Genetic Disorder: Cause, Types, Diagnosis, and Treatment

Genetic Disorder: Have you heard of a disease called the royal disease? It is medically known as haemophilia. The name royal disease was given to haemophilia because the royal family of England was affected by this hereditary disease.  It is believed that Queen Victoria was the carrier of the gene, which her children inherited, and it led to the death of most male children at a young age for many generations. It is astounding how a single gene can lead to a fatal condition for generations. Read along to learn more fascinating things about genetic disorders, types, diagnosis, and treatment.

What is Genetic Disease?

A genetic disorder or genetic disease is defined as the condition in which disease appears due to one or more abnormalities in the genome of an individual. A genetic disease can be inherited from generation to generation. The effect of a genetic disease can be minor to lethal depending on the gene affected. Genetic diseases can be caused due to various factors like Single gene mutation, Multiple gene mutations, environmental factors, Damaged chromosomes, chromosomal aberration, etc.

Types of Genetic Disorder

A genetic disease can be categorized  into four broad categories:

1. Single Gene Inheritance

Single gene inheritance is caused due to mutation in a single gene. These are also called monogenic disorders, and these genes follow the Mendelian pattern of inheritance; hence they are often called Mendelian disorders. This disease can be diagnosed by pedigree analysis.

Single gene inheritance can be of four types: Autosomal dominant, autosomal recessive, sex-linked dominant, sex-linked recessive.

Fig: Types of Mendelian Disorders

(a) Autosomal Recessive Disease

Autosomal recessive diseases are those where both copies of a mutated gene located in the autosome are required to affect an individual. If only one copy of a gene is present, the person becomes a carrier but does not affect the individual. If one of the parents is affected by this, there is a 25% chance that the child will be affected.

i. Sickle-cell anaemia: This is an autosomal recessive condition that affects the clotting of blood. HB^A is a normal allele, and the HB^s gene is the defective allele. The three possible genotypes are  HB^AHB^A , HB^AHB^s, and HB^sHB^s. The presence of HB^s in homozygous conditions (HB^sHB^s) causes the disease. The defect occurs due to single base substitution at the sixth codon of the beta-globin gene from GAG to GTG, which causes substitution of Glutamic acid (Glu) by Valine (Val) of the haemoglobin molecule. Due to the mutation, haemoglobin molecules undergo polymerisation under low oxygen tension resulting in the sickle shape of the RBC.

Fig: Change in Shape of RBC in Sickle Cell Anaemia

ii. Phenylketonuria (PKU): This is an autosomal recessive condition that results in metabolic errors. The affected individual lacks the enzyme phenylalanine hydroxylase (PAH). This converts the amino acid phenylalanine into tyrosine. Due to the absence of enzymes,  phenylalanine is accumulated and converted into phenylpyruvic acid and its other derivatives. They start to accumulate in the blood and other organs like the brain resulting in mental retardation. These can be diagnosed by urine samples, as they are excreted through urine because of their poor absorption by the kidney.

iii. Thalassemia: This is an autosomal recessive blood disorder. Production of \( \propto \) and \(\beta \) haemoglobin chain is disrupted due to the mutation in HBA1 and HBA2 genes and HBB genes present on chromosomes 16 and 11, respectively. Condition with defected \( \propto \) chain is called \(\beta \) thalasseemia and defect in \(\beta \) chain is called \(\beta \) thalassemia. Due to the defects, the quantity of haemoglobin is reduced.

Fig: Change in Cell Shape in Thalassemia

(b) X-Linked Recessive Disorders

X-linked recessive diseases affect mostly males because even a single copy can show its impact. If the mother is a carrier of the affected gene, Chances are 50% of male children will be affected, but no female child will be affected.

i. Colour blindness: It is X -linked recessive disorder that affects males predominantly. The defective gene affects the cone cells of a person so that he is unable to differentiate between the colours red and green. The affected gene is present on the X chromosