Inheritance of Autosomal Dominant and X-linked

Babak Nami Department of Medical Genetics Seluk University

Mendelian diseases
Definition: Diseases in which the phenotypes are largely determined by the action, lack of action, of mutations at individual loci. Rare 1% of all live born individuals 4 types of inheritance :Autosomal dominant :Autosomal recessive :X linked dominant :X linked recessive

Autosomal Dominant Inheritance

A genetic trait is often said to be dominant or recessive. A dominant trait is more likely to cause disease, because only one of the two copies of each gene needs to be damaged. The single defective copy is sufficient to over-ride the normal functioning copy, resulting in abnormal protein functioning or expression.

 In dominant genetic diseases, the "bad" gene overcomes the "good" gene and disease occurs.

In recessive genetic diseases, the good" gene overcomes the bad" gene

 More than half of Mendelian diseases inherited as an autosomal dominant. Autosomal dominant diseases are related with geographical regions. For example incidence of some diseases for different regions: Huntington, Familial hypercholesterolemia.

List of autosomal dominant disorders

Marfans Syndrome Huntingtons Disease Adult Polycystic Kidney Disease Hereditary Spherocytosis Familial Hypercholesterolemia Ostegenesis Imperfecta Tuberous Sclerosis Myotonic Dystrophy Criggler Najar type 2 Neurofibromatosis Retinoblastoma Retinitis Pigmentosa Van Hippel Lindaus Disease Von Willebrands Disease Acute Intermittent Porphyria Hereditary Hemangiotelangiectasia Breast CA (BRCA 1, BRCA 2) Romano Ward Syndrome Idiopathic Hypertrophic Subaortic Stenosis Noonans Syndrome Multiple Endocrine Neoplasia (Type 1. 2a, 2b)

Incomplete dominant inheritance

A heterozygous condition in which both alleles at a gene locus are partially expressed, often producing an intermediate phenotype.
Incomplete dominance is when the two alleles inherited from the parents are neither dominant or recessive, but blend together to give a physical trait that is somewhere between the two.

Autosomal dominant inheritance:

Achondroplasia
Inherited in an autosomal dominant disorder that is a common cause of dwarfism. Achondroplastic dwarfs have short stature, with an average adult height of 131 cm (4 feet, 3 inches) for males and 123 cm (4 feet, inch) for females.
Jason Acuna, alias "Wee-Man", a star of Jackass

Autosomal dominant inheritance:

Achondroplasia
occurs as a sporadic mutation in approximately 85% of cases (associated with advanced paternal age). In normal circumstances, FGFR3 (Fibroblast growth factor receptor 3) has a negative regulatory effect on bone growth. In Achondroplasia, the mutated form of the receptor is constitutively active and this leads to severely shortened bones.

Autosomal dominant inheritance:

Achondroplasia
People with achondroplasia have one normal copy of the fibroblast growth factor receptor 3 gene and one mutant copy. Two copies of the mutant gene are invariably fatal before or shortly after birth. Only one copy of the gene has to be present for the disorder to occur. The prevalence is approximately 1 in 25,000 birth.

Autosomal dominant inheritance:

Achondroplasia
New gene mutations leading to achondroplasia are associated with increasing paternal age. new gene mutations for achondroplasia are exclusively inherited from the father and occur during spermatogenesis. In about 98% of cases, a G to A point mutation at nucleotide 1138 of the FGFR3 gene causes a glycine to arginine. About 1% of cases are caused by a G to C point mutation at nucleotide 1138.

Autosomal dominant inheritance:

Familial hypercholesterolemia
FH is a autosomal dominant disorder characterized by high cholesterol levels, specifically very high levels of LDL, (bad cholesterol), in the blood and early cardiovascular diseases.

Xanthelasma palpebrarum , yellowish patches consisting of cholesterol deposits above the eyelids. These are more common in people with FH.

New mutation in autosomal dominant inheritance

In a autosomal dominant pedigree, each patient has a suffer parent. This status continues to back until reach to the responsible mutation. In fact the most conditions of dominances resulted not only inheritance of mutant allele from carrier parent, associate with an spontaneous mutation in a gamete from parent, (new gene mutations leading to achondroplasia are associated with increasing paternal age).

Example of autosomal dominant conditions include Tuberous sclerosis, neurofibromatosis and many other cancer causing mutations such as retinoblastoma.

Sex limited phenotype in autosomal dominant disorders

Some autosomal genes may only come to phenotypic expression in one of the sexes (either male or female). Any of the secondary Sexual characters of man depend on sex limited genes, i.e. the development of beard in man and development of mammary glands (breasts) in women.

Sex limited phenotype in autosomal dominant disorders

Male-limited precocious puberty is an autosomal dominant condition that appear only in boys with a mutation of the LH receptor. It is a form of gonadotropin-independent precocious puberty in which boys experience early onset and progression of puberty. Signs of puberty can develop as early as an age of 1 year. he spinal length in boys may be short due to a rapid advance in epiphyseal maturation.

