Diseases and genetics 6/10/22

Question 1

What is xeroderma pigmentosum and its symptoms?

Answer 1

XP causes extreme sensitivity to UV rays from sunlight which mostly affects the eyes and skin exposed to the sun, but the nervous system can also be involved.

Symptoms appear in infancy or early childhood by the child being extremely easily burnt, extreme facial freckling, eye sensitivity, vision impairment (cloudy cornea), dry skin, and changes in skin pigmentation.

There is a much higher chance of developing skin cancer, eye cancer, brain tumors, and lung cancer (if exposed to cigarettes).

30% of people with XP develop progressive neurological abnormalities such as hearing loss, poor coordination and walking, loss of intellect, swallowing, talking, and seizures.

Question 2

Is XP a loss or gain of function?

Answer 2

XP is a loss of function disorder.

Question 3

What is the inheritance of XP?

Answer 3

This is an autosomal recessive inherited condition.

Question 4

What genetics are involved in XP?

Answer 4

There are 8 forms of XP. Some forms of it are XPC, ERCC1 (neurological abnormalities), and a POLH variant type (XP-V).

Question 5

How common is XP?

Answer 5

Very rare, 1 in 1 million people. More common in Japan, North Africa, and the middle east.

Question 6

What causes XP?

Answer 6

Mutations occur in the genes responsible for repairing DNA damage. This means nucleotide excision repair and POLH doesn’t happen. For nucleotide excision repair (NER) XP, expression of XP requires inherited germline mutations of an NER gene as well as subsequent uncorrected somatic mutations of genes in skin cell.

Question 7

What is nucleotide excision repair in relation to XP?

Answer 7

UV radiation can make cytosine and thymine bases react with neighbouring bases that are also Cs or Ts, forming bonds that distort the double helix and cause errors in DNA replication. The most common type of linkage, a thymine dimer, consists of two thymine bases that react with each other and become chemically linked.

In nucleotide excision repair, the damaged nucleotide(s) are removed along with a surrounding patch of DNA. Helicase open the DNA to form a bubble, endonuclease cuts the DNA at site of dimer. An exonuclease removes the dimer and nearby nucleotides and a polymerase that fills the gap with DNA bases. DNA ligase seals the gap in the backbone of the strand. Inherited abnormalities in the NER-related genes prevent cells from carrying out one or more of these steps for people with XP.

Question 8

What is POLH in relation to XP?

Answer 8

POLH provides instructions for making a protein called DNA polymerase Eta. A mutation in POLH causes the XPV variant of XP.

POLH plays a critical role in DNA repair. The major function of DNA polymerase Eta is to replicate DNA that has been damaged, particularly by UV from sunlight. Most other DNA polymerases are unable to replicate DNA with this type of damage as the damage causes the replication process stalls.

When DNA polymerase Eta encounters UV-damaged DNA, it skips over the abnormal segment and continues copying. This is translesion synthesis which allows cells to tolerate some abnormalities created by UV exposure. Without this tolerance, unrepaired DNA damage would block DNA replication and cause apoptosis.

DNA polymerase eta is a relatively “error-prone” polymerase. When it bypasses damaged DNA, it often inserts an incorrect nucleotide. This type of error results in a mutation in the replicated DNA.

Question 9

What is Rubinstein-Taybi syndrome and its symptoms?

Answer 9

This condition is characterized by short stature, moderate to severe intellectual disability, distinctive facial features, and broad thumbs and first toes. Additional features of the disorder can include eye abnormalities, heart and kidney defects, dental problems, and obesity. There is also an increased risk of developing particular types of noncancerous brain and skin tumors.

Question 10

Is RST a loss or gain of function?

Answer 10

This is a loss of function disorder.

Question 11

What is the inheritance of RST?

Answer 11

This is an autosomal dominant pattern of inheritance, however, most people develop the condition from a mutation and not inheritance so will have no past history of the disease.

Question 12

What genetics are involved in RST?

