Genetics 2024

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528 Terms

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Chromosome Disorders

A type of genetic disease in which entire chromosomes (or large segments of them) are missing, duplicated, or are otherwise altered

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Single Gene Disorders (Mendelian)

a type of genetic disease in which a single gene is altered

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Multifactorial Disorders

a type of genetic disease in which single genes are altered, but the disease is also influenced by environmental factors (ex, DM)

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Mitochondrial Disorders

a small number of genetic dieases which are caused by alterations in the small cytoplasmic mitochondrial chromosome.

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Pattern of DNA coiling

DNA + Histone > Nucleosome > Solenoids > Chromatin Loops > Chromatid x 2 > Chromosome

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Transciption Factors

  • Required for the transcription of DNA to mRNA

  • Regulated by enhancer and silencer sequences, which can be located thousands of bases away from the transcribed gene

  • Contain DNA binding motifs

    • Helix-turn-Helix

    • Helix-loop-helix

    • Zinc finger

    • Leucine zipper

    • Beta sheets

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Gene

The basic unit of inheritance

  • passed from parents to offspring

  • most code for specific proteins or segments of proteins

  • italicized in questions

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Gene structure

Note that TATA box (promoter) and AATAAA are counted as introns

<p>Note that TATA box (promoter) and AATAAA are counted as introns </p>
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Chromosome

Threadlike structures made of protein and a single molecule of DNA that serve to carry the genomic information from cell to cell

  • 22 pairs that are numbered

  • 1 pair of sex

  • For a total of 46

  • in each pair - one is from mom and one is from dad

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Splicing

  • The process of removing introns from pre-mRNA and joining exons together to form a mature mRNA molecule.

  • exons contain the mRNA that specifies proteins

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Single Copy DNA

  • 45% of the genome

  • unique and dispersed throughout the genome

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Dispersed Repetitive DNA

  • 45% of the genome

  • repetitive DNA elements that occur together in clusters

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Satellite DNA

  • 10% of the genome

  • Dispersed repeats that are like one another but do not cluster together

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Cytogenetics

a branch of biology focused on the study of chromosomes and their inheritance

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Germline

referrs to the sex cells that pass on their genomes to offspring

  • DNA varients in these cells ARE passed onto offspring

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Somatic Cells

diploid cells that contain two sets of chromosomes

  • DNA variants in these cells can affect the individual, but they CANNOT be passed on to their offspring

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Single Nucleotide Variant

Change in a single gene

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Copy Number Variant

change in a chromosome

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Allele

one of two or more versions of a DNA sequence at a given genomic location

  • one is given from each parent

A capital letter indicates wild type

A lowercase letter indicates a variant

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Homozygous

two alleles are the same

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Heterozygous

two alleles are different

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Hemizygous

only one allele available (eg, varient is in X chromosome in males)

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Locus

a physical site, or loctation, within a chromosome

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Genotype

a scoring of a type of vairient present at a given location (BB, Bb, bb). These can contribute to an individual’s obserable traits.

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Phenotype

Refers to an individual’s obserable traits, such as height, eye color, and blood type.

Determined by both genomic makeup and environmental factors

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Autosomal Dominant

pattern of mendelian genetics

  • gene is on one of the numbered chomosomes

  • a single copy of this variable gene is enough to cause this disorder

  • A child of the affected individual has a 50% chance of being affected

    • rare for an individual to be homozygous for this inheritance type (it would be lethal)

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De Novo

New Mutation (parents did not pass it)

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Autosomal Dominant Pedigree

  • Equal distribution between genders

  • vertial pedigree (one parent must have the condition)

  • multiple generations affected

  • Each affected person (normally) has one affected parent

    • if not, due to something like reduced penetrance

<ul><li><p>Equal distribution between genders</p></li><li><p>vertial pedigree (one parent must have the condition)</p></li><li><p>multiple generations affected</p></li><li><p>Each affected person (normally) has one affected parent</p><ul><li><p>if not, due to something like reduced penetrance</p></li></ul></li></ul><p></p>
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Autosomal Recessive

pattern of mendelian genetics

  • gene is located on one of the numbered chomosomes

  • two copies of the variable gene are needed to cause the disorder

  • A child a of the affected individual has a 25% chance of being affected via inheritance of two variant alleles

