Classification of Hereditary and Genetic Disorders

108Genetic disorder are either hereditary disorders or a result of mutations. Some disorders may confer an advantage, at least in certain environments. There are a number of pathways to genetic defects, the simplest of which are summarized below.

There are genetic disorders caused by the abnormal chromosome number, as in Down syndrome (three instead of two “number 21” chromosomes, therefore a total of 47).
Triplet expansion repeat mutations can cause fragile X syndrome or Huntington’s disease, by modification of gene expression or gain of function, respectively.

Defective genes are often inherited from the parents. In this case, the genetic disorder is known as a hereditary disease. This can often happen unexpectedly when two healthy carriers of a defective recessive gene reproduce, but can also happen when the defective gene is dominant.

Currently around 4,000 genetic disorders are known, with more being discovered. Most disorders are quite rare and affect one person in every several thousands or millions. Cystic fibrosis is one of the most common genetic disorders; around 5% of the population of the United States carry at least one copy of the defective gene.

Terms you should know:

GENE: A small segment of DNA that codes for the synthesis of a specific protein. Genes are located on the chromosomes. Examples: ABO blood group gene, Rh blood group gene.

CHROMOSOMES: genes for the same traits, in the same order.

LOCUS: Position or location of a gene on a chromosome.

ALLELE: Refers to the different forms of a gene at one locus.

GENOTYPE: The specific pair of alleles present at a single locus. This are features seen genetically but may or may not have phenotypic (observable) characteristics.

PHENOTYPE: The clinical features or the observable characteristics of an individual determined by a pair of genes at a given locus (or genotype). The phenotype can vary following interaction with modifying genes or the environment.

PENETRANCE: The frequency with which individuals carrying a given gene will show the clinical manifestations associated with the gene.

DOMINANT: A gene (allele) which is expressed clinically in the heterozygous state. In a dominant disorder only one mutant allele need be present as it covers up, or masks, the normal allele.

RECESSIVE A gene (allele) which is only expressed clinically in the homozygous state i.e. it can be suppressed if present with a dominant gene and will not show it’s character in presence of a dominant gene. In a recessive disorder, both genes at a given locus must be abnormal to manifest the disorder

Types of Genetic Disorders

1 Single gene disorders including Mendelian Disorders (i.e, follow mendelian order of inheritance i.e. Autosomal and X-linked and Y-linked) and Non-Mendelian disorders (i.e, do not follow mendelian order of inheritance e.g. mitochondrial inheritance)

2 Multifactorial and polygenic disorders

3 Disorders with variable modes of transmission

4 Cytogenetic disorder: including autosomal disorders and sex chromosome disorders.

I] Single gene disorders

Where genetic disorders are the result of a single mutated gene they can be passed on to subsequent generations in the ways outlined in the table below. Genomic imprinting and uniparental disomy, however, may affect inheritance patterns. The divisions between recessive and dominant are not “hard and fast” although the divisions between autosomal and X-linked are (related to the position of the gene).

For example, achondroplasia is typically considered a dominant disorder, but young goats or children with two genes for achondroplasia have a severe skeletal disorder that achondroplasics could be viewed as carriers of. Sickle-cell anemia is also considered a recessive condition, but carriers that have it by half along with the normal gene have increased immunity to malaria in early childhood, which could be described as a related dominant condition.

Subclasses of single gene disorders are as follows:

Autosomal dominant Only one mutated copy of the gene is needed for a person to be affected by an autosomal dominant disorder. Each affected person usually has one affected parent. There is a 50% chance that a child will inherit the mutated gene. Conditions that are autosomal dominant have low penetrance, which means that, although only one mutated copy is needed, a relatively small proportion of those who inherit that mutation go on to develop the disease, often later in life.

E.g. Huntingtons disease, Neurofibromatosis 1, Marfan Syndrome.

Autosomal recessive Two copies of the gene must be mutated for a person to be affected by an autosomal recessive disorder. An affected person usually has unaffected parents who each carry a single copy of the mutated gene (and are referred to as carriers). Two unaffected people who each carry one copy of the mutated gene have a 25% chance with each pregnancy of having a child affected by the disorder. E.g. Cystic fibrosis, Sickle cell anemia, Tay-Sachs disease, Spinal muscular atrophy.

X-linked dominant X-linked dominant disorders are caused by mutations in genes on the X chromosome. Only a few disorders have this inheritance pattern. Males are more frequently affected than females, and the chance of passing on an X-linked dominant disorder differs between men and women. The sons of a man with an X-linked dominant disorder will not be affected, and his daughters will all inherit the condition. A woman with an X-linked dominant disorder has a 50% chance of having an affected daughter or son with each pregnancy. Some X-linked dominant conditions, such as Aicardi Syndrome, are fatal to boys, therefore only girls have them (and boys with Klinefelter Syndrome).

