Medical genetics involves the application of genetics for the diagnosis and management of hereditary disorders. With the advancement of medical technology, the scope of medical genetics has widened to include the gene interactions, control of gene expressions, gene variations, and environmental interactions. Genetic diseases are now categorized as classical and non-classical. Classical diseases include the chromosomal disorders, Mendelian disorders, and multifactorial disorders. In the non-classical genetic diseases, there is a single gene disorder with an atypical pattern of inheritance. They include the diseases caused by mutations in mitochondrial genes, triplet repeat mutations, genomic imprinting, gonadal mosaicism, uniparental disomy.
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Karyotype human 46,XX (woman)

Image: “Human karyotype.” by Doc. RNDr. Josef Reischig, CSc. – Author’s archive. License: CC BY-SA 3.0

History of Medical Genetics

Until the 21st century, medical genetics was considered as the detection and treatment of a few phenotypic rare hereditary disorders like:

  • Pre- and perinatal diagnosis
  • Analysis of congenital defects
  • Treatment of developmental abnormalities

Present of Medical Genetics

Advancement in the fields of genomics, proteomics and DNA sequencing allowed for the development of genomic medicine. This includes:

  • Personalized healthcare
  • Previvorship – surveying a condition before it happens
  • Predictive (precision) medicine
  • Potential application of gene therapies

Applying the analysis of human genome and its products to medicine, genetics and genomics go hand in hand. We now consider the following factors together:

  • Gene interactions
  • Control of gene expressions
  • Gene variations
  • Environmental interaction

Categories of Genetic Diseases

Classical genetic diseases

  • Chromosomal disorders
  • Single gene disorders (Mendelian disorders/unifactorial disorders)
  • Multifactorial disorders

Non-classical genetic diseases

These are single gene disorders with atypical pattern of inheritance.

  • Diseases caused by mutations in mitochondrial genes
  • Triplet repeat mutations
  • Genomic imprinting
  • Gonadal mosaicism
  • Uniparental disomy

There are a large group of disorders, congenital malformations, which manifest at birth. Genetic disorders cause many of these.

Chromosomal Disorders

Each nucleated cell in the human body has 46 chromosomes in the form of 22 homologous pairs and 1 pair of sex chromosomes that can either be XX or XY. The arrangement of these pairs on the length of upper and lower arms of the chromosomes, based on the position of the centromere, is known as a karyotype.

  • Chromosomal disorders are large scale mutations of chromosomes.
  • There is no mutation in individual genes.
  • There is a duplication or deletion of smaller segments.
  • An estimate of 1 in every 200 newborns has some form of chromosomal abnormality.

Chromosomal disorders can effect autosomes or sex chromosomes, and they can be a result of an alteration in the number or structure. Hence,

  • Numerical abnormalities
  • Structural abnormalities

Numerical abnormalities

There is a gain or loss of one or more chromosomes, autosomal or recessive. A whole set of chromosomes can also be affected.

As the chromosomes are arranged in two sets (2n), the normal chromosomal count is 46.

  • genetic pattern of trisomy 21

    Image: “Trisomy 21” by UPO649 1112 mreycor1. License: CC BY-SA 3.0

    Euploid: an exact multiple of haploid number n.

  • Aneuploid: any number other than the exact multiple of haploid number n. (It is the most common change seen in malignant tissues.)
  • Polyploidy: A gain of one or more sets of chromosomes. Polyploidy is not long lived; it results in abortions. It can be of two types:
    • Triploidy is when cells have 3n.
    • Tetraploidy is when cells have 4n.
  • Trisomy: It is the gain of one chromosome. Examples of autosomal trisomies are:
    • Trisomy of chromosome 21 is called Down’s syndrome
    • Trisomy of chromosome 18 is called Edward’s syndrome
    • Trisomy of chromosome 13 is called Patau’s syndrome
    • Autosomal trisomies are not very common. Examples of trisomy of the sex chromosome are:
      • Klinefelter’s syndrome (XXY) in males
      • Triple X (XXX) syndrome in females
  • Monosomy: It is a loss of one chromosome. Turner’s syndrome (45 XO) is the monosomy of sex chromosome in a female.

All trisomies and monosomies by definition are aneuploidies.

Gain or loss of X and Y chromosomes is more common. It is compatible with life. However, any loss of autosomal chromosomes leads to abortions in the early stages of pregnancy.

The causes of trisomy and monosomy:

  • Nondisjunction of a homologous pair of chromosomes at the 1st meiotic division
  • A failure of sister chromatids to separate during the 2nd meiotic division
  • A failure of sister chromatids to separate during somatic cell division, leading to the production of two aneuploidy cells

Structural abnormalities

In the case of structural abnormalities, chromosome number is normal, but there are morphological and structural abnormalities. The usual cause of such abnormalities is chromosomal breakage resulting in loss or rearrangement of material.

