation alleles - 35-49 CTG repeats
Full penetrance alleles - >50 CTG repeats.

skeletal and smooth muscle, eye, heart, endocrine system, CNS

Question 7

Huntington Disease shows what genetic phenomenons? What is its inheritance and triple repeat codon?

Genotype-phenotype correlation
adult-onset form = 40 to 50 CAG repeats

Juvenile-onset form = form > 60 CAG repeats.

mean age of onset is 35 to 44 years and the median survival time is 15 to 18 years after onset.

Symptoms:
-Progressive motor disability featuring chorea (uncontrolled movement)
-Mental disturbances including cognitive decline
changes in personality, and/or depression
abnormal body postures

Answer 7

incomplete and complete penetrance
autosomal dominant
CAG repeats

Normal allele. p.Gln18, –>36 or more CAG repeats.

Intermediate allele: incomplete-penetrance HD-causing alleles - 36-39

HD-allele: Full-penetrance HD-causing alleles. p.Gln18 –> 40 CAG repeats development of HD.

CAG repeats = at risk for HD

Question 8

Cancer is mosaic genetic disorder. What are the 3 main types?

Answer 8

somatic, gonosomal, and germline

Question 9

What are the different mechanisms of getting Beckwith Wiedemann syndrome which behaves as AD?
Maternal transmission = high penetrance
Paternal transmission = low penetrance

Answer 9

Paternal UPD chr 11p15: Beckwith- Weidemann syndrome (overgrowth syndrome/macrosomia)–> both chromosome from dad
OR
One chromosome from dad and one from mom but abnormal methylation of the mom’s –> Beckwith- Weidermann Syndrome

OR
Hemophilia A can occur where there is father to son

Question 10

What are the different mechanisms of getting Angelman Syndrome?

Answer 10

Normal Imprinting: dad is imprinted in this region, mom is usually expressed

• If you have a deletion in the mother’s chromosome for genes related to AS (only dad will be expressed) –> AS
• Abnormally imprint mom, dad will be expressed –> AS
• two chromosome from dad and nothing from mom –> AS
• genetic mutation in the region for AS genes–> AS

Question 11

What are the different mechanisms of getting Prader Willi syndrome?

Answer 11

Normal Imprinting: mom is imprinted in this region, dad is usually expressed

• If you have a deletion in the father’s chromosome for genes related to Prader-willi syndrome (only mom will be expressed) –> PWS
• Abnormally imprint dad, mom will be expressed –> PWS
• two chromosome from mom and nothing from dad –> PWS

Question 12

can only be transmitted through mothers only

Affected males do not pass on the genes

Often non-homogeneity to phenotype because of heteroplasmy

female has a mitochondrial trait, all of her offspring inherit it

only 1 allele is present in each individual, so dominance is not an issue

Answer 12

Mitochondrial inheritance

Question 13

What disorder display allelic heterogeneity?

same gene: different phenotypes

Answer 13

Dystrophin gene – outcome of mutation effects
Duchenne Muscular Dystrophy – frameshifts, null allele
Becker Muscular Dystrophy – non-frameshifts , abnormal but present protein
X-linked Dilated Cardiomyopathy

Paired Box 3 transcription factor (Pax3) gene - Loss-of-function and gain-of-  function mutations mutations
Waardenburg syndrome (LOF)
Alveolar rhabdosarcoma (GOF) –chromosomal translocation creates a
novel chimeric gene, fusing PAX3- FKHR fusion.

Androgen receptor gene – LOS and GOF
Testicular feminization (AIS) - inactivation , null allele
Spinal and bulbar muscular atrophy (Kennedy disease) – Triplet Repeat
Expansion (CAG) leads to >38 Gln tract

Question 14

The mitochondria has its own genome.

Variable expressivity in mitochondrial inheritance is due to what?

Answer 14

heteroplasmy

Question 15

The mitochondria has its own genome.

Variable expressivity in mitochondrial inheritance is due to what?

Answer 15

heteroplasmy

levels of heteroplasmy increases with aging

Leber’s hereditary optic atrophy
Mitochondrial encephalopathy, lactic acidosis, and
stroke like syndrome (MELAS)
Maternal Inherited Diabetes and Deafness (MIDD)

Question 16

Polygenic inheritance involves what and consist of what 3 types?

