Principles of Genetic Inheritance

Question 1

Autosomal dominant inheritance

Answer 1

• only one allele of a gene is needed for expression
• affected offspring only needs one affected parent
• unaffected individuals do not transmit trait (aa)
• males and females can transmit trait to both males and females - autosomal
• trait is expected in every generation
• recurrent risk is 50%

Question 2

Autosomal recessive inheritance

Answer 2

• 2 copies of a mutant allele is needed to influence phenotype
• males and females affected equally
• if two heterozygous parents: 25:50:25
• pedigree may show affected individual with two phenotypically normal parents

Question 3

Oculocutaneous albinism type 1A (OCA1A)

Answer 3

Autosomal recessive disease
Caused by a mutation in the TYR gene encoding tyrosinase, completely inactive or incomplete tyrosinase
melanin biosynthetic pathway is completely blocked
- white skin and hair at birth, irises are blue to pink and fully translucent, photophobia
nystagmus may be present at birth or it may develop in the first 3-4 months of life
sun-exposed skin becomes rough, coarse, thickened, and can have solar keratoses

Question 4

X-Linked Recessive

Answer 4

disease allele on X in males is termed “hemizygous”, females can be heterozygous or homozygous

• always expressed in male “carriers”
• Female carriers transmit disease allele to 50% of sons and 50% of daughters
• all daughters of affected males are heterozygous carriers

Question 5

Duchenne Muscular Dystrophy

Answer 5

X-linked disorder

• absence or defect in dystrophin
• muscle weakness usually occurs around teh age of 4 and progressively worsens, ability to walk completely disintigrates by age 9-12, most men essentially “paralyzed from the neck down” by age 21

Question 6

Mitochondrial DNA (mtDNA)

Answer 6

• encodes rRNA, tRNA, and 13 polypeptides involved in oxidative phosphorylation
• txn takes place in mitochondrion, independently of the nucleus
• inherited exclusively through the maternal line
• pedigree would show all offspring of an affected woman will be affected. Affected males will not pass on to offspring
• severity depends on the percentage of dysfunctional mt.DNA (heteroplasmy)

Question 7

Leber’s Hereditary optic neuropathy (LHON)

Answer 7

• mitochondrial DNA (maternally inherited)
• degeneration of retinal ganglion cells
• caused by one of three pathogenic mt. DNA point mutations affecting NADH dehydrogenase
• Starves RGCs of energy, making them unable to transmit signals to the brain
• acute or subacute loss of vision (typically in early teens or 20s, inter-eye delay of 8 weeks)
• impaired glutamate transport and increased ROS causing apoptosis of retinal ganglion cells (RGC)

Question 8

Myoclonic epilepsy and ragged red ribers (MERRF)

Answer 8

• mitochondrial DNA (maternally inherited)
• mutation in the gene encoding tRNA for lysine, disrupts the synthesis of cytochrome-c oxidase
• patients with myclonus dinated muscle movement (twitching or jerking), ataxia, seizures, dementia
• particularly affects the muscles and nerves
• large variability of presentation due to heterplasmy

Question 9

Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS)

Answer 9

most common maternally inherited mitochondrial disease
- affects many body systems, particularly brain, nervous system, and muscles
stroke and dementia, diabetes, deafness, cognitive impairment, short stature, migraines

Question 10

X-Linked Dominant

Answer 10

only one copy is needed

• affected males transmit the disease to all females, but never to males
• females with the disease allele transmit the trait to both females and equally, with 50% transmission to offspring

Question 11

Vitamin D resistant rickets: hypophosphatemia

Answer 11

• X linked dominant
• low phosphorus in blood due to defective reabsorption of phosphate in kidney
• Deficient absorption of calcium in intestines causes softening of bone (rickets)
• vitamin D metabolism is abnormal
  short stature
  treatment is oral phosphate and vitamin D

