GENETIC DISORDERS

Nabil MTIROUI, MSc. PhDLecture 6

Nondisjunction – a problem with meiosis

A “junction” is a place of meeting or joining. So, to “disjunct” is to unjoin – or separate… During which phase of meiosis do the

chromosomes separate? Anaphase I and Anaphase II So nondisjuction indicates that the

chromosomes (or chromatids) do not separate as they should…

Nondisjunction results in sex cells

Nondisjunction disorders

During fertilization, a “normal” sperm is joined with a egg that has either an extra or is missing a chromosome.

The chromosome involved will determine the disorder.

Larger chromosomes involved with nondisjunction will often result in miscarriage.

The Karyotype…

Trisomies with the sex chromosomes

Klinefelter syndrome : 47, XXY males. Male sex organs; unusually small testes, sterile. Breast enlargement and other feminine body characteristics. Normal intelligence.

Trisomies with the sex chromosomes

47, XYY males : Individuals are somewhat taller than average and often have below normal intelligence. At one time (~1970s), it was thought that these men were likely to be criminally aggressive, but this hypothesis has been disproven over time.

Trisomy X: 47, XXX females. 1:1000 live births - healthy and fertile - usually cannot be distinguished from normal female except by karyotype

Trisomies with the sex chromosomes

Monosomy X (Turner's syndrome): 1:5000 live births; the only viable monosomy in humans - women with Turner's have only 45 chromosomes!!! XO individuals are genetically female, however, they do not mature sexually during puberty and are sterile. Short stature and normal intelligence. (98% of these fetuses die before birth)

Trisomies in Autosomes

Patau syndrome (trisomy 13) : serious eye, brain, circulatory defects as well as cleft palate. 1:5000 live births. Children rarely live more than a few months.

Trisomies in Autosomes

Edward's syndrome (trisomy 18): almost every organ system affected 1:10,000 live births. Children with full Trisomy 18 generally do not live more than a few months.

Down’s syndrome

Down syndrome (trisomy 21): The result of an extra copy of chromosome 21. People with Down syndrome are 47, 21+. Down syndrome affects 1:700 children and alters the child's phenotype either moderately or severely:

Down Syndrome is correlated with age of mother but can also be the result of nondisjunction of the father's chromosome 21.

Maternal age is an important factor…

Other genetic disorders Sickle Cell Anemia – this genetic disorder is

autosomal homozygous recessive (ss). Autosomal means that it is NOT a gene on the sex

chromosomes and so males and females will have equal inheritance.

Homozygous recessive means that the person will have two recessive genes. This person must inherit a recessive gene from both the mother and the father. (Both the mother and father would be heterozygous).

 Ss X Ss

Two heterozygous parents would have a 1 in 4 (25%) chance of having a child with Sickle Cell Anemia.

S s

S SS Ss

s Ss ss

Heterozygote Advantage

This is due to the fact that the heterozygote (carrier) has an increased resistance to malaria. If you follow the family history of the people that are carriers back in time, most likely their ancestors are from central Africa where malaria was a problem hundreds of years ago. The carriers were more likely to have survived malaria and passed their genes on to their offspring. This has kept this gene in the population.

Sickle cell anemia is more common in African Americans

The heterozygote has survival advantage.

Tay Sach’s Disease

Tay Sach’s Disease – this disorder is also autosomal homozygous recessive. A baby with Tay Sach’s would have to inherit a recessive gene from each parent.

Tt X Tt

Again, there is a 25% chance of these two parents having a child with Tay Sach’s disease.

T t

T TT Tt

t Tt tt

Cystic Fibrosis

Cystic Fibrosis – this disorder is autosomal homozygous recessive. A person with Cystic Fibrosis had to have inherited a recessive gene from each parent. Both parents would be carriers. (heterozygous).

Cc X Cc

Again, there is a one in four chance of having a child with Cystic Fibrosis.

C c

C CC Cc

c Cc cc

Heterozygote advantage

Cystic fibrosis is most common in Caucasians (whites) whose ancestors can be traced back to western Europe. As with the disease discussed above, the heterozygote (carrier) has resistance to a disease. In this case, it is Cholera. Cholera depletes the system of fluid very rapidly and having slightly thicker body fluids is an advantage in surviving Cholera.

Phenylketonuria (PKU)

This disorder is autosomal homozygous recessive. (Can you guess the inheritance pattern?). The person would receive a recessive gene from each parent. Commonly, both parents would be heterozygous and would have a one in four chance of having a child with PKU.

Pp X Pp

P p

P PP Pp

p Pp pp

Hemophilia

This disorder is caused by a sex-linked recessive gene. It has the same inheritance pattern as colorblindness. Males will have this disorder if they inherit the gene from only one parent (the mother). Females would have to receive this gene from both parents.

XHXh x XHY

Neither parent has hemophilia, but the mother is a carrier (heterozygous).

With a carrier mother and a normal father, the daughters have a 50% chance of being a carrier, but will NOT have hemophilia. The sons have a 50% chance of having hemophilia.

XH Xh

XH XHXH XHXh

Y XHY XhY

Huntington’s Disease

This disease has an unusual inheritance pattern for a genetic disorder. It is caused by an autosomal dominant gene.

What this means is that any person that develops Huntington’s disease will have a parent that has had this disorder.

Hh X hh

All children of a person with Huntington’s have a 50% chance of developing this disorder.

H h

h Hh hh

h Hh hh

Prenatal testing

This procedure involves the insertion of a long needle into the woman’s abdomen and the removal of a small amount of amniotic fluid (about 2 teaspoons).

This test is done after the 15th week of pregnancy and the location of the fetus is monitored with ultrasound.

This is a relatively safe test, but does carry about a 1 in 200 risk of miscarriage.

The test is not done on all pregnant women – only those that carry a higher risk of genetic abnormalities (those with genetic disorders in their family history or women over 35).

Amniocentesis Amniocentesis

Prenatal testing

This procedure is done between the 10th and 12th week of pregnancy and involves the removal of a small amount of the placenta.

This can be done either with the insertion of a needle through the abdomen or with a catheter inserted through the vagina and cervix.

There is a slightly higher risk of miscarriage with this procedure than with amniocentesis.

Chorionic Villi Sampling CVS

Many disorders that can be determined with prenatal testing.

Achondroplasia Huntington disease Cystic fibrosis Sickle cell disease Tay-Sachs disease Beta-thalassemia Chromosomal disorders such as

Down’s syndrome Spina bifida Anencephaly