Complex Genes

Describe Trisomy

• What is it?

• Common Cause

Trisomy

• What is it?

  • Gain of single autosome

• Common Cause:

  • Non-disjunction:

    • Failure of pair of chromosomes to separate during meiosis

• STATs:

  • 40-50% of chromosomal abnormalities identified in first trimester miscarriages

Describe Trisomy 21: Down:

• 3 causes

• Characteristics/Predisposition

3 Causes:

• 95%: 21 (47 chromosomes)

• 4%: Translocation

• 1%: Mosaics

  • Mixtures of cells w/ 46/47 chromosomes 

    • Mitotic nondisjunction

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Characteristics

• Intellectual disability

• 40% = congenital heart defects 

  • (atrioventricular septal defects…)

• High risk of leukemia 

  • (20x increased risk acute lymphoblastic leukemia, 500x risk developing acute myeloid leukemia)

• Pts >40 develop Alzheimer type changes

• abnormal immune response -> serious infections

List the Symptoms associated w/ Down Syndrome

Symptoms:

• flat facial profile,

•  Oblique palpebral fissure,

•  epicanthic fold

• Altered neural maturation -> malformation in CNS and heart

Differentiate between Robertsonian vs Translocation relative to cause of Down Syndrome

Robertsonian Translation:

• Fusion of two acrocentric chromosomes

  • Long arm of chromosome 21 to another chromosome (usually 14)

• chromosome count: 45

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translocation trisomy 21:

• Chromosome Count: 46

  • Higher recurrence rate in inherited cases 

    • (mothers who have a translocation have higher risk of having a child with trisomy 21 than caused by non-disjunction)

List the symptoms of Trisomy 18

Trisomy 18: Edwards Syndrome Symptoms

• Growth + structure failure -> Heart/Limbs malformation 

  • Growth restriction

  • Clenched fists

  • Rocker-bottom feet

List the symptoms of Trisomy 13: Patau Syndrome

Trisomy 13: Patau Syndrome

• Midline patterning failure -> Brain, Face, Heart malformation 

  • Holoprosencephaly

  • polydactyly

Describe Micro deletion Syndromes

• What is it?

• How?

• Consequence?

Micro deletion Syndromes

• What is it?

  • deletions of genes with predictable breakpoints

• How?

  • Non-allelic homologous recombination

    • Recombination between non-alleles

• Consequence:

  • 50% gene dosage -> abnormal development

Describe Cri du Chat Syndrome 

• Deletion of?

• Symptoms?

Cri du Chat Syndrome 

• Deletion?

  • 5p

• Symptoms:

  • Crying = cat meowing

    • Laryngeal and brainstem development genes

  • Intellectual disability

    • Loss of CTNND2 gene critical for neuronal development

  • Others:

    • microcephaly, 

    • epicanthal folds, 

    • low set ears

    • Hypotonia

Describe 22q11.2 Deletion Syndrome

• Deletion of

• Symptoms/Syndromes associated?

22q11.2 Deletion Syndrome

• Deletion of?

  • 30-40 genes responsible for clinical heterogeneity

• Symptoms:

  • Malformations

    • face, heart, thymus and parathyroids

  • Velocardiofacial syndrome

    • outflow tracts, 

    • facial dysmorphism 

    • developmental delay

  • DiGeorge Syndrome

    • thymic hypoplasia w/ T-cell deficiency

    • parathyroid hypoplasia -> hypocalcemia

    • Due to  failure of third and fourth pharyngeal pouch development

  • High risk for psychiatric illness

Describe Williams syndrome

• Deletion of?

• Symptoms?

Williams syndrome

• Deletion of?

  • 7q; ELN gene encodes for elastin

    • 50% supravalvular aortic stenosis

Symptoms:

• Characteristic facial appearance

  • sagging cheeks and wide mouth

  • small chin, 

  • broad forehead

• Small stature

• Outgoing sociable personality

• Mild-moderate learning difficulties

1. [REVIEW] Trinucleotide -repeat

2. Pathology?

Pathology:

• Loss of function

  • ->  epigenetic silencing

• RNA Toxicity

  • Transcriptional dysregulation

• Toxic gain of function

  • misfolded protein

Describe Fragile X Syndrome

• Pathophysio

• symptoms

• Anticipation

• Expansion numbers (Normal, premutation, full)

• Describe the two syndromes linked to premutation of fragile X

Pathophysiology:

