Genetics

Chromatin

The complex of DNA wound around histone proteins that makes up the genetic material inside the nucleus

Euchromatin

Loosely packed, transcriptionally active, genes are accessible and being read

Heterochromatin

Tightly packed, transcriptionally silent

Chromosome

A thread like structure made of protein and a single molecule of DNA that serve to carry the genetic information from cell to cell

Humans have __ chromosomes (__ pairs)

46, 23

There are __ pairs of autosomes and _ pair of sex chromosomes

22,1

Gene

The basic unit of heredity, a specific segment of DNA that codes for a particular protein or RNA product and is passed from parent to offspring

Locus

The fixed, specfic physical position of a gene on a chromosome

Allele

An alternative version of a gene found on a given locus

Since we inherit one copy each of autosomal chromosome from each parent, we normally have __ alleles for every autosomal gene

2

Genotype

An individual’s genetic makeup, the specific combination of alleles present at a given locus

Phenotype

The physical, biochemical, or clinical characteristics that emerge from the interaction of a genotype and environment

Homozygous alleles

having two identical alleles at a given locus

HH and hh are examples of which type of alleles

homozygous alleles

Heterozygous alleles

Having two different types of alleles at a given locus, one from each parent but are not matching each other

Hh is an example of what type of allele

Heterozygous allele

Dominant allele

An allele whose phenotypic effect is expressed with one copy present

Recessive allele

An allele whose phenotypic effect is expressed with both copies present

When a recessive allele is paired with a dominant allele, the phenotype is

masked.

Codominant alleles

Two different alleles at a locus are both fully expressed simultaneously

AB blood is a classic example of

Codominance

Carrier

An individual who heterozygous for a recessive disease-causing allele.

A carrier does not display the disease phenotype because

The dominant allele masks the recessive disease-causing allele

Euploid

Having the normal, complete chromosome complement (23 pairs)

Aneuploidy

The presence of an abnormal number of individual chromosomes, either one or two missing rather than an entire set

Two forms of aneuploidy are

• Monosomy (one copy of a chromosome instead of two)

• Trisomy (Three copies instead of two)

Centromere

The point on a chromosome to which the spindle attaches during cell division

The short arm (p) is the ___ half of a centromere while the long arm (q) is the ___ half

top, bottom

Nondisjunction

The failure to separate homologous chromosomes or sister chromatids during cell division

The most common cause of aneuploidy is

Nondisjunction

Autosomal monosomy is essentially always ______ in early embryonic development

lethal

A missing autosome means the complete loss of every gene on that chromosome, which is autosomal monosomy is lethal.

True

Autosomal trisomy is also lethal in the great majority of cases, however these three chromosomes are exceptions compatible with live birth.

21, 18, 13

The only exception to the “monosomy is lethal” is

Sex chromosome aneuploidy

Structural rearrangements

In which the amount or arrangement of genetic material on a chromosome is altered

Translocation

An exchange of material between two non-homologous chromosomes

A balanced translocation is described as

Involves no net gain or loss of genetic material

An unbalanced translocation is best described as

Translocation resulting in extra or missing genetic material

Robertsonian translocation

Fusion of two acrocentric chromosomes at the (13,14,15,21,22) centromere

Deletion

Loss of a chromosomal segment

Cri-du-chat syndrome

(short arm) Deletion of chromosome 5, Producing a characterisitc high-pitched, cat-like infant cry, microcephaly, and intellectual disability

Microdeletion syndromes

Deletions too small to see, detectable on higher resolution techniques such as FISH or chromosomal microarray

22q11.2 deletion syndrome (DiGeorge syndrome) is associated with

Cardiac defects, thymic hypoplasia with immune deficiency, hypocalcemia, and characteristic facial features

Additional structural rearrangement patterns

Duplication, inversion, isochromosome, and ring chromosome

Down-syndrome (trisomy 21)

Autosomal aneuploidy which is Most common chromosomal cause of intellectual disability compatible with survival to adulthood

95% of cases of trisomy 21 are caused by

Meiotic nondisjunction

Robertson translocation accounts for 3-4% of cases for trisomy 21. The reason is…

Phenotypically normal parent who carries balanced translocation and therefore carries a substantially higher recurrence risk

Mosaicism accounts for 1-2% of cases for trisomy. What is mosaicism?

Nondisjunction event occuring after fertilization, a subset of cells carry the extra chromosome, producing milder phenotype

The incidence for trisomy 21 in the United States is about 1 in ___ births

700-800

Being over the age of __ can increase risk for trisomy 21

35

Screening tests (estimating probability) for trisomy 21

• Nuchal translucency ultrasound (PAPP-A, beta-hCG)

• Second-trimester quad screen (AFP, hCG, estriol, inhibin-A): Occurs if first trimester screening has not occured

• Cell-free DNA screening (NIPT/NIPS): Analysis of small fragments of placental DNA, available from 10-wks gestation

Diagnostic Tests

• Chorionic villus sampling (CVS): Performed at 10-13 weeks of gestation

• Amniocentesis: performed at approximately 15-20 weeks of gestation

- Epicanthal fold

- Congenital heart disease

- Poor muscle tone

- Mental retardation

- Low nasal bridge

- Protruding tongue

- Low-set ears

- Intestinal malformation

- Acute lymphoblastic leukemia

- Short broad hands with simian crease

- Wide gap between first and second toes

- Flat occiput

This are all symptoms

Trisomy 21

Turner Syndrome (monosomy X)

Complete or partial absence of one X chromosome, affecting females.