Types of structural abnormalities are as follows:

  • Deletion is the loss of a terminal or interstitial piece of chromosome.
    • Terminal: There is only one break in the chromosome, and the portion distal to the break is lost. Loss of this piece produces signs and symptoms based on the genes that were lost.
    • Interstitial: There are two breaks, and the piece between these two breaks is lost, resulting in a shorter chromosome. The consequences are the same as that of terminal Example: Cri du chat which is the loss of short arm of chromosome.
  • Inversion: There are two breaks in the chromosome. The piece between these two breaks rotates 180 degrees and is fixed back in the same rotated position. The breaks can involve either the short arm or the long arm. This type of inversion is called paracentric. The break can also involve both arms and is called pericentric. This type is more severe.
  • Translocation is the exchange of chromosome segments between the non-homologous chromosomes.
  • Isochromosomes: this type of abnormality results from the aberrant division of the centromere. The resulting chromosomes are such that once is formed of two short arms and the other has two long arms. Each of these is called isochromosome. They are seen in some cases of Down’s syndrome and Turner’s syndrome.
  • Ring chromosomes: there is a deletion of both ends of chromosomes and these ends, due to sticky nature of DNA, stick together to form a ring or a circle shaped chromosome.

Single Gene Disorders (Mendelian Disorders/Unifactorial Disorders)

There are more than 5,000 known Mendelian disorders. They account for a total 1 % of adult hospital admissions and 6-8 % of all hospital pediatric admissions. These disorders represent the most common genetic abnormality. They are caused by mutation in a single gene.

Part of the DNA that codes for a polypeptide chain is called a gene. DNA that codes directly for information is only 2 %. Non-coding sequence within the genes (intronic sequence) is 24 %. The remaining 74 % is the non-coding sequence that is outside the genes. There are almost 30,000 genes in the human body.

Exon is the coding sequence of the genes. Some genes have many exons, and some have only a few. Some genes are large in size while others are small. This is the reason why chromosomal deletion or duplication of some genes have minimal or no clinical presentation.

Genes behave as:

  • Dominant, i.e. when only one of the alleles becomes mutated it results in a genetic disease
  • Recessive, i.e. the diseases result only when both alleles (of both the maternal and paternal origin) are affected by the same mutation
  • The 3rd category of genes is the ones that are situated on the sex chromosomes, but they determine the autosomal character. They are called sex-linked genes.

So we have:

  • Autosomal dominant (AD) disorders
  • Autosomal recessive (AR) disorders
  • Sex-linked disorders

Why do some genes act in a dominant manner while others behave in a recessive one?

Previously, it was thought that one gene is responsible for the formation of only one type of protein. However, today, the fact is that a single gene is responsible for the formation of a single type of polypeptide. The structure and function of our body is determined by proteins. There are different kinds such as:

  • Structural proteins (fibrous tissue, elastic tissue)
  • Immunoglobulins
  • Signal transducing proteins
  • Receptors
  • Enzymes
  • Hormones

Whether the action of a gene is dominant or recessive, depends upon the type and function of the protein being produced by that gene, e.g. HLA and ABO blood group antigens.

Usually, the dominant genes produce following types of proteins:

  • Major structural/non-enzymatic proteins, which form or are present in many parts of the body such as:
    • Collagen
    • Spectrin
    • Fibrillin
    • Elastin

Mutation in genes producing these proteins will lead to achondroplasia, Ehlers-Danlos syndrome, etc.

  • A key enzyme in a complex metabolic pathway usually under feedback control e.g. AD porphyria.
  • A membrane receptor regulating a metabolic pathway, e.g. when the receptors for LDL are mutated, it leads to AD familial hypercholesterolemia disease.
  • Membrane transport proteins.

Therefore, one single defected copy of a dominant gene can produce signs and symptoms related to the deficient protein.

Relevant terms

  • Pleiotropy: Multiple phenotypic effects are seen as a result of single gene mutation. For example, there is skeletal, cardiovascular and eye defect in Marfan’s syndrome.
  • Genetic heterogeneity: When the same trait is produced as a result of mutations at several genetic loci. For example, retinitis pigmentosa.
  • Recessive genes usually produce those enzymes which share in catabolic pathways and are generally non-key enzymes. Loss of one copy of the gene is compensated by the other copy of the active and normal gene, and therefore, 50 % of the protein is still present. Examples:
    • Some types of thalassemia
    • Mucopolysaccharidosis
    • Lipidosis
    • Phenylketonuria (PKU)
Autosomal Dominant Pedigree Chart

Image: “Autosomal dominant pedigree chart. In autosomal dominance the chance of receiving and expressing a particular gene is 50 % regardless of the sex of parent or child.” by Jerome Walker – Own work. License: CC BY 2.5

Sex-linked diseases

The pattern of sex-link disease transfer is shown in the following figures.

Gene mutations can be of following types:

  1. Point mutations: single base substitution, which is the most common type.
    •  Silent
    • Neutral
    • Missense
    • Non-sense
    • Longer protein
  1. Unequal crossing over

    Autosomal recessive pedigree chart

    Image: “An example of a family pedigree displaying an autosomal recessive trait.” by Jerome Walker – Own work. License: CC BY 2.5

  1. Addition or deletion mutation
    • Single base addition/deletion leads to frame shift
    • Two bases lead to frame shift mutation
    • 3 or a multiple of 3
    • A piece of DNA

Multifactorial Disorders

Multifactorial disorders affect many of the physiologic characteristics such as:

  • Weight
  • Height
  • Blood pressure
  • Hair color

These disorders have abnormalities in two or more genes of small effect, but environmental non-genetic factors are also involved. Even monozygotic twins can have different weights and heights because of environmental influences. Examples of multifactorial disorders are:

Future of Medical Genetics

Ever expanding database of human genetic variations, and our understanding of genomics will inevitably lead to extensive discovery and development in public health and availability of tools in practice medicine.

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