E.g Hypophosphatemia, Aicardi Syndrome,

X-linked recessive X-linked recessive disorders are also caused by mutations in genes on the X chromosome. Males are more frequently affected than females, and the chance of passing on the disorder differs between men and women. The sons of a man with an X-linked recessive disorder will not be affected, and his daughters will carry one copy of the mutated gene. With each pregnancy, a woman who carries an X-linked recessive disorder has a 50% chance of having sons who are affected and a 50% chance of having daughters who carry one copy of the mutated gene.

E.g Hemophilia A, Duchenne muscular dystrophy, Color blindness, Muscular dystrophy, Androgenetic alopecia and also includes G-6-PD (Glucose-6-phosphate dehydrogenase) deficiency.

Y-linked Y-linked disorders are caused by mutations on the Y chromosome. Only males can get them, and all of the sons of an affected father are affected. Since the Y chromosome is very small, Y-linked disorders only cause infertility, and may be circumvented with the help of some fertility treatments.

E.g.Male Infertility

Mitochondrial This type of inheritance, also known as maternal inheritance, applies to genes in mitochondrial DNA. Because only egg cells contribute mitochondria to the developing embryo, only females can pass on mitochondrial conditions to their children.

E.g. Leber’s Hereditary Optic Neuropathy (LHON)

II] Multifactorial and polygenic disorders

Genetic disorders may also be complex, multifactorial or polygenic, this means that they are likely associated with the effects of multiple genes in combination with lifestyle and environmental factors. Multifactoral disorders include heart disease and diabetes. Although complex disorders often cluster in families, they do not have a clear-cut pattern of inheritance. This makes it difficult to determine a person’s risk of inheriting or passing on these disorders.

Complex disorders are also difficult to study and treat because the specific factors that cause most of these disorders have not yet been identified. On a pedigree, polygenic diseases do tend to “run in families”, but the inheritance does not fit simple patterns as with Mendelian diseases. But this does not mean that the genes cannot eventually be located and studied. There is also a strong environmental component to many of them (e.g., blood pressure).

E.g Gout: It is a genetic/acquired disorder of uric acid metabolism that leads to hyperuricemia and consequent acute and chronic arthritis. The recurrent but transient attacks of acute arthritis are triggered by the precipitation of monosodium urate crystals into joints from supersaturated body fluids which accumulate in and around the joints and other tissues causing inflammation.

Cause of gout: Unknown enyme defects or known enzyme defects leading to overproduction of uric acid like partial deficiency of hypoxanthine guanine phosphoribosyl transferase (HGPRT) enzyme (as person lacks the genes to produce this enzyme). Also high dietary intake of purines as in pulses, as purines are metabolized to uric acid. Thus it has both a genetic (due to enzyme malfunction) and environmental predisposition(such as diet) and hence multifactorial.
Other examples are

heart disease, hypertension, diabetes, obesity, cancers.

III]Disorders With Variable Modes of Transmission:

Heredity malformations are congenital malformations which may be familial and genetic or may be acquired by exposure to teratogenic agents in the uterus. Heredity malformations are associated with several modes of transmission. Some multifactorial defects are cleft lip, congenital heart defects, pyloric stenosis etc. Certain congenital malformations are either multifactorial or by a single mutant gene (thus a different class of their own).

E.g. Ehlers-Danlos Syndrome: It is characterized by defects in collagen synthesis and structure. These abnormal collagen fibres lack adequate tensile strength and hence the skin is hyperextensible and the joints are hypermobile. Causes include either of the following- deficiency of the enzyme lysyl hydroxylase, deficient synthesis of type 3 collagen due to mutations in their coding genes, and deficient conversion of procollagen type 1 to collagen due to mutation in the type 1 collagen gene.

IV]Cytogenetic Disorders:

These may be from alterations in the number or structure of the chromosomes and may affect autosomes or sex chromosomes.

E.g. Fragile X chromosome. It is characterized by mental retardation and an inducible cytogenetic abnormality in the X chromosome. It is one of the most common causes of mental retardation. The cytogenetic alteration is induced by certain culture conditions and is seen as a discontinuity of staining or constriction of in the long arm of the X-chromosome.

Other disorders include Down’s Syndrome in which the number of chromosomes is increased by a third “21st chromosome” and hence a total of 47 chromosomes occur.