Feature of autisomal dominant traits

Phenotype appears in every generation (usually). Each suffer has a sick parent, except: 1- New mutation cases; 2- Ineffective wasted allele cases. The probability of trait inheritance from a sick parent to children is 50%. When parent are normal in terms of phenotype, will not transfer the abnormal phenotype to their children. The probability of transfer by mother and father is identical.

X-Linked Inheritance
X-linked diseases are single gene disorders that reflect the presence of defective genes on the X chromosome. X chromosome contains about 1100 genes in which 40% are associated with disorder phenotypes. This chromosome is present as two copies in females but only as one copy in males.

X-Linked Inheritance
Some genetics experts suggest that the dominant and recessive terms not used for X-linked disorders. Heterozygote show the influence in more than 85% of women.

X-linked recessive inheritance

X-linked recessive inheritance is a mode of inheritance in which a mutation in a gene on the X chromosome causes the phenotype to be expressed in males (who are necessarily hemizygous
for the gene mutation because they have only one X chromosome) and in females who are homozygous for the gene mutation (i.e., they have a copy of the gene mutation on each of their two X chromosomes).

Haemophilia
Haemophilia is a X-linked recessive disorder that impair the body's ability to control blood clotting or coagulation, which is used to stop bleeding when a blood vessel is broken.

Queen Victoria passed haemophilia on to some of her descendants.

Haemophilia
Haemophilia A (clotting factor VIII deficiency) is the most common form of the disorder, occurring at about 1 in 5,00010,000 male births. Haemophilia B (factor IX deficiency) occurs at about 1 in about 20,00034,000 male births. Haemophilia is more likely to occur in males than females. Because females have two X chromosomes and haemophilia is rare.

Feature of X-linked recessive traits

The incidence is higher in male than women. Heterozygous women are Healthy, but not always. The liable gene inherits to all daughters from father. The mutant allele is not passed directly from father to sons (never). But can be transfer to grandsons through daughters. Significant percentage of cases related to nevel mutations.

X-linked dominant inheritance

It is a mode of genetic inheritance by which a dominant gene is carried on the X chromosome. As an inheritance pattern, it is less common than the X-linked recessive type. only one copy of the allele is sufficient to cause the disorder when inherited from a parent who has the disorder. All daughters of an affected father will also be affected but none of his sons will be affected (unless the mother is also affected)

X-linked dominant inheritance works differently depending upon whether the mother (left image) or father (right image) is the carrier of a gene that causes a disease or disorder.

X-linked dominant inheritance

In X-linked dominant inheritance, when the mother alone is the carrier of a mutated, or defective gene associated with a disease or disorder; she herself will have the disorder. Her children will inherit the disorder as follows: Of her daughters and sons: 50% will have the disorder, 50% will be completely unaffected

X-linked dominant inheritance

When the father alone is the carrier of a defective gene associated with a disease or disorder, he too will have the disorder: Of his daughters: 100% will have the disorder, since all of his daughters will receive one copy of his single X chromosome. Of his sons: none will have the disorder; sons do not receive an X chromosome from their father

X-linked dominant inheritance

If both parents were carriers of a defective gene associated with a disease or disorder, they would both have the disorder: Of their daughters: 100% will have the disorder, since all of the daughters will receive a copy of their father's X chromosome. Of the sons: 50% will have the disorder, 50% will be completely unaffected. Sons have an equal chance of receiving either of their mother's X chromosomes.

X-linked hypophosphatemia (XLH) rickets

X-linked hypophosphatemia (XLH) is an X-linked dominant disorder characterized by growth retardation, rickets (softening and weakening of the bones), and hypophosphatemia (too little PO4 in the blood) due to kidney defects in phosphate reabsorption and Vitamin D metabolism. The condition can be caused by mutations in the phosphate-regulating endopeptidase gene, also known as the PHEX gene and is nearly always inherited.

X-linked male-lethal disorders

There are some x-linked dominant disorder that cause death in male before birth. These anomalies seen more in women. The passage of these model disorder is only by carrier or involved mother. A famous example is Rett syndrome

Rett syndrome
Rett syndrome is a neurodevelopmental disorder of the grey matter of the brain that affects girls almost exclusively. It is caused by mutations in the gene MECO2 located on the X chromosome. In less than 10% of Rett Syndrome cases, mutations in the genes CDKL5 or FOXG1 have also been found to cause Rett Syndrome

 The clinical features include small hands and feet and a deceleration of the rate of head growth (including microcephaly in some). Rett syndrome is usually caused (95% or more) by a de novo mutation in the child, i.e., not inherited from either parent Male fetuses with the disorder rarely survive to term.

Feature of X-linked recessive traits

In childbearing of Suffer men and normal women: no sick son and no normal daughter. In terms of number, female patients are twice than male patients. Female indicate phenotype as lighter than male.

Enovy
I prefer to walk with shoes and think about God, to sit in the mosque and think the shoes. Ali Shariati