3 NonMendelian Genetics

any pattern of inheritance in which traits do not segregate in accordance with Mendel’s laws

• includes Mitochondrial, Trinucleotide Repeats, Mosaicism, Genomic Imprinting (Uniparental Disomy), Multifactorial, Chromosomal

in families affected by triplet repeat disorders, the area is unstable, leading to progressive amplification of the gene sequence with each succeeding generation

• in general, TRs are present throughout the genome & are usually stable during mitosis & meiosis

• 1. Myotonic Dystrophy
• 2. Fragile X Syndrome
• 3. Huntington Disease

the tendency of certain diseases to appear at earlier ages with increased severity in successive generations

• greater number of trinucleotide repeats may be unstable, & progressive amplification of repeat number can be seen in successive generations

Myotonic Dystrophy

• affects skeletal & smooth muscle as well as the eye, heart, endocrine system, & CNS

• Myotonia = sustained muscle contractions

• is an Autosomal Dominant disease showing anticipation

1. Mild: cataracts, mild myotonia, normal life span

2. Classic: muscle weakness, wasting, myotonia, cataract, possibly shortened life span

3. Congenital: severe hypotonia at birth, often with respiratory insufficiency & early death; intellectual disability is common; *congenital form occurs from maternal transmission only

by the number of repeats

when the trinucleotide repeat size isn’t long enough to result in symptoms, but the person with the premutation is at risk of having a child who may exhibit symptoms

Fragile X Syndrome

• subtle facial feature: long face, large ears

• caused by CGG repeat expansion in FMR1 gene on X chromosome (a fragile site)

• also an example of a disease that exhibits anticipation

ONLY through FEMALE meiosis

• the meiosis of a daughter of a healthy male who carries a premutation is UNSTABLE

• trinucleotide expansion won’t occur during his meiosis but when his daughter (who has a healthy carrier male father) has an offspring, expansion can happen

• 45 repeats: normal; no associated phenotype

• 45 - 54: intermediate; no associated phenotype [child of this person is at risk for a premutation though]

• 55 - 200: premutation; at risk for Fragile X-associated Tremor/Ataxia Syndrome (FXTAS)

• > 200: FULL mutation; all males are intellectually disabled, 50% of females will have an ID & 50% will be normal

- it doesn’t matter if you have 205 or 2,000 repeats; gene is turned off in both situations (disease severity doesn’t depend on # of repeats)

• • when someone has a Full Mutation (>200 CGG repeats) their FMR1 gene is completely methylated
• - this means the gene is turned off & nonfunctional

• all other mutation forms (normal, intermediate, pre), the FMR1 gene is unmethylated, meaning the gene is turned on & working

• females have increased risk of Premature Ovarian Insufficiency (POI), menopause before age 40

• • males are at risk for FXTAS, a late-onset condition with progressive intention tremor, ataxia, cognitive decline, generalized brain atrophy
• - don’t screen for this because you might pick up on adult onset symptoms that people don’t want to be aware of

• doesn’t affect intelligence, IQ tends to be normal

presence of more than one cell line in an individual

some cells have one X active, other cells have the other X active (because of Lyonization)

usually caused by a post-zygotic mutation which affects a certain percentage of cells in an individual

• disease severity is variable because it depends on proportion of mutated cells in each tissue

1. Mosaic Down Syndrome

2. Pallister-Killian Syndrome (ALWAYS MOSAIC, would be lethal otherwise)

• accounts for 1-2% of DS cases

• may be less severe than individuals with full trisomy 21

• features depend on proportion of cells with trisomy 21 in each tissue type

• severity is impossible to predict

• • caused by mosaic tetrasomy 12p
• - 4 copies of the short arm of chromosome 12

• characterized by low muscle tone, characteristic facies, high arched palate, hypopigmentation, extra nipples, developmental delays, diaphragmatic hernias

presence of more than one cell line in the gonadal cells but not in the rest of the body

• person with the GM is unaffected by the condition

• the mutation occurred in precursor egg or sperm cell

• is important for recurrrence risk assessment for apparently de novo dominant disorders

• when at least 2 offspring have an AD disorder with no other family history

- eg. if children with an “apparently” new mutation had unaffected parents & a negative family history

• the different epigenetic modifications of maternal & paternal genetic contributions to the zygote

- eg. silencing (via methylation) of maternal or paternal genes in the zygote

• some genes are expressed preferentially in either the maternal or paternal genotype

• 1. Uniparental Disomy
• 2. Heterozygous Deletion
• 3. Mutation

• 2 sets of maternal chromosomes, one set of paternal chromosomes

• very small fetus & placenta

• 2 sets of paternal chromosomes, one set of maternal chromosomes

• normal to slightly small fetus with large cystic placenta

* SAB triploidy pregnancies tell us there’s something different about maternal & paternal chromosomes → serves as evidence of imprinting*

the presence of 2 homologous chromosomes inherited from only 1 parent

• this means 1 parent has contributed 2 copies of a chromosome & the other parent has contributed no copies

• may play a role in unexplained pregnancy loss & IUGR (intrauterine growth restriction)

non-disjunction in meiosis I occurs, resulting in a parent passing on 1 copy of each homolog



(meiosis I → hetero)

non-disjunction in meiosis II occurs, resulting in a parent passing on 2 copies of the same chromosome

• 
• (meiosis II → iso)

1. trisomic conception with postzygotic loss of a chromosome

2. fertilization of a nullisomic gamete by a disomic gamete (a gamete that's missing a copy of a chromosome joins with a gamete that has two copies)

3. compensatory duplication of the chromosome in a monosomic cell

when it involves chromosomes with imprinted genes or chromosomes containing an autosomal recessive (eg. CF) mutation (isodisomy)

if an oocyte or spermatocyte that has 2 copies of a chromosome is joined by sperm or oocyte with 1 chromosome in question, there are 3 copies of the chromosome, & the copy of the chromosome most likely to be lost is from the parent who only gave ONE

a gamete that's missing a copy of a chromosome

a previous non-disjunciton event in the parent must have occurred to produce a gamete without a chromosome

if a patient has uniparental disomy or a heterozygous deletion for an imprinted region of a chromosome

• • growth disorder with prenatal onset
• • characterized by small, triangular face with distinctive facial features
• • ~10% of cases are caused by maternal UPD of chromosome 7

• • caused by
• 1. Paternal gene deletion on chromosome 15 (Prader → P for Paternal)

2. Maternal UPD of chromosome 15

• hypotonia, intellectual disability, hyperphagia, obesity :(

• in a normal individual, the corresponding maternal gene is imprinted & the paternal gene is expressed

• with no functional paternal copy of the gene there is no expression → disorder

• • caused by:
• 1. Maternal gene deletion on chromosome 15 (Angel = feminine)

2. Paternal UPD of chromosome 15

• severe intellectual disability, movement disorder, seizures

• in a normal individual, the corresponding paternal gene is imprinted & the maternal gene is expressed

• caused by a lack of expression from genes in the critical region that are normally only expressed from the maternal allele