    • The parents must be carriers of the vatiant allele - will NOT occur de novo

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Compound heterozygous

When an individual with an autosomal recessive condition inherited alleles from their mother and father that have different mutations. (however, both are still mutated)

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Autosomal Recessive Pedigree

  • Horizontal pedigree pattern, with one or more siblings affected (however, often only one)

  • Skips generations

  • Males and Females equally affected

  • can be the product of consanguineous relations

<ul><li><p>Horizontal pedigree pattern, with one or more siblings affected (however, often only one)</p></li><li><p>Skips generations</p></li><li><p>Males and Females equally affected</p></li><li><p>can be the product of <strong>consanguineous relations</strong></p></li></ul>
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Consanguinity

having a highly shared genetic background due to being in the same family (incest is really only used if there is a close relationship, like with a parent, child, sibling, or grandchild)

  • increases the chances of autosomal recessive conditions

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Penetrance

The percent of individuals who have a particiular genome who also present with the associated phenotype.

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Reduced penetrance

Occurs when individuals with a disease-causing gene variant do not exhibit the associated traits or symptoms.

  • in this image, “A” has the genotype for the condition, but does not display the expected phenotype

<p>Occurs when individuals with a disease-causing gene variant do not exhibit the associated traits or symptoms.</p><ul><li><p>in this image, “A” has the genotype for the condition, but does not display the expected phenotype</p></li></ul>
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Variable Expressivity

When the phenotypes among individuals with the same genotype show variable features.

  • predigrees will typically have various shades to represent this phenomena

    • ex, Marfan syndrome, Neurofibromatosis Type I

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Pleitropy

a single-gene disease with many symptoms that affect many body parts/symptoms

  • seen in genes that controll several functions

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Allelic Heterogeneity

Several pathogenic variants at a given loci result in the same phenotype

ex, 1000 different mutations in the CFTR gene cause Cystic Fibrosis

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Locus Heterogeneity

When variants of genes at different loci (locations) have similar and even indinstinguishable disorders

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Clinical Heterogeneity

When different variants in the same gene may produce different phenotypes (eg, different disorders)

ex, Charcot-Marie Tooth and Hutchinson-Gilford Progeria are caused by different variations on the same gene, LMNA

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Marfan Syndrome mode of inheritance, gene, and molecular tests

Inheritance: AD

Gene: FBN1

Tests: FBN1 sequencing

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Marfan Syndrome Clinical Features

  • CV:

    • dilation or dissection of the ascending aorta

  • Skeletal

    • pectus carinatum or excavatum

    • reduced upper/lower segment or arm span

    • scoliosis

    • pes planus

  • Eye

    • extopia lentis (the dislocation or displacement of the natural crystalline lens)

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Marfan Syndrome Disease mechanism and key genetic concepts

Disease Mechanism:

  • Dominant negative effect of mutant forms of fibrillin

Key Genetic Concepts:

  • Dominant Negative Mutations (variants)

  • Variable expressivity

  • Allelic Heterogeneity (eg, several different mutations to the gene can cause this diease)

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Achondroplasia mode of inheritance, gene, and molecular tests

Inheritance: AD, 80% De Novo

Gene: FGFR3

Molecular Tests: 98% FGFR3 G1138A; ~1% FGFR3 G1138C

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Achondroplasia Clinical Features

  • Short stature

  • rhizomelic shortening (shortening of limbs)

  • trident hand (digits are all of equal length)

  • frontal bossing (prominent forehead)

  • midface hypoplasia

  • macrocephaly

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Achondroplasia disease mechanism and key genetic concepts

Diease mechanism:

  • constitutive activation of FGFR (Fibroblast growth factor receptors)

  • GOF mutation - activation of negative growth controls

Key Genetic Concepts:

  • Gain of Function mutations

  • Advanced paternal age influences development of condition

  • De Novo mutation

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Neurofibromatosis mode of inheritance, gene, and molecular tests

Inheritance: AD

Gene: NF1

Molecular Tests: over 500 mutations reported

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Neurofibromatosis clinical features

  • Cafe au lait spots (flattened areas of dark skin)

  • 2 or more neurofibromas

  • axillary or inguinal freckling

  • optic glioma

    • 2 or more lisch nodules

  • 1st degree realtive with the same condition

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Neurofibramatosis Disease Mechanism and Key Genetic Concepts

