Lecture 3 - Genetic Disorders

What does haploid mean?

Number of chromosomes in a gamete (n)

What does diploid mean?

Human somatic cells, two haploid sets (2n)

What does polyploidy mean?

Extra set of the entire genome eg. 3n, 4n

What does aneuploidy mean?

The number of chromosomes is not a multiple of the normal haploid number eg. monosomy (2n-1) and trisomy (2n+1)

What is a translocation?

Relocation of genetic material

What is a missing chromosome?

Loss of genetic material

What is an extra chromosome?

Gain of genetic material

What is duplication?

An extra segment of chromosome is added

What is inversion?

Segment breaks off, flips and reattaches

What is deletion?

A segment of chromosome is lost

What is triploidy?

The presence of three complete sets of chromosomes (69 chromosomes: 69XXX, 69XXY, 69XYY)

How common is triploidy in conceptions and live births?

• About 1% of all conceptions are triploid; 99% die before birth

• Seen in 1 in 10,000 live births

What proportion of spontaneous abortions are triploid?

Triploidy represents approximately 17% of spontaneous abortions

What are the main causes of triploidy?

Dispermy (two sperm fertilise one egg), diploid egg, or diploid sperm

What is tetraploidy?

The presence of four complete sets of chromosomes (92 chromosomes), usually lethal

How common is tetraploidy in spontaneous abortions?

Observed in about 5% of spontaneous abortions

What is the main cause of tetraploidy?

Often due to failure of cytokinesis during cell division

What is the primary mechanism causing aneuploidy?

Non-disjunction, the failure of chromosomes to separate properly during anaphase

What is hypoploidy?

Missing one or more chromosomes, leading to a reduced chromosome number

What is hyperploidy?

Gain of one or more chromosomes, leading to an increased chromosome number

How common is autosomal monosomy in humans?

Rarely observed in spontaneously aborted fetuses or live births; usually lethal.

What is Trisomy 18?

Edward’s syndrome, a rare autosomal trisomy

How common is Edward’s syndrome in live births?

About 1 in 10,000 live births; most die in utero or within 6 months

What are key physical features of Trisomy 18?

Clenched fists with the 5th finger overlapping the 3rd and 4th digits, and other unusual physical features

What is the main cause of Trisomy 18?

Non-disjunction in meiosis II of the oocyte

What is Trisomy 21?

Down’s syndrome, the most common human chromosomal abnormality

What is the main cause of Down’s syndrome?

Non-disjunction causing trisomy of chromosome 21; 90% from maternal meiosis I errors

How does maternal age affect Down’s syndrome?

Increased maternal age is a significant risk factor

Can paternal non-disjunction cause Down’s syndrome?

Yes, about 10% of cases are due to non-disjunction in meiosis I or II in males

How can translocations cause Down’s syndrome?

About 1 in 20 cases are due to a Robertsonian translocation between chromosome 21 and 14; a parent can carry the rearranged chromosome and pass it to offspring

Key facial features of Down’s syndrome?

Broad flat face, slanting eyes, epicanthic eye fold, short nose

Other physical and health features of Down’s syndrome?

Big tongue, dental abnormalities, congenital heart disease, low-set ears, short stature, intellectual disability

Why can chromosomes 14 and 21 undergo Robertsonian translocation?

Both are acrocentric, so their short arms can fuse and be lost without affecting the carrier's phenotype

How can a parent with a Robertsonian translocation between chromosomes 14 and 21 have a child with Down syndrome?

The parent can pass on the fused chromosome along with a normal chromosome 21, resulting in three copies of chromosome 21’s long arm in the offspring, causing Down syndrome

Where is the Down syndrome critical region (DSCR) located?

On chromosome 21, specifically at 21q22.2

Do trisomies of other parts of chromosome 21 cause Down syndrome?

No, only the DSCR region is involved in the DS phenotype

What is DYRK1A and its role in Down syndrome?

DYRK1A is a dual specificity tyrosine phosphorylation-regulated kinase that produces dosage-sensitive learning defects

What is DSCR1 and its role in Down syndrome?

DSCR1 (Down syndrome critical region gene 1) interacts with calcineurin A, affecting apoptosis and possibly CNS development

How does trisomy 21 affect DSCR1 and DYRK1A protein levels?

Cells have extra copies of DSCR1 and DYRK1A, leading to increased protein levels

How does increased DSCR1 affect calcineurin activity?

DSCR1 directly inhibits calcineurin activity

What is the consequence of calcineurin inhibition in Down syndrome?

Calcineurin cannot activate NFAT, which disrupts proper gene expression in developing neurons

How does reduced NFAT activity contribute to neurological symptoms in DS?

It delays neuron differentiation and alters brain structure, explaining some neurological deficits in Down syndrome

How does maternal age affect the risk of Down’s syndrome?

As maternal age increases, spindle fibres and chromosome cohesion weaken, increasing the chance of nondisjunction

What is the risk of having a child with Down’s syndrome at maternal age 20?

1 in 1500

What is the risk of Down’s syndrome at maternal age 30?

1 in 900

What is the risk of Down’s syndrome at maternal age 35?

1 in 400

What is the risk of Down’s syndrome at maternal age 40?

1 in 100

What is the risk of Down’s syndrome at maternal age 45?

1 in 30

What are examples of female non-disjunction?

Klinefelter, Turner, triplo-X, nonviable Y

What are examples of male non-disjunction in meiosis I?

Turner and triplo-X

What are examples of male non-disjunction in meiosis II?

