Genetics 2024

Chromosome Disorders

Chromosome Disorders

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

Single Gene Disorders (Mendelian)

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

Multifactorial Disorders

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

Mitochondrial Disorders

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

Pattern of DNA coiling

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

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

Gene

The basic unit of inheritance

• passed from parents to offspring

• most code for specific proteins or segments of proteins

• italicized in questions

Gene structure

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

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

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

Single Copy DNA

• 45% of the genome

• unique and dispersed throughout the genome

Dispersed Repetitive DNA

• 45% of the genome

• repetitive DNA elements that occur together in clusters

Satellite DNA

• 10% of the genome

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

Cytogenetics

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

Germline

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

• DNA varients in these cells ARE passed onto offspring

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

Single Nucleotide Variant

Change in a single gene

Copy Number Variant

change in a chromosome

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

Homozygous

two alleles are the same

Heterozygous

two alleles are different

Hemizygous

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

Locus

a physical site, or loctation, within a chromosome

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.

Phenotype

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

Determined by both genomic makeup and environmental factors

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)

De Novo

New Mutation (parents did not pass it)

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

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

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)

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

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

Penetrance

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

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

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

Pleitropy

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

• seen in genes that controll several functions

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

Locus Heterogeneity

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

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

Marfan Syndrome mode of inheritance, gene, and molecular tests

Inheritance: AD

Gene: FBN1

Tests: FBN1 sequencing

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)

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)

Achondroplasia mode of inheritance, gene, and molecular tests

Inheritance: AD, 80% De Novo

Gene: FGFR3

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

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

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

Neurofibromatosis mode of inheritance, gene, and molecular tests

Inheritance: AD

Gene: NF1

Molecular Tests: over 500 mutations reported

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

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

Holoproscencephaly mode of inheritance, gene, and molecular tests

Inheritance: AD

Gene: SHH (Sonic Hedgehog)

Molecular Tests: Sequencing

Holoprocencephaly Clinical Features

• Ventral forebrain maldevelopment

• Cleft lip palate

• Facial dysmorphism

• Developmental delay

• microcephaly

• seizures

• short stature

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

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

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

Polycystic Kidney Disease disease mechanism and key genetic concepts

Mechanism:

• unclear

Key Genetic Concepts

• Variable expressivity

• locus heterogeneity

• two-hit hypothesis

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

Inheritance: AD

Genes: MANY

Molecular tests: gene sequencing

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

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

Cystic Fibrosis mode of inheritance, gene, and molecular tests

Inheritance: AR

Gene: CFTR

Testing: various (dont need to know)

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)

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

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

Sickle Cell Disease clinical features

• vaso-occlusive events

• chonic hemolytic events

• anemia

Sickle Cell Disease Disease mechanism and key genetic concepts

Mechanism:

• LOF

Key Genetic Concepts

• heterozygote advantage

• ethnic variation in allele frequencies

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

Inheritance: AR (sometimes…)

Gene: GJB2 (Cx26), GJB6 (Cx30)

Molecular tests: multiple

Deafness Diagnotic criteria

• congenital mild-profound SNHL

  • sensorineural ___ ____

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

PKU mode of inheritance, gene, and molecular testing

Inheritance: AR

Gene: PAH

Molecular Testing: newborn screening, sequencing

PKU clinical features

• Prenatal onset

• microcephaly

• seizures

• short stature

• phenylalanine elevation in blood

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

Tay Sach Disease mode of inheritance, gene, and testing

Inheritance: AR

Gene: HEXA

Testing: Cherry Red Spot on eye exam

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

Tay Sach disease mechanism and key genetic concepts:

Disease Mechanism:

• acculmulation of GM2 gangliosides in the brain

Key genetic concepts:

• enzyme

• founder effect

X linked disorders

Genetic disorders of traits that are on the X chromosome

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

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.

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.

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

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.

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

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

Y linked

• ONLY in males, NEVER in females

• Fathers will pass to ALL their sons

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

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

Homoplasmy

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

• most often mRNA/rRNA is altered

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

Threshold Effect

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

Organs specifically targeted with mitochondrial disorders

• Brain

• Colon

• Inner ear

• Blood

• Pancreas

• Kidney

• Liver

• Eye

• Heart

• Skeletal Muscle

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

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

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

MELAS

Inheritance: Mitochondrial aka Maternal

• Heteroplasmic

Gene: Point mutations in tRNA^leu(UUR) most commonly 3243A>G

Phenotypes:

• Myopathy

• Mitochondrial Encephalomyopathy

• Lactic Acidosis

• Stroke

Deafness (NOT MENDELIAN)

Inheritance: Mitochondrial aka Maternal

• Homoplasmic

Gene: 12S rRNA gene with either

• 1555A>G

• 7445A>G

Phenotypes:

• progressive sensorineural deafness

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

MERRF

Inheritance: Mitochondrial aka Maternal

• Heteroplasmic

Gene: Point mutations in tRNA^lys most commonly 8344A>G

Phenotypes:

• Myoclonic Epilepsy with Ragged Red muscle Fibers

• myopathy

• ataxia

• sensorineural deafness

• dementia

Rett Syndrome Mode of Inheritance, genes, and tests

Inheritance: XLD

Gene: MECP2

Tests: MECP2 Sequencing

Rett Syndrome Clinical Features

• Developmental regression (esp language and hand use)

• microcephaly

• wringing hand movements

• paroxysmal laughing

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

Duchenne Muscular Dystrophy mode of inheritance, gene, and tests

Inheritance: XLR

Gene: DMD

Tests: PCR