Answer 16

This involves the inheritance and expression of a phenotype being determined by many genes at different loci, with each gene exerting a small additive effect.

Polymorphic – combinations of polygenic alleles

Continuous (quantitative) – traits that
exhibit a range of values

Discrete (qualitative) – traits that are converted to a dichotomous or bimodal phenotypic distribution

Question 17

Several human characteristics show a continuous distribution in the general population. Give examples.

Answer 17

Height
Intelligence
Blood Pressure
Skin Color

Question 18

What’s the recurrence risk of hypertension that has 3 genes involved that all act dominantly? What about if they all acted recessively?

Answer 18

Loci X, Y, and Z

0.1 x 0.1 x 0.1= 0.001 or 1/1000 frequency will have genotype x-/y-/z-.

Question 19

Multifactorial diseases that show familial clustering, have no recognized Mendelian pattern of inheritance.

They are determined by the additive effects of many genes at different loci together with the effect of environmental factors.

Answer 19

These conditions show familial incidence in close relatives of affected ~ 2-4%, instead of mutations rate seen in Mendelian (25-50%).

Question 20

What is the empiric risk in familial aggregation?

Parents who have several affected children have higher risk alleles than parents with only one affected child.

Answer 20

Relative Risk - The rule of Thumb (1st degree)

1. one affected → chance of a 2nd ~ 3-4%
2. two affected→ Chance for 3rd ~ 5-8%
3. three affected → chance of 4th ~ 9-12%

recurrence risk = √ (population incidence)

Question 21

The recurrence risk is greatest among close relatives of the index case and decreases rapidly in more distant relatives. Give an example

Answer 21

spina bifida the risks to first -, second-, and third - degree relatives approximately 4%, 1% and < 0.5%, respectively.

Question 22

If the condition is more common in individuals of one particular sex, recurrence risk varies according to sex of index case. Give an example

Answer 22

Pyloric stenosis shows a male to female ratio of 5 to 1. Offspring (relatives) of an affected girl has higher susceptibility

Offspring of male proband - sons risk 6.4% and
daughters risk 2.5% .

Question 23

Incidence increases among relatives of the most severely affected patients. Give an example.

Answer 23

index patient has bilateral cleft lip and palate, risk to future sibling is 6 %.
index patient has unilateral cleft lip, risk to future
sibling is 2 %.

Question 24

Recurrence risk increases with increasing number of

previously affected children. Give an example.

Answer 24

neural tube defect, recurrence risk is about 2 - 4%.
2 children with NTD, recurrence risk rises to 10%.

The rule of Thumb

1. one affected → chance of a second ~ 3-4%
2. two affected→ Chance for third ~ 5-8%
3. three affected → chance of fourth ~9-12%

Question 25

Heritability (H) is the estimate of the contribution that the genetic component makes to a trait and ranges from 0 → 1.

Answer 25

A childs expected phenotype will be displaced from the parental mid- parental value toward the population mean One approach to calculating heritability which to avoid the confounding of genotype with shared environment between parents and child: compare the phenotypic concordance of MZ versus DZ twins. Allows isolate the contribution of that half shared genome to phenotypic concordance.

Question 26

Narrow sense heritability, h2 = Va /Vp, is variance due to additive genetic factors. What does it determine?

Answer 26

h2 – determines: (1) the resemblance of offspring to their parents (2) the population’ s evolutionary response to selection (3) Number between 1 and 0 h2 = 1 all variation is due to genetic factors ~ no variation h2 = 0 all variation is due to environmental factors

Question 27

Heritability applies to individuals and number is fixed. True or false?

Answer 27

False. Only applies to variations within a GROUP The number is NOT fixed. Differences among groups will result in different estimates of heritability

Question 28

These are examples of heritability estimates. ``` Schizophrenia 85% Asthma 80% Pyloric stenosis 75% Stress perception 44% Alcohol misuse 33% ``` Which is the most contributable to genetic factor and which is the most contributable to environmental factors?

Answer 28

most contributable to genetic factor: Schizophrenia most contributable to environmental factors: alcohol misuse

Question 29

Diabetes type 1 (IDDM) | In Type 2 diabetes (NIDDM) there is polygenic heterogeneity, locus heterogeneity. There are monogenic diabetes type 1.