Jacobs and Turner

How common is Turner syndrome (TS) in female births?

1 in 2,000 female births

What is often the first indication of Turner syndrome?

Delayed sexual development

How many X chromosomes are needed for normal female sexual development?

Two X chromosomes for sexual development, but one X is enough for other traits

What percentage of all conceptions are 45,X?

1%

What percentage of 45,X foetuses die before birth?

99%

Where do most Turner syndrome cases originate from?

75% originate in the father

How do cells completely lacking a partner sex chromosome arise in TS?

From spontaneous non-disjunction during meiosis

What is mosaicism in Turner syndrome?

Occurs when tissues contain two or more genetically different cell lines derived from a single zygote, caused by non-disjunction after fertilisation

Give examples of mosaicism in Turner syndrome.

45,X/46,XX and 45,X/46,XY

What is the role of the SHOX gene?

SHOX (Short Stature Homeobox) is a transcription factor essential for skeletal development and growth of bones in arms and legs

How does SHOX haploinsufficiency affect Turner syndrome individuals?

TS individuals have only one copy of SHOX, leading to shorter stature due to haploinsufficiency

What is the location of the SHOX gene?

Xpter-p22.32 on the X chromosome and Yp11.3 on the Y chromosome

What are the characteristics of Turner syndrome?

• Short stature

• Redundant skin at the back of the neck

• Poor breast development and widely spaced nipples

• Rudimentary ovaries and underdeveloped gonadal structures

• No menstruation

Can Turner syndrome individuals have children naturally?

No, they cannot have children naturally

How can Turner syndrome patients develop normal secondary sex characteristics?

Treatment with oestrogens allows development of normal secondary sex characteristics

How can some Turner syndrome patients bear children?

Modern reproductive technology with donor eggs allows some patients to have children

How can growth be improved in Turner syndrome individuals?

Treatment with growth hormone can improve growth and final height

What is Klinefelter syndrome?

A condition in males with an extra X chromosome

How common is Klinefelter syndrome?

1 in 1000 live male births

What karyotypes can be seen in Klinefelter syndrome besides 47, XXY?

XXYY, XXXY, XXXXY

When is Klinefelter syndrome most often discovered?

During evaluation of male infertility or puberty

What is the effective treatment for Klinefelter syndrome?

Testosterone injections

What happens to the second X chromosome in Klinefelter syndrome?

It is often X-inactivated, so it no longer expresses most of its genes

How does Klinefelter syndrome arise?

Spontaneous non-disjunction in meiosis, either maternal or paternal, creating a 47, XXY zygote

What percentage of Klinefelter cases are due to paternal non-disjunction in meiosis I?

53%

What percentage of Klinefelter cases are due to maternal non-disjunction in meiosis I?

34%

What else can Klinefelter be caused by?

Meiosis II

What percentage of Klinefelter patients are mosaics (47, XXY/46, XY)?

15%

Can any genes on the extra X chromosome in Klinefelter syndrome be expressed?

Yes, a few genes in the pseudoautosomal regions of the X chromosome are expressed, corresponding to Y chromosome genes

What are the characteristics of Klinefelter syndrome?

• Hypogonadism

• Reduced testosterone levels

• Infertility

• Tall stature

• Gynaecomastia

• Educational difficulties

• Behavioural problems

What is the minimum number of X chromosomes needed for viability?

At least one X chromosome

Are 44, — and 45, -Y seen in spontaneous abortions?

No

Is a single X chromosome viable and fertile?

A single X is viable but not fertile

How many X chromosomes are needed for normal female development?

At least two X chromosomes

What effect does an extra X or Y chromosome have?

It interferes with normal development

How does severity of symptoms relate to the number of sex chromosomes?

Severity increases as the number of extra Xs or Ys increases, ranging from very mild to severe

What causes a chromosomal deletion?

A single break causing a lost end piece or two breaks causing loss of an interior segment

What happens when an individual inherits one normal chromosome and one with a deletion?

They no longer have a pair of alleles for each trait in the deleted region

Which chromosome is deleted in Prader-Willi syndrome?

Chromosome 15

What is genomic imprinting?

A process where the specific gene expressed from a chromosome pair is determined by the sex of the parent transmitting it

Which parent’s genes are normally expressed in the Prader-Willi critical region?

Genes (PWS critical region) from the father are expressed; genes from the mother are normally inactivated

How does Prader-Willi syndrome occur?

Children have a deletion or disruption of the father’s chromosome 15 or have two copies of the region from the mother (maternal uniparental disomy)

What is a chromosomal duplication?

A duplication occurs when a chromosome segment is repeated in the same chromosome or in a non-homologous chromosome, producing extra alleles for a trait

What is a reciprocal translocation?

A reciprocal translocation occurs when two non-homologous chromosomes exchange information

What is a Robertsonian translocation?

• A Robertsonian translocation occurs when two non-homologous acrocentric chromosomes break at the centromere and their long arms fuse

• The short arms are often lost

What is the risk for translocation carriers?

Translocation carriers have a high risk of producing unbalanced gametes during meiosis due to chromosomal pairing problems

What can unbalanced gametes from translocation carriers lead to?

Unbalanced gametes can produce abnormal offspring and may result in embryonic death

What is a chromosomal inversion?

An inversion occurs when a segment of a chromosome is turned 180 degrees, reversing the sequence of alleles and potentially altering gene activity

How can crossing-over affect inverted chromosomes?

Crossing-over between inverted and normal chromosomes can produce recombinant chromosomes because the inverted segment must form a loop to align during meiosis