Disease Mechanism

  • Impairs RAS GTPase mediated cellular proliferation and tumor supression

  • LOF mutation

Key Genetic Concepts

  • Variable expressivity

  • Extreme pleiotropy

  • tumor supressor gene

  • Loss of function mutations

  • Allelic heterogeneity

  • De novo variants

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Holoproscencephaly mode of inheritance, gene, and molecular tests

Inheritance: AD

Gene: SHH (Sonic Hedgehog)

Molecular Tests: Sequencing

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Holoprocencephaly Clinical Features

  • Ventral forebrain maldevelopment

  • Cleft lip palate

  • Facial dysmorphism

  • Developmental delay

  • microcephaly

  • seizures

  • short stature

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Holoprocencephaly Disease Mechanism and Key Genetic Concepts

Disease mechanism

  • gene is involved in establishing fate of cells in development

  • LOF mechanism

Key Genetic Concepts

  • Developmental Regulatory gene

  • Allelic Heterogeneity

  • Position effect variants

  • Reduced penetrance

  • variable expressivity

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Polycystic Kidney Disease mode of inheritance, gene, and genetic tests

Inheritance:

  • AD for PKD1 and PKD2

  • AR for PKD3

Genes:

  • PKD1

  • PKD2

  • PKHD1

Tests: US, MRI

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Polycystic Kidney Diease Clinical Features

  • Enlargement of both kidneys

  • renal cysts

  • hematuria

  • polyuria

  • flank pain

  • renal stones

  • urinary infection

  • cysts in thr liver, pancreas, and intestine

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Polycystic Kidney Disease disease mechanism and key genetic concepts

Mechanism:

  • unclear

Key Genetic Concepts

  • Variable expressivity

  • locus heterogeneity

  • two-hit hypothesis

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Charcot Marie Tooth Disease mode of inheritance, genes, and molecular tests

Inheritance: AD

Genes: MANY

Molecular tests: gene sequencing

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Charcot Marie Tooth Disease clinical features

  • Slow, progressive weakness and atrophy of distal mucles in the feet/hands beginning in the 1-3rd decade of life

  • hearing loss

  • pes cavus foot deformity

  • hip dysplasia

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Charcot Marie Tooth Disease disease mechanism and key genetic concepts

Mechanism:

  • abnormal peripheral myelination

  • GOF (for PMP22)

Key Genetic Concepts:

  • GOF for PPM2

  • Dominant negative mutations

  • Locus Heterogeneity

  • Gene dosage

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Cystic Fibrosis mode of inheritance, gene, and molecular tests

Inheritance: AR

Gene: CFTR

Testing: various (dont need to know)

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Cystic Fibrosis clinical features

  • Chronic Airway infection

  • chronic sinusitis

  • meconium ileus

  • malabsorption due to pancreatic insufficiency

  • male infertility (azoospermia)

  • progression to end stage lung disease

  • congenital bilateral absence of the vas deferens (CBAVD)

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Cystic Fibrosis Disease mechanism and key genetic concepts

Disease Mechanism:

  • CFTR forms a cell membrance Cl- channel - w/o it massive issues occur

Key genetic Concepts:

  • Ethnic variation in mutation frequency

  • variable expressivity

  • allelic heterogeneity

  • tissue specific expression of mutations

  • genetic modifiers

  • environmental modifiers

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Sickle Cell Diease mode of inheritance, gene, and molecular tests

Inheritance: AR

Gene: HBB

Molecular Tests: E7V pathogenic variant, also commonly referred to as E6V

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Sickle Cell Disease clinical features

  • vaso-occlusive events

  • chonic hemolytic events

  • anemia

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Sickle Cell Disease Disease mechanism and key genetic concepts

Mechanism:

  • LOF

Key Genetic Concepts

  • heterozygote advantage

  • ethnic variation in allele frequencies

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Deafness mode of inheritance, gene(s), and molecular tests

Inheritance: AR (sometimes…)

Gene: GJB2 (Cx26), GJB6 (Cx30)

Molecular tests: multiple

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Deafness Diagnotic criteria

  • congenital mild-profound SNHL

    • sensorineural ___ ____

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Deafness disease mechanism and key genetic concepts

Mechanism:

  • loss of Gap Junctions prevents recycling of toxic ions and metabolites away from hair cells leading to their death

Key Genetic Concepts:

  • Allelic Heterogeneity with both AD and AR patterns

  • Locus heterogeneity

  • Newborn screening

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PKU mode of inheritance, gene, and molecular testing