The classic karyotype for complete monosomy that appears in about half of cases is

45,X

The incidence rate for Monosomy X us

1 in 2,000-2500 female births

Manifestations of Monosomy X

- Webbing of the neck

- High number of aborted fetuses

- Underdeveloped ovaries (sterile)

- Short stature (NOT MIDGET)

- Underdeveloped breasts; wide nipple

- Edema

What are some ways to manage Monosomy X?

• Growth hormone therapy (for short stature)

• Estrogen replacement therapy beginning around puberty

• Cardiac and renal monitoring.

Klinefelter Syndrome

A condition affecting males resulting from one or more extra X chromosomes

A common karyotype for Klinefelter Syndrome is

47,XXY

Abnormalities related to Klinefelter Syndrome increase with

The number of X present

Manifestations of Klienfelter Syndrome

• Tall Stature

• Lack of Facial hair

• Long limbs

• Wide hips

• Small testes (usually sterile)

• Gynecomastia

• Sparse body hair

Increased long-term risks for individuals with Kleinfelter Syndrome are

Osteoporosis, metabolic syndrome, increased breast cancer risk

Incidence for Kleinfelter Syndrome is

1 in 500-1000 male births

Females with Monosomy X are likely to have _______ ovaries

dysgenetic

The key hormones that are deficient in Monosomy X and Kleinfelter Syndrome are

Estrogen and testerone

Infertile in Monosomy X is seen in _____ of cases

A great majority

Infertility in Kleinfelter is seen in ____ of cases

Most

Which type of therapy is considered for Kleinfelter Syndrome

Testosterone Replacement

Key associated anomlies of Monosomy X are

Bicuspid aortic valve, coarctation of the aorta, and horseshoe kidney

Single-gene (Mendelian) disorder patterns include

Autosomal dominant, autosomal recessive, X-linked recessive

Pedigree table

A table used to study genetic disorders within a family

Recurrence risk

The probability that an individual will develop a particular genetic disease

For an autosomal dominant condition, when one parent is affected (heterozygous, Hh) and the other is unaffected (hh), each child's risk of being affected is

50%

Penetrance

Percentage of individuals with a given disease-causing genotype who go on to actually express the corresponding phenotype

• “Will the trait show up or not?”

Expressivity

The extent of a phenotypic variation seen among individuals who do express a given genotype

Incomplete penetrance

Describes a genotype that does not always produce the phenotype

A classic example of incomplete penetrance

Retinoblastoma, 90% penetrance, about 10% who inherit RB1 never develop a tumor

Autosomal Dominance

Inheritance of one copy is enough to cause the disorder (Dd). Only one parent needs to carry and transmit the defective gene.

Autosomal dominant inheritance DOES NOT have carriers

True

Autosomal dominant skips/does not skip generations.

Does not skip

If one parent is heterozygous (Dd) and the other is (Dd), what are the odds of the offspring getting an autosomal dominant disorder

75%

Autosomal recessive inheritance

Both parents must carry and pass affected allele for a child to be affected

Most autosomal recessive disorders are caused from

Consanguinity

If both parents are carriers for an autosomal recessive disease, the odds of the offspring having the disease are

25%

Cystic fibrosis, Sickle cell anemia, Phenylketonuria, and Tay-Sach disease are

Autosomal recessive

Cystic fibrosis is most common in

Caucasian

Cystic fibrosis affects

Lungs and pancreas

Maldigestion (sign of cystic fibrosis)

Pancreas not able to secrete mucus containing enzymes

Sickle cell disease

- Replace glutamic acid with valine

- RBC sickle under conditions that cause oxygen levels to be low

X-linked recessive disorders are caused by

Mutations of genes located X chromosome

In X-linked recessive disorders, the father can/cannot pass the condition to his sons

cannot

In X-linked disorders, the an affected father can/cannot pass the disorder to ALL daughters

can

For X-linked recessive diseases, females are mostly carriers. In what scenario would a female be affected

The father has to be affected while the mother has to either be a carrier or affected themselves

Consanguinity can be the cause of X-linked recessive disorders

True

The only two disorder that skip generations is

X-linked recessive and autosomal recessive

An example of disease that does not follow X-linked recessive rules are

Fragile X syndrome

Mitochondrial DNA is inherited exclusively from the

mother

An affected mother can transmit a mitochondrial disorder all her children but a father cannot transmit to any children. This describes

Mitochondrial inheritance

Polygenic/multifactorial disease

Combined effectives of genes and environmental factors