Question 12

Fragile X syndrome

Answer 12

X-linked dominant

• mild-to-moderate intellectual disability, long and narrow face, large ears, flexible fingers, and large testicles
• features of autism such as problems with social interactions and delayed speech
• hyperactivity is common, seizures occur in about 10%
• expansion of the CGG triplet repeat within FMR1 gene on X chromosome, results in silencing and a deficiency of the FMRP, which is required for normal development of connections between neurons

Question 13

Euploidy

Answer 13

cells with a normal number of chromosomes

Ex. haploid gametes and diploid somatic cells

Question 14

Nondisjunction

Answer 14

meiotic error

• abnormal separation of one or more pairs of homologous chromosomes or sister chromatids
• germline error during meiosis in spermatocyte or oocyte is transmissible to the next generation
• if occurs during mitosis (after fusion of ovum and sperm) individual will exhibit mosaicism, only some of the cells will be with aneuploid
• nondisjunction increases with maternal age

Question 15

Polyploidy

Answer 15

meiotic error
cells contain a complete set of extra chromosomes in a cell
- multiple of 23, incompatible with human life
- often seen in plants

Question 16

Aneuploidy

Answer 16

meiotic error
cells contain a missing or additional individual chromosomes
- monosomy, trisomy

Question 17

uniparental disomy

Answer 17

both chromosomes are inherited from one parent

• along with the parent-specific imprinting, but since most genes are not imprinted it usually has no effect on health or development
• loss of function genes in that chromosome will cause issue

Question 18

Genomic imprinting

Answer 18

• we receive one copy of each gene from each parent, but genomic imprinting states that some genes are only expressed from the mother or the father
• imprinted alleles are silenced, so the non-imprinted allele is expressed (only from one parent)
• epigenetic process involving methylation and histone modification of egg or sperm cells during their formation while genetic sequence is unchanged - duplicated in all somatic cells

Question 19

Prader-Willi and Angelman Syndromes

Answer 19

UPD or deletion in chromosome 15

• phenotype/disease depends on if deletion is on maternal or paternal chromosome
• paternal = Prader-Willi (short stature, hypotonia, small ahnds/feet, obesity, mild to moderate intellectual disability, uncontrolled eating)
• maternal = Angelman Syndrome (severe intellectual disability, seizures, ataxic gait)

Question 20

Translocations

Answer 20

non-homologous chromosomes exchange genetic material

• reciprocal - exchange of material between nonhomologous chromosomes
• Robertsonian - long arm of two acrocentric chromosomes combined, short arm is typically lost

Question 21

Karyotyping

Answer 21

technique that allows the determination of the number, size, and gross structures of metaphase chromosomes
- Traditional gold standard cytogenic method used in identifying several chromosomal abnormalities associated with genetic disorders, but does not provide information on the genetic level

Question 22

Turner Syndrome

Answer 22

Karyotype: 45, XO
Monosomy (X), Female (no Y)
- short stature, ovarian hypofunction/premature ovarian failure, many do not undergo puberty, most are infertile
- webbed neck, low hairline on neck, CV defects (coarctition of aorta, bicuspid aortic valve), no cognitive defects

Question 23

Klinefelter Syndrome

Answer 23

Karyotype 47, XXY

• Varying presentation, varying degrees of cognitive, social, behavioral, and learning difficulties
• primary hypogonadism (low T)
• small and/or undescended testes, gynecomastia, infertility, tall stature
• variability in X numbers can increase symptoms (48 XXXY, 49 XXXXY)

Question 24

Downs Syndrome

Answer 24

Trisomy 21 (47, XX +21)

• most common trisomy, strongly associated with maternal age
• results most commonly from maternal meiotic nondisjunction (in the ovum)
• also due to unbalanced translocation
• varying degrees of cognitive impairment
• increased nuchal translucency, cardiac defects, duodenal atresia, ventriculomegaly, absent nasal bone, and short limbs
• Trisomy 21 (nondisjunction) is most common (95% of cases)
• translocation (usually piece of 21 onto chrom 14) 4% of cases
• mosaicism - nondisjunction occurs in one of the initial cell divisions after fertilization, causing some cells with 46 chromosomes and some with 47 (1% of cases)

