Biochemistry - Genetics

• Both alleles contribute to the phenotype of the heterozygote
• blood groups A, B, AB

• Phenotype varies among individuals with same genotype
• 2 patients with neurofibromatosis type 1 (NF1) may have varying disease severity

• Not all individuals with a mutant genotype show the mutant phenotype
• BRCA1 gene mutations do not always result in breast or ovarian cancer

• One gene contributes to multiple phenotypic effect
• PKU causes many seemingly unrelated symptoms,  ranging from mental retardation to hair/skin changes

• Differences in gene expression depending on whether the mutation is of maternal or paternal origin
• Prader-Willi and Angelman's syndromes

• Increased severity or earlier onset of disease in succeeding generations
• Huntington's disease
• Trinucleotide repeat disorders

• If a patient inherits or develops a mutation in a tumor suppressor gene , the complementary allele must be deleted/mutated before cancer develops
• NOT true of oncogenes
• Retinoblastoma and the "two-hit hypothesis"

• Exerts a dominant effect
• A heterozygote produces a nonfunctional altered protein that also prevents the normal gene product from functioning
• Mutation of a transcription factor in its allosteric site
• Nonfunctioning mutant can still bind DNA, preventing wild-type transcription factor from binding

• Tendency for certain alleles at 2 linked loci to occur together more often than expected by chance
• Measured in a population, NOT in a family, and often varies in different populations

• Occurs when cells in the body differ in genetic makeup due to postfertilization loss or change of genetic information during mitosis
• Can be a germ-line mosaic (gonadal mosaicism), which may produce disease that is not carried by parent's somatic cells
• Mutation in the embryonic precursor of the bone marrow stem cell → a hematologic mosaic individual
• A chimeric individual  is derived from 2 zygotes that subsequently fuse

• Mutations at different loci can produce the same phenotype
• Marfan's syndrome, MEN2B and homocystinuria; ALL cause marphanoid habitus
• Albunism

Presence of both normal and mutated mtDNA, resulting in variable expression in mitochondrial inherited disease

• Offspring receives 2 copies of a chromosome from 1 parent and no copies from the other parent
• Heterodisomy (heterozygous) indicates a meiosis I error
• Isodisomy (homozygous) indicates a meiosis II error or postzygotic chromosomal duplication of one of a pair of chromosomes, and loss of the other of the original pair
• Uniparental is eUploid (correct number of chromosomes)
• Most occurrences of UPD → normal phenotype
• Consider UPD in an individual manifesting a recessive disorder when only one parent is a carrier

• If a population is in Hardy-Weinberg equilibrium and if p and q are the freqencies of separate alleles, then:
• p² + 2pq + q² = 1 
• p + q = 1
• p² = frequency of homozygosity for allele p
• q² = frequency of homozygosity for allele q
• 2pq = frequency of heterozygosity (carrier frequency, if autosomal recessive)
• The frequency of an X-linked recessive disease in males = q; in females = q²

• No mutation occurring at the locus
• No selection for any of the genotypes at the locus
• Completely random mating
• No net migration

• At some loci, only 1 allele is active; the other is inactive (imprinted/inactivated by methylation)
• With 1 allele inactivated, deletion of the active allele leads to disease
• Prader-Willi, Angelman's syndromes due to inactivation or deletion of genes on chromosome 15 (Can also occur as a result of uniparental disomy)

• Prader-Willi syndrome
• Paternal allele is not expressed
• Presents: mental retardation, hyperphagia, obesity, hypogonadism, hypotonia

• AngelMan's syndrome
• Maternal allele is not expressed
• Presents: mental retardation, seizures, ataxia, inappropriate laughter

• Autosomal dominant/recessive
• X-linked recessive/dominant
• Mitochondrial inheritance

• Autosomal dominant
• Often due to defects in structural genes.
• Many generations
• Both male and female affected
• Often pleiotropic
• Family history is crucial to diagnosis