Answer 29

90% IDDM patients are homozygous for DQB1 allelles p.Asp 57X MHC is a major genetic factor for diabetes type 1, HLA-DR3 or HLA-DR4 at the HLA class II loci MHC assoc. in Type I – MZ twin concordance is ~ 40% vs. 5% in DZ λs - 7%/0.2% = ~ 35

Question 30

Beckwith-Wiedemann Syndrome: | there has to be two different testing for BWS

Answer 30

Principles Imprinting, UPD, multiple pathogenic mechanisms Sporadic but may be Aut. Dom. imbalance in expression of genes on chr11 p15 KCNQOT1 and IGF2 normally imprinted (silenced) on maternal and expressed from paternal allele H19 and CDKN1C norm only expressed from maternal allele only Majority of BWS – Imprinting (Loss of expression) of Mat. CDKN1C allele, 60% hypomethylation of Mat. KCNQOT1

Question 31

Spina Bifida and anancephaly

Answer 31

Causes of Folate Deficiency: - Diet - Disease (i.e infections: rubella, CMV, Syphillis, etc.) - Genetics MTHFR, DHFR genes - Anemia - Geographical, social , and seasonal factors associated with risk Clinical variability : ranges from spina bifida occulta (defect in bony arch only) to spina bifida aperta (protrusion of meniges) or meningomyelocele (protrusion of neural elements) Single greatest factor for NTD is Maternal folic acid deficiency

Question 32

What are some epigenetic changes?

Answer 32

Epigenetic modification - Changes that are heritable but do not depend on changes in DNA sequence - DNA methylation/ DNA phosphorylation The pattern of DNA methylation of the cytosine residue of CpG dinucleotides is transmitted to daughter cells via replication Methylation controls transcription, x-inactivation (Lyonization), DNA repair

Question 33

What are the mechanisms to lack of penetrance and variable expressivity?

Answer 33

- lincRNA (long intergenic non-coding RNA) - RNA mediated gene silencing - SiRNA (small interfering RNA) – long dsRNA species that degrade mRNA. - miRNA (micro RNA) – small dsRNA with hairpin loops structures interfere with RNA translation. - Molecular medicine: investigated as a form of Gene Therapy and Pharmocological treatment

Question 34

Lyonization is due to a gene called?

Answer 34

- Xist which is a long intervening noncoding RNAs. - When Xist gets made and binds to all of the -X-chromosome promoters that will get turned off. It acts in cis.

Question 35

What are some diseases associated with aberrant methylation?

Answer 35

Disease Associated with aberrant methylation: Tumors – p16 tumor suppressor gene is abrogated by methylation of promoter Function of the CDKN2A tumor suppressor gene is abrogated by methylation Fragile-X syndrome, the FMR1 gene is silenced by methylation, triggered by expansion of a trinucleotide repeat Prader Willi/Angelman Syndrome – Abarrant imprinting disrupts dosage compensation Mosacism – normal X-chromosome dosage compensation

Question 36

Familial hypercholesterol shows what heterogeneity?

Answer 36

locus heterogeneity

Question 37

Duchenne's muscular dystrophy, cystic fibrosis, beta-thalessmia, PKU, achondroplasia, albinism, and alkaptonuria are what type of heterogeneity?

Answer 37

allelic heterogeneity

Question 38

Structural Maintenance of Chromosomes (SMC) family of genes and proteins they don't allow the chromatin going through meiosis or mitosis to fold well if you have mutation in these chromatids it can lead to improper kinetochore attachment and pulling away to the poles resulting in nondisjunction.

Answer 38

This could be a mechanism leading to uniparental disomy or aneuploidies. Cornelia De Lange Syndrome: Dysmorphic Child Incidence 1/10,000-1/50,000 live births Genetic Lesion: NIPBL, RAD21, or SMC3 or HDAC8 or SMC1A Pathogenic mechanism: Disruption in gene regulation during critical stages of early development.

Question 39

Empiric risk of type 1 diabetes, first degree relatives with the HLA DR3 and DR4, their risk for IDDM is 20%. What about first degree relatives with HLA DR3 or HLA DR4? What about with HLA-DR2 with DQB1*0502 or HLA-DR2 with DQB1*0602?

Answer 39

first degree relatives with HLA DR3 or HLA DR4 ---> 5% first degree relatives with HLA-DR2 with DQB1*0502 ---> 5% first degree relatives with HLA-DR2 with DQB1*0602 --> <0.2%