Question 25

Edwards Syndrome

Answer 25

Trisomy 18 (47, XX +18)
Often IUGR
- 95% die in utero, <10% of births survive to 1 year
- microencephaly, prominent occiput, malformed and low-set ears, small mouth and jaw, cleft lip/palate, rocker bottom feet, overlapped fingers

Question 26

Patau Syndrome

Answer 26

Trisomy 13 (47, XX +13)

• severe developmental abnormalities, heart abnorm., kidney malformations, CNS dysfunction, microcephaly, malformed ears, closely spaced/absent eyes, clenched hands and polydactyl, cleft lip/palate
• most die before birth, and most peinatal death within one week
• free trisomy of chromosome 13 (75% of cases) and tisomy from Robertsonian translocations (25% of cases)

Question 27

Reduced/incomplete penetrance

Answer 27

frequency a gene manifests itself is called penetrance

• proportion of individuals in a population who carry a disease-causing allele and express the disease phenotype
• reduced penetrance often occurs with familiar cancer syndromes, (ex. BRCA1 or BRCA 2 or Rb gene for retinoblastoma)
• Huntington’s disease also presents with incomplete penetrance
• on pedigree, may appear to skip a generation of affected individuals - false conclusion that it is recessive

Question 28

Retinoblastoma

Answer 28

Autosomal dominant inheritance

• phenotype occurs in 90% of individuals inheriting gene defect: so 90% penetrance
• primarily affects children, caused by defects in the Rb gene

Question 29

Variable expressivity

Answer 29

describes the range of phenotypes that vary between individuals with a specific genotype
- the extent to which a given genotype is expressed at the phenotypic level

Question 30

Neurofibromatosis

Answer 30

develop tumor-like growths called neurofibromas

• variable expressivity, spots differ in number, shape, size, and position
• patients have cafe-au-lait spots, pigmented areas the color of coffee with cream

Question 31

Marfan Syndrome

Answer 31

Affects the connective tissue, subsequently many different systems. Defects in Fibrillin
Variable expressivity - ectopia lentis (dislocated lens), weakened and stretched aorta may lead to an aneurysm and aortic dissection

Question 32

Locus heterogeneity

Answer 32

single disorder, trait, or pattern of traits caused by mutations in genes at different chromosomal loci
- only one mutant locus is needed for the phenotype to manifest

Question 33

Osteogenesis imperfecta

Answer 33

Brittle bone disease, mutations in collagen genes

• two loci: chromosome 7 and 17, either mutation exhibits similar phenotypes (with varying severity)
• 90% cases with mutations in COL1A1, COL1A2,
• CRTA and P3H1 with more severe phenotypes
• blue sclerae, short stature, hearing loss, respiratory problems, disorder of tooth development.
• most severe forms can result in abnormally small, fragile rib cage and underdeveloped lungs - often die shortly after birth

Question 34

hardy weinberg equation

Answer 34

p^2 + 2pq + q^2 = 1
p+q = 1
- simplifies relationship between gene frequency and genotype frequency

Question 35

Polygenic

Answer 35

traits in which variations are thought to be caused by the combined effects of multiple genes (say two different spots that have alleles relating to height)

Question 36

Multifactorial inheritance

Answer 36

• when environmental factors cause variation in the trait
• for diseases that do not follow the bell curve distribution there is an underlying liability distribution
• for multifactorial diseases that are either present or absent, it is thought that a “threshold of liability” must be crossed before the disease is expressed - below the threshold the person appears normal, above the threshold they are affected with the disease

Question 37

pyloric stenosis

Answer 37

muscular hypertrophy between stomach and duodenum - multifactorial inheritance

• leads to vomiting and obstruction
• five times more common in males than females, males need less risk genes to show the disease, females need more to show it
• the least affected sex has a higher risk threshold (in this case females) and transmits the condition more often