• Autosomal recessive
• 25% of offspring from 2 carrier parents are affected
• Often due to enzyme deficiencies
• Usually seen in only 1 generation
• Commonly more severe than dominant disorders
• Patients often present in childhood

• X-linked recessive
• Sons of heterozygous mother have 50% chance of being affected
• No male-to-male transmission
• Commonly more severe in males
• Females usually must be homozygous to be affected

• Transmitted through both parents
• Either male or female offspring of the affected mother may be affected
• All female offspring of the affected father are affected
• Hypophosphatemic rickets: formerly known as vitamin D-resistant rickets
• -inherited disorder resulting in ↑ phophate wasting at proximal tubule

-Rickets-like presentation

• Mitochondrial inheritance
• Transmitted only through mother
• All offspring of affected females may show signs of disease
• Often due to failures in oxidative phosphorylation
• Variable expression in population due to heteroplasmy
• Mitochondrial myopathies: group of rare disorders resulting from mutations affecting mitochondrial function
• -Often present with myopathy and CNS disease
• -Muscle biopsy shows "ragged red fibers"

• Achondroplasia
• ADPKD
• Familial adenomatous polyposis
• Familial hypercholesterolemia (hyperlipidemia type IIA)
• Hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)
• Hereditary spherocytosis
• Huntington's disease
• Marfan's syndrome
• Multiple endocrine neoplasias (MEN)
• Neurofibromatosis type 1 (von Recklinghausen's disease)
• Neurofibromatosis type 2
• Tuberous sclerosis
• von Hippel-Lindau disease

• Cell-signaling defect of fibroblast growth factor (FGF) receptor 3
• Presentation: dwarfism, short limbs, larger head, but trunk size normal
• Associated with advanced paternal age

• Bilateral, massive enlargement of kidneys due to multiple large cysts
• Presentation: flank pain, hematuria, hypertension, progressive renal failure
• 855 of cases are due to mutation in PKD1 (chrom 16)
• Associated with polycyctic liver disease, berry aneurysm, mitral valve prolapse

• Colon becomes covered with adenomatous polyps at puberty
• Progresses to colon cancer unless colon is resected 
• Mutations on chromosome 5 (APC gene)

• Elevated LDL due to defective or absent LDL receptor
• Heterozygotes (1:500) have cholesterol ~ 300mg/dL
• Homozygotes (rare) have cholesterol >700mg/dL:
• -severe atherosclerotic disease early in life
• -tendon xanthomas (classically the Achilles tendon)
• -MI may develop before age 20

• Inherited disorder of blood vessels
• Findings: telangiectasia, recurrent epistaxis, skin discolorations, arteriovenous malformations (AVMs)

Trinucleotide repeat disorder: (CAG)_n

• Findings:
• -Depression
• -Progressive dementia
• -Choreiform movements
• -Caudate atrophy
• -↓ levels of GABA and ACh in the brain

• Sx manifest in affected individual s between the age of 20 and 50
• Gene located on chromosome 4: "Hunting 4 food"

• Fibrillin-1 gene mutation → connective tissue disorder affecting skeleton, heart, and eyes
• Findings:
• -tall with long extremities
• -pectus excavatum
• -hypermobile joints
• -long, tapering fingers and toes (arachnodactyly)
• -Subluxation of lenses
• -Cystic medial necrosis of the aorta → aortic incompetence and dissecting aortic aneurysms
• -Floppy mitral valve

• Several distinct syndromes (1, 2A, 2B) characterized by familial tumors of endocrine glands
• -Pancreas
• -Parathyroid
• -Pituitary
• -Thyroid
• -Adrenal medulla

MEN 2A and 2B are associated with ret gene

Mutation on long arm of chromosome 17

• Findings:
• -café-au-lait spots
• -neural tumors
• -Lisch nodules (pigmented iris hamartomas)
• -Marked by skeletal disorders (e.g. scoliosis)
• -Optic pathway gliomas