Answer 12

Mutations in the CREBBP and EP300 are the most common cause.

Question 13

How common is RST?

Answer 13

It is uncommon as it occurs in an estimated 1 in 100,000 to 125,000 newborns.

Question 14

What causes RST?

Answer 14

Mutations in the CREBBP gene cause about half of the cases of RST. This gene provides instructions for making the protein CREB-binding protein. It helps control the activity of many other genes, regulating cell growth, cell division, and is essential for normal development before birth. One copy of the CREBBP gene is deleted or mutated in people with RST, their cells make only half of the normal amount of CREB binding protein.

Mutations in the EP300 gene cause a small percentage of cases of RST. This gene provides instructions for making the protein p300 which helps control the activity of other genes. It also appears to be important for development before and after birth. EP300 gene mutations result in the loss of one functional copy of the gene in each cell. EP300 causes milder symptoms.

Several cases of severe RST have resulted from a deletion of genetic material from the short (p) arm of chromosome 16. Multiple genes, including the CREBBP gene, are missing as a result of this deletion.

Question 15

What is CHOPs and its symptoms?

Answer 15

CHOPS syndrome has symptoms visible from birth. Features of the disorder include cognitive impairment, coarse facial features, heart defects, obesity, lung pulmonary involvement, short stature, and skeletal abnormalities.

Question 16

What is the inheritance of CHOPs?

Answer 16

CHOPS syndrome is inherited in an autosomal dominant pattern. All known cases of this condition result from new mutations in the gene that occurs during the formation of reproductive cells or in early embryonic development. Affected individuals have no history of the disorder in their family.

Question 17

Is CHOPs a loss or gain of function?

Answer 17

This is a gain of function mutation.

Question 18

What genetics are involved in CHOPs?

Answer 18

CHOPS syndrome is caused by mutations in the AFF4 gene.

Question 19

How common is CHOPs?

Answer 19

CHOPS syndrome is a rare disorder whose prevalence is unknown. Only a few affected individuals have been described in the medical literature.

Question 20

What causes CHOPs?

Answer 20

The AFF4 gene provides instructions for making part of a protein complex called the super elongation complex (SEC). During embryonic development, the SEC is involved in transcription. SEC works by re-starting the transcription of certain genes after pauses that normally occur, the SEC helps ensure that development proceeds appropriately before birth.

Mutations in the AFF4 gene are thought to result in an AFF4 protein that is not broken down when it is no longer needed, so more AFF4 protein is available than usual. The excess AFF4 protein interferes with normal pauses in transcription. This dysregulation of transcription leads to problems in the development of multiple organs and tissues.

Question 21

What are copy number variants?

Answer 21

Copy number variants refers to a circumstance in which the number of copies of a specific segment of DNA varies among different individuals’ genomes. The individual variants must be 100bp long but may be short or include thousands of bases. These structural differences may have come about through duplications, deletions or other changes and can affect long stretches of DNA. This can mean that the different disorders can be caused by the same gene.

Question 22

What is MECP2 and its symptoms?

Answer 22

MECP2 duplication syndrome is a condition that occurs almost exclusively in males and is characterized by moderate to severe intellectual disability. Most people with this condition also have weak muscle tone in infancy, feeding difficulties, poor or absent speech, or muscle stiffness.

Question 23

How common is MECP2?

Answer 23

The prevalence of MECP2 duplication syndrome is unknown. More than 200 affected individuals have been described in the scientific literature.

Question 24

What is Rett’s syndrome and its symptoms?

Answer 24

Rett syndrome is a brain disorder that occurs almost exclusively in girls. After birth, girls with classic Rett syndrome have 6 to 18 months of apparently normal development before developing severe problems with language and communication, learning, coordination, and other brain functions. Other signs and symptoms that can develop include breathing abnormalities, spitting or drooling, unusual eye movements such as intense staring or excessive blinking, cold hands and feet, irritability, sleep disturbances, seizures, and scoliosis.