Inheritance: AR

Gene: PAH

Molecular Testing: newborn screening, sequencing

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PKU clinical features

  • Prenatal onset

  • microcephaly

  • seizures

  • short stature

  • phenylalanine elevation in blood

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PKU disease mechanism and key genetic concepts

Disease mechanism:

  • LOF in the enzyme that catalyzes the hydroxylation of phenylalanine to tyrosine

Key genetic concepts:

  • enzyme

  • allelic heterogeneity

  • pleiotropy

  • mutations

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Tay Sach Disease mode of inheritance, gene, and testing

Inheritance: AR

Gene: HEXA

Testing: Cherry Red Spot on eye exam

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Tay Sach Disease clinical features

  • infantile weakness starts at 6 months

  • exaggerated startle response

  • seizures and vision loss by the end of first year

  • neurodegeneration —>

    • deafness

    • inability to swallow

    • weakening of muscles

    • eventual paralysis

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Tay Sach disease mechanism and key genetic concepts:

Disease Mechanism:

  • acculmulation of GM2 gangliosides in the brain

Key genetic concepts:

  • enzyme

  • founder effect

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X linked disorders

Genetic disorders of traits that are on the X chromosome

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Why do men have more of a disposition to X-linked disorders

Men only have one X chromosome, so if the one they inherit has the mutated trait, they will display the disease

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X inactivation

The natural process where one of a females X chromosomes is condensed into a barr body in their cells because it is not needed.

  • This process is random - which accounts for why females who only have one X chromosome with a mutant allele may have milder (or no) symptoms.

  • There are some genes that remain active in both X chromosomes (approx 15% expressed in both)

NO genes on the single X chromosome of males are turned off.

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X inactivation Center

A region on the X chromosome that plays a crucial role in the X inactivation process, ensuring that one of the two X chromosomes in females is inactivated.

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XIST

A gene located on the X chromosome that is crucial for initiating X inactivation by coating the inactive X chromosome. Expressed only on the inactivated X chromosome

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Skewed X-inactivation

This process of barr body production is normally split 50-50 between the X chromosomes inherited from the mother and father in a womans cells

When this process is not even, more of a working gene can be expressed, or more of the mutant gene can be expressed.

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X linked dominant

  • Both males and females affected, but affected females are greater in number

    • in males this Mode of inheritance is normally lethal

  • Affected males can only transmit to their daughters, and ALL their daughters will be affected

    • they WILL NEVER pass to their sons

  • Ex, Rett Syndrome, Ornithine Transcrabamylase deficiency, Fabry disease

<ul><li><p>Both males and females affected, but affected females are <u>greater in number</u></p><ul><li><p>in males this Mode of inheritance is normally lethal</p></li></ul></li><li><p>Affected males can <u>only transmit to their daughters, and ALL their daughters will be affected</u></p><ul><li><p>they WILL NEVER pass to their sons</p></li></ul></li><li><p> Ex, Rett Syndrome, Ornithine Transcrabamylase deficiency, Fabry disease</p></li></ul>
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X linked Recessive Pedigree

  • “Knights move” pedigree pattern

  • Affects mainly Males, with females most often being carriers that pass to their sons.

  • NEVER transmitted father to son

  • Affected males may have affected maternal uncles

  • Frequently De Novo

  • Ex, Duchene Muscular Dystrophy, Hemophilia A, G6Pase Dehydrogenase deficiency, Red/Green color blindness

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Y linked

  • ONLY in males, NEVER in females

  • Fathers will pass to ALL their sons

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Mitochondrial Disorders

  • Inheritance of this type will only be passed through a child’s mother

  • Mutations of this inheritance type often result in

    • Loss of energy production

    • excessive production of ROS

    • Abnormal integration of apoptotic signaling

    • Abnormal retrograde signaling

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Mitochondrial Inheritance

  • Vertical pedigree patten

  • children of affected men are never affected

  • all children of an affected woman MAY be affected - but diseases of this inheritance are overall variable

  • Heteroplasmy, which induces variable expressivity, and threshold effect can be reasons why individuals are not being affected in the pedigree

<ul><li><p>Vertical pedigree patten</p></li><li><p>children of affected men are never affected</p></li><li><p>all children of an affected woman MAY be affected - but diseases of this inheritance are overall variable</p></li><li><p><span>Heteroplasmy, which induces variable expressivity, and threshold effect can be reasons why individuals are not being affected in the pedigree</span></p></li></ul>
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Homoplasmy

Mitochondrial DNA within a cell contains ALL the same DNA - either all wild type or mutant

  • most often mRNA/rRNA is altered

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Heteroplasmy

Mitochondrial DNA is mixed - a cell has both wild type and mutant DNA

  • most often tRNA is altered

_________ + AGE = variable expression in mitochondrial disorders

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Threshold Effect

The point where the number of mutant variants of mitochondrial DNA is enough to show a phenotype

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Organs specifically targeted with mitochondrial disorders

  • Brain

  • Colon

  • Inner ear

  • Blood

  • Pancreas

  • Kidney

  • Liver

  • Eye

  • Heart

  • Skeletal Muscle

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Leber Hereditary Optic Neuropathy (LHON)

Inheritance: Mitochondrial aka Maternal

  • Largely homoplasmic

Gene: 1178A>G in the ND4 subunit of Complex I ETC

Phenotypes:

  • BIlater central vision loss

    • optic nerve atrophy

  • some recovery of vision depending on mutation

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Leigh Syndrome

Inheritance: Mitochondrial aka Maternal

  • Heteroplasmic - variable expression

Gene: Point mutations in ATPase subunit 6 gene

Phenotypes:

  • early onset progressive neurodegeneration w/ hypotonia

  • developmental delay

  • optic atrophy

  • respiratory abnormalities

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POLG

  • Inhertiance: AR

  • name is the same as the gene that encodes mitchondrial DNA polymerase gamma

  • Causes: mtDNA depletion syndrome-4A(MTDPS4A), which manifests as Alpers Syndrome

  • Phenotype → Triad seen in young children:

    • psychomotor retatdation

    • intactable epilepsy

    • liver failure

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MELAS

Inheritance: Mitochondrial aka Maternal

  • Heteroplasmic

Gene: Point mutations in tRNAleu(UUR) most commonly 3243A>G

Phenotypes:

  • Myopathy

  • Mitochondrial Encephalomyopathy

  • Lactic Acidosis

  • Stroke

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Deafness (NOT MENDELIAN)

Inheritance: Mitochondrial aka Maternal

  • Homoplasmic

Gene: 12S rRNA gene with either

  • 1555A>G

  • 7445A>G

Phenotypes:

  • progressive sensorineural deafness

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Kearns-Sayre Syndrome

Inheritance: Mitochondrial aka Maternal

  • Heteroplamic

Gene: the ~5kb large deletion (dont need to know really)

Phenotypes:

  • Triad of:

    • onset before age 20

    • pigmentary retinopathy

    • PEO → Progressive External Ophthalmoplegia

  • progressive myopathy

  • cardiomyopathy

  • heart block

  • ataxia

  • DM

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MERRF

Inheritance: Mitochondrial aka Maternal

  • Heteroplasmic

Gene: Point mutations in tRNAlys most commonly 8344A>G

Phenotypes:

  • Myoclonic Epilepsy with Ragged Red muscle Fibers

  • myopathy

  • ataxia

  • sensorineural deafness

  • dementia

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Rett Syndrome Mode of Inheritance, genes, and tests

Inheritance: XLD

Gene: MECP2

Tests: MECP2 Sequencing

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Rett Syndrome Clinical Features

  • Developmental regression (esp language and hand use)

  • microcephaly

  • wringing hand movements

  • paroxysmal laughing

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Rett Syndrome Disease mechanism and key genetic concepts

Mechanism:

  • Decreased function or LOF MECP2, which normally binds methylated CpG islands

Key genetic concepts:

  • LOF mutation

  • Variable expressivity

  • Sex-dependent phenotype

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Duchenne Muscular Dystrophy mode of inheritance, gene, and tests

Inheritance: XLR

Gene: DMD

Tests: PCR

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Duchenne Muscular Dystrophy clinical features

  • present before age 5

  • progressive symmetrical muscle weakness

  • calf hypertrophy

  • dilated cardiomyopathy (DCM)

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Duchenne Muscular Dystrophy disease mechanism and key genetic concepts

Mechanism:

  • Mutation that leads to lack of Dystropin expression

    • Dystrophin binds actin and other membrane proteins

Key Genetic Concepts:

  • High frequency of new mutations

  • allelic heterogeneity

  • manifesting carriers

  • variable expressivity