• Bilateral acoustic schwannomas
• Juvenile cataracts
• NF2 gene on chromosome 22; type 2 = 22

• Findings:
• -Facial lesions (adenoma sebaceum)
• -hypopigmented "ash leaf spots" on skin
• -cortical and retinal hamartomas
• -seizures
• -mental retardation
• -renal cysts
• -renal angiomyolipomas
• -cardiac rhabdomyomas
• -↑ incidence of astrocytomas

Incomplete penetrance, variable presentation

• Findings:
• -hemangioblastomas of retina/creebellum/medulla
• -multiple bilateral renal cell carcinomas and other tumors (most)

Associated with deletion of VHL gene (tumor suppressor) on chromosome 3

Constitutive expression of HIF (transcription factor) and activation of angiogenic growth factors


**Von hippel-lindau = 3 words for chromosome 3

• Albinism
• ARPKD
• Cystic fibrosis
• Glycogen storage diseases
• Hemochromatosis
• Mucopolysaccharidoses (except Hunter's)
• Phenylketonuria
• Sickle cell anemias
• Sphingolipidoses (except Fabry's)
• Thalassemias

• Autosomal recessive defect in CFTR
• -Chromosome 7; most common is deletion of Phe508 (ΔF508)
• -CFTR channel: secretes Cl^- in lungs, GI tract; reabsorbs Cl^- from sweat
• -Most common lethal genetic disease of white population

• Mechanism of disease:
• Defective Cl- channel → secretions of thick mucus that plugs lungs, pancreas, liver → recurrent pulmonary infections, chronic bronchitis, bronchietasis, pancreatic insufficiency, nasal polys, meconium ileus
• -Pseudomonas; S. aureus
• -malabsortpion and steatorrhea

• Presentation (other):
• -infertility in males due to BAVD
• -Fat soluble vitamin deficiencies (A, D, E, K)
• -Failure to thrive in infancy

• Dx:
• -increased concentration of Cl- ions in swat test

• Tx:
• -N-acetylcystein to loosen mucous plugs (cleaves disulfide bonds within mucous glycoproteins

• **Be Wise, Fool's GOLD Heeds Silly HOpe
• Burton's aagammaglobulinemia
• Wiskott-Aldrich syndrome
• Fabry's disease
• G6PD deficiency
• Ocular albinism
• Lesh-Nyhan syndrome
• Duchenne's (and Becker's) muscular dystrophy
• Hunter's Syndrome
• Hemophilia A and B
• Ornithine transcarbamoylase deficiency

• Female carriers may be affected
• May have less severe symptoms due to random X chromosome  inactivation in each cell

• X-linked frameshift mutation → deletion of dystrophin gene → accelerated muscle breakdown
• -Weakness begins in pelvic girdle muscles and progresses superiorly
• -Pseudohypertrophy of calf muscles due to fibrofatty replacement of muscle
• -Cardiac myopathy
• *Gower's maneuver to stand
• -Onset: <5 years of age
• **Duchenne's deleted dystrophin

**Dystrophin gene (DMD) is the longest known human gene: ↑ rate of spontaneous mutation

-Dystrophin helps anchor muscle fibers, primarily in skeletal and cardiac muscle

Diagnose: ↑CPK and muscle biopsy

• X-linked mutated dystrophin gene
• less severe than Duchenne's
• Onset in adolescence or early adulthood

• X-linked defect affecting the methylation and expression of FMR1 gene
• Trinucleotide repeat disorder (CGG)_n
• 2nd most common cause of genetic mental retardation (after Down syndrome)
• Findings:
• -macro-orchidism (enlarged testes)
• -long face with large jaw
• -large everted ears
• -autism
• -mitral valve prolapse
• **Fragile X = eXtra large testes, jaw, ears

Try (trinucleotide) hunting for my fried eggs (X): Huntington's disease, myotonic dystrophy, Friedreich's ataxia, fragile X syndrome