Question 25

How common is Rett’s syndrome?

Answer 25

This condition affects an estimated 1 in 9,000 to 10,000 females.

Question 26

What causes MECP2 and Rett’s syndrome?

Answer 26

These are caused by a genetic change in which there is an extra copy of the MECP2 gene in each cell. This extra copy of the MECP2 gene is caused by a duplication of genetic material on the long (q) arm of the X chromosome 28. The size of the duplication varies from 100,000 to a few million DNA base pairs. The MECP2 gene provides instructions for making the protein MeCP2 which is critical for normal brain function. Although the exact function of the MeCP2 protein is unclear, it is likely involved in maintaining synapses between neurons. It may also be necessary for the normal function of other types of brain cells.

Question 27

What genetics cause MECP2 and Rett’s syndrome?

Answer 27

A mutation in which there is an extra copy of MECP2 on the long (q)arm of the x chromosome 28.

Question 28

How is the MECP2 mutation inherited?

Answer 28

Rett syndrome and MECP2 are caused by MECP2 gene mutations which have an X-linked dominant pattern of inheritance, however, in more than 99 percent of people with Rett syndrome, there is no history of the disorder in their family. Many of these cases result from new mutations in the MECP2 gene.

Males with mutations in the MECP2 gene often die in infancy. However, a small number of males with a genetic change involving MECP2 survive and have the disorder.

The reason why males only have MECP2 and females only have Rett’s syndrome is that males only have one X chromosome so when they have the disorder they experience more severe symptoms as they have no other X chromosome to take DNA from, whereas females have two X chromosomes so different cells will use different X chromosomes and therefore, girls may have the mutation but not display it or will display it but to a lesser extent as they have a second X chromosome to rely on.

Question 29

Fragile X syndrome and its symptoms?

Answer 29

Fragile X syndrome is a genetic condition that causes a range of developmental problems including learning disabilities and cognitive impairment. Symptoms are anxiety and hyperactive behaviour such as fidgeting or impulsive actions. They may have attention deficit disorder (ADD) and about one-third of individuals with fragile X syndrome have features of autism spectrum disorder that affect communication and social interaction. Seizures occur in about 15 percent of males and about 5 percent of females with fragile X syndrome. Facial features include a long and narrow face, large ears, a prominent jaw and forehead, unusually flexible fingers, flat feet, and in males, enlarged testicles (macroorchidism) after puberty.

Usually, males are more severely affected by this disorder than females.

Question 30

Is fragile X syndrome a loss or gain of function?

Answer 30

It is a loss of function mutation.

Question 31

What is the inheritance of fragile X Syndrome?

Answer 31

Fragile X syndrome is inherited in an X-linked dominant pattern. This is why men are more commonly affected as they only have one X chromosome.

Question 32

What genetics are involved in fragile X syndrome?

Answer 32

Mutations in the FMR1 gene cause fragile X syndrome.

Question 33

How common is fragile X syndrome?

Answer 33

Fragile X syndrome occurs in approximately 1 in 4,000 males and 1 in 8,000 females.

Question 34

What causes fragile X syndrome?

Answer 34

The FMR1 gene provides instructions for making the protein FMRP. This protein helps regulate the production of other proteins and plays a role in the development of synapses. Fragile X syndrome is a mutation in the CGG triplet repeat DNA segment, this is expanded within the FMR1 gene. Normally, this DNA segment is repeated about 5 to 40 times. In people with fragile X syndrome, however, the CGG segment is repeated more than 200 times. The abnormally expanded CGG segment silences the FMR1 gene, which prevents the gene from producing FMRP. A deficiency of this protein disrupts nervous system functions and leads to the signs and symptoms of fragile X syndrome.

Males and females with 55 to 200 repeats of the CGG segment are said to have an FMR1 gene premutation. Most people with this premutation are intellectually normal. In some cases, however, individuals with a premutation have lower-than-normal amounts of FMRP. As a result, they may have mild versions of the symptoms seen in fragile X syndrome.