• Trinucleotide expansion of CGG in FMR1 

  • familial mental retardation 1 gene 

• FMR1 loss -> absence of translational repression -> excessive synaptic protein synthesis -> abnormal plasticity

• Lies on X Chromosome

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Symptoms:

• long face w/ large mandible

• large everted ears, 

• macro- orchidism 

• Int. disability

• Aggressive + Autism

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Anticipation:

• symptoms worsens w/ each successive generation due to increased expansion

  • Oogenesis
    

Expansion

• Normal: 29-55 CGG repeats 

• Premutation:  55-200 CGG repeats 

• > 200 CGG repeats full mutation 

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Premutation

• Ataxia Syndrome

  • Progressive intention tremors 

  • cerebellar ataxia -> Parkinson disease

• Fragile X associated Primary Ovarian Failure

  • Premature ovarian failure before 40 years old

Describe Huntington Disease

• Pathophysiology

• Symptoms

• Anticipation

• Pathophysiology

  • Auto. Dom

  • Triple repeat (CAG) in huntingtin gene (HTT) -> misfolded proteins

    • Protein aggregation

    • Impaired transcription

    • Neuronal apoptosis

• Symptom:

  • Striatum atrophy

  • progressive choreiform movement Disorders

  • psychiatric disturbance 

  • dementia

• Anticipation:

  • Repeat expansion occurs during spermatogenesis

Describe Friedreich Ataxia

• Pathophysio

• Symptoms

Pathophy:

• Auto. recessive 

• trinucleotide repeat expansion (GAA) in frataxin gene

  • Frataxin protein = in mitochondria membrane -> iron accumulation -> rxt. O2 species  -> Mit. DNA damage -> decreased ox. Phorphylation -> reduced ATP

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Symptoms:

• progressive ataxia, 

• spasticity, 

• weakness, 

• sensory neuropathy 

• Hypertrophic  Cardiomyopathy

• Unsteady Gait @ 10

  • Cardiac arrhythmias, CHF

  • Can’t walk w/in 5 yrs

• Diabetes

  • pancreatic beta-cell dysfunction

1. Which organs have High/Low Threshold for mutant mit.

2. What is Heteroplasmy

Brain/heart has low threshold

Liver/kidney has higher threshold

---

• Cells containing normal and mutant mitochondria are termed heteroplasmy

What does a mitochondrial disease pedigree look like?

Describe MELAS

• AKA?

• Symptoms?

• AKA:

  • Mitochondrial Encephalopathy w/ lactic acidosis and stroke-like episodes 

• Symptoms:

  • Initial development is normal

    • Affect children ages 2-10

  • target neurons

  • Energy disruption -> alt. Path + increased lactate levels

  • stroke-like neurological reversible deficits (hemiparesis)

  • Cognitive changes and muscle weakness

What are the symptoms of Myoclonic epilepsy with ragged red fibers

Symptoms:

• Abnormal aggregates of mitochondria in skeletal muscle

• myoclonic seizure disorder

• Ataxia 

  • due to neuronal loss

[REVIEW] Imprinting

Differentiate between Prader-Willi Syndrome and Angelman Syndrome

• Loss of which genes?

• Symptoms?

Prader-Willi Syndrome

• Loss of Genes:

  • Normally: 15q11 on maternal is imprinted

  • Abnormal: Loss on Paternal

• Symptoms:

  • intellectual disabilities, 

  • short stature

  • Hypotonia 

  • Hyperphagia

  • small hands and feet

  • hypogonadism

---

Angelman Syndrome

• Loss of genes:

  • Normally:  15q11  on paternal is imprinted

  • Abnormal: Loss of Maternal

• Symptoms:

  • intellectual disabilities, 

  • Ataxia,

  • Seizures

  • inappropriate laughter

Describe Beckwith-Wiedemann Syndrome

• Pathophysiology

• Symptoms

Beckwith-Wiedemann Syndrome

• Pathophysiology

  • imprinted gene 11: IGF2 and CDKN1C Dysregulation

• Symptoms:

  • Large Fetus (macrosomia)

  • Large tongue (macroglossia)

  • Hemi-hyperplasia (one side of the body grows more)

  • Abdominal wall defect (omphalocele)

  • Increased risk of developing embryonal tumors

    • (Wilms tumor and hepatoblastoma)

Describe Alzheimer Disease

• Early Onset

  • Genetics

  • Pathophysiology

• Late Onset

  • Pathophysiology

Early Onset: <65

• Genetics:

  • Auto. Dom

  • mutations in APP, PSEN-1,PSEN-2 ->  increase amyloid-beta production -> neurodegeneration

• Pathophysiology:

  • Amyloid precursor protein: APP

    • Mutation = production of AB42 peptides (toxic)

      • -> early + aggressive amyloid accumulation (extracellular amyloid plaques)

  • Presenilin

    • Alters cleavage of APP  -> increase AB42 production

    •  most common early onset Alzheimer disease gene

      • PSEN-1

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Late Onset: > 65 years

• Pathophysiology:

  • Predisposition based on Apolipoprotein E (component of amyloid plaques)

    • APOE e4 – increases risk (one copy=2-3x, two copies=10-14x)

      • Decrease amyloid-B clearance

      • Increase AB aggregation

      • Increase Tau phosphorylation

    • APOE e2 – protective

    • APOE e3 - neutral

Describe Fanconi Anemia

• Pathophysiology

• Symptoms

• Pathophysiology:

  • cannot repair DNA crosslinks -> increased chromosomal breakage ->  bone marrow stem cell depletion

• Symptoms:

  • Congenital Defects

    • Thumb/radial defects

    • Skin pigmentation: café au lait spots

  • Bone marrow failure 

    • Age 5-10

    • -> aplastic anemia

  • Marked cancer predisposition

    • acute myeloid leukemia, myelodysplastic syndrome, head and neck carcinoma

Describe Neurofibromatosis Type 1

• Genetics

• Pathophysio

• Symptoms

Neurofibromatosis Type 1

• Genetics:

  • Auto. Dom

  • Loss of function mutation in the NF1 gene located at 17q11

    • High penetrance but variable expression

• Pathophysio:

  •  Neurofibromin = tumor suppressor -> inhibits Ras signaling. 

    • Loss = Schwann cells  proliferation and survival 

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Symptoms:

•  Seizures

  • ~70-90%: brain lesion

•  intellectual disability

• structural brain abnormalities

  • cortical dysplasia 

  • abnormal neuronal migration

• Lisch nodules

  • Pig. nodules on iris

• cafe au lait spots

• Neurofibromas

  • benign peripheral nerve sheath tumors

Describe Neurofibromatosis Type 2

• Genetics

• Symptom

• Genetics:

  • Auto. Dom

  • Mutation in the NF2 gene located at 22q12

    • Codes for  cytoskeleton protein merlin

• Symptoms:

  • bilateral eight nerve schwannoma 

  • multiple meningiomas 

  • ependymomas of spinal cord

Describe Tuberous Sclerosis

• Genetics

• Pathophysiology

• Symptoms

• Genetics:

  • Autosomal dominant

  • TSC1 gene: hamartin

  • TSC2 gene: tuberin

• Pathophysiology

  • Loss of TSC gene -> mTOR act. -> Cellular overgrowth + hamartomas formation 

• Symptoms:

  • Hamartomas and benign neoplasm of brain

    • (subependymal giant cell astrocytoma)

  • seizure, autism and intellectual disability

Describe Von Hippel-Lindau

• Genetics

• Symptoms

• Genetics

  • Autosomal dominant

  • VHL = tumor suppressor gene

• Symptoms:

  • Hemangioblastomas (vascular lesions of CNS)

  • Cysts that involve pancreas, liver, kidney

  • Renal cell carcinoma, pheochromocytoma

Describe Multiple Endocrine Neoplasia Type 1

• Gene

• Symptoms

Describe Multiple Endocrine Neoplasia Type 2a

• Gene

• Symptoms

Multiple Endocrine Neoplasia Type 1

• GENE:

  • Auto. Dom

  • loss of function mutation in the MEN1 

    • Tumor suppressor gene

• Symptoms:

  • High risk for tumors:

    • Parathyroid hyperplasia

      • Hypercalcemia first manifestation

    • Pituitary adenoma (especially prolactinoma)

    • Pancreatic islet cell tumor (especially gastrinoma)

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Multiple Endocrine Neoplasia Type 2a

• Gene:

  • Auto. Dom

  • Gain of function in RET oncogene

• Symptoms:

  • High risk for tumors:

    • parathyroid hyperplasia,

    • adrenal pheochromocytoma

    • Thyroid medullary carcinoma

[REVIEW] Li-Fraumeni Syndrome