• **X-Girlfriend's First Aid Helped Ace My Test
• Fragile X syndrome: (CGG)_n
• Friedreich's ataxia: (CAA)_n
• Huntington's disease: (CAG)_n
• Myotonic dystrophy: (CTG)_n

May show genetic anticipation

• Down syndrome (trisomy 21): 1:700
• Edwards' syndrome (trisomy 18): 1:8000
• Patau's syndrome (trisomy 13): 1:15,000

Meiotic nondisjunction

• -Most common viable chromosomal disorder
• -Most common cause of genetic mental retardation

• 95% are due to meiotic nondisjunction of homologous chromosomes
• -Associated with advanced maternal age (1:25 in women >45)

• 4% are due to Robertsonian translocation
• 1% are due to Down mosaicism (no maternal association)

• Findings:
• -mental retardation
• -flat facies
• -prominent epicanthal folds
• -simian crease
• -gap between 1st 2 toes
• -duodenal atresia
• -congenital heart disease (most commonly ostium primum type ASD)
• --Associated with increased risk of ALL and Alzheimer's disease (for those >35 years of age)

*Down syndrome (trisomy 21): Drinking age (21)

• Results of pregnancy QUAD screen:
• ↓ α-fetoprotein
• ↑ β-hCG
• ↓ estriol
• ↑ inhibin A

Ultrasound: ↑ nuchal in first trimester translucency

2nd most common trisomy resulting in live birth (after Down)

• Findings:
• -severe mental retardation
• -rocker-bottom feet
• -micrognathia
• -low-set Ears
• -clenched hands
• -prominent occiput
• -congenital heart disease
• *Death usually occurs within 1 year of birth

**Edwards'; trisomy 18: Election age (18)

• Pregnancy quad screen:
• ↓ α-fetoprotein
• ↓ β-hCG
• ↓ estriol
• Normal inhibin A

• Findings:
• -Severe mental retardation
• -Rocker-bottom feet
• -microphthalmia
• -microcephaly
• -cleft liP/Palate
• -HoloProsencephaly
• -Polydactyly
• -Congenital heart disease
• *Death usually within 1st year of life

Patau's syndrome (trisomy 13): Puberty (13)

• First-trimester pregnancy screen:
• ↓ free β-hCG
• ↓ PAPP-A
• ↑ nuchal translucency

• Nonreciprocal chromosomal translocation that commonly involves chromosome pairs 13, 14, 15, 21, and 22
• Common type of translocation
• Occurs when long arm of 2 acrocentric chromosomes fuse at the centromere and the 2 short arms are lost
• Balanced translocations normally do not cause any abnormal phenotype
• Unbalanced tranlsocations can result in miscarriage, stillbirth, chromosomal imbalance (e.g. Down syndrome, Patau's syndrome)

• Congenital microdeletion of short arm of chromosome 5 (46,XX or XY, 5p-)
• Findings:
• -microcephaly
• -moderate to severe mental retardation
• -high-pitched crying/mewing
• -epicanthal folds
• -cardiac abnormalities (VSD)

*Cri du chat = Cry of the cat

Congenital microdeletion of long arm of chromosome 7 (deleted region includes elastin gene)

• Findings:
• -distinctive "elfin" facies
• -intellectual disability
• -hypercalcemia (↑ sensitivity to Vitamin D)
• -Well-developed verbal skills
• -extreme friendliness with strangers
• -cardiovascular problems

Microdeletion at chromosome 22q11; Due to aberrant development of 3rd and 4th branchial pouches

• Variable presentation: **CATCH-22
• -Cleft palat
• -Abnormal facies
• -Thymic aplasia → T-cell deficiency
• -Cardiac defects
• -Hypocalcemia 2° to parathyroid aplasia

DiGeorge syndrome: thymic, parathyroid, and cardiac defects

Velocardiofacial syndrome: palate, facial, and cardiac defects