The premutation is also associated with an increased risk of disorders called fragile X-associated primary ovarian insufficiency (FXPOI) and fragile X-associated tremor/ataxia syndrome (FXTAS).

Question 35

How do the extra base repeats occur in fragile X syndrome?

Answer 35

This can happen in two ways, slippage mispairing mechanism and unequal crossover.

Slippage mispairing happens when a strand of DNA is being replicated and the replicating strand detaches inappropriately from the template strand during the replication. The replicating strand has now slipped from its proper alignment with the template strand and the newly synthesized strand contains an extra repeat.

Unequal crossover happens during meiosis, maternal and paternal chromosomes align alongside each other, and recombination takes place via crossing over. Unequal crossing over requires a measure of similarity between the sequences for misalignment to occur. The more similarity within the sequences, the more likely unequal crossing over will occur.
Unequal crossing over may create a tandem repeat on one chromosome and a deletion on the other. The rate of unequal crossing over will increase with the number of repeated sequences around the duplication. This is because these repeated sequences will pair together, allowing for the mismatch in the cross over point to occur.

Question 36

What is Tay Sachs disease and its symptoms?

Answer 36

Tay Sachs is characterized by neurological problems caused by the death of neurons in the brain and spinal cord. Infantile Tay-Sachs disease is most common and becomes apparent early in life.

Symptoms are slowed development and weakening muscles, previously acquired skills such as turning over, sitting, and crawling are lost. Infants with this condition develop an exaggerated startle reaction to loud noises. As the disease progresses, children with Tay-Sachs disease experience involuntary muscle twitches (myoclonic jerks), seizures, difficulty swallowing (dysphagia), vision and hearing loss, and intellectual disability. An eye abnormality called a cherry-red spot, which is identified by eye examination, is characteristic of this disorder. Children with infantile Tay-Sachs disease usually live only into early childhood. Two other forms of Tay-Sachs disease, known as juvenile and late-onset, are rare.

Question 37

Is Tay Sachs a loss or gain of function?

Answer 37

It is a loss of function mutation.

Question 38

What inheritance is Tay Sachs disease?

Answer 38

This condition is inherited in an autosomal recessive pattern. This is inherited from parents who are not affected but have one recessive form of the disease.

Question 39

What genetics are involved in Tay Sachs disease?

Answer 39

Mutations in the HEXA gene cause Tay-Sachs disease.

Question 40

How common is Tay Sachs disease?

Answer 40

Tay-Sachs disease is very rare in the general population (1 in 300). The genetic variants that cause this disease are more frequently found in people of Ashkenazi (eastern and central European) Jewish heritage than in those with other backgrounds (1 in 25/30). The variants responsible for this disease are also more common in certain French-Canadian communities of Quebec, the Old Order Amish community in Pennsylvania, and the Cajun population of Louisiana.

Question 41

What causes Tay Sachs?

Answer 41

The HEXA gene provides instructions for making the alpha subunit of an enzyme called beta-hexosaminidase A. Beta-hexosaminidase A is located in lysosomes, which are structures in cells that break down toxic substances and act as recycling centers. Within lysosomes, beta-hexosaminidase A helps break down a fatty substance called GM2 ganglioside found in cell membranes.

Due to this enzyme deficiency, GM2 ganglioside accumulates to toxic levels, particularly in neurons in the central nervous system. Damage caused by the build-up of GM2 ganglioside leads to the dysfunction and eventual death of these neurons, which causes the signs and symptoms of Tay-Sachs disease.

HEXA gene variants that eliminate or severely reduce beta-hexosaminidase A enzyme function likely lead to the infantile form of Tay-Sachs disease, and variants that allow some residual enzyme activity tend to cause the juvenile or late-onset form of the condition.

Typically, a hexosaminidase A enzyme test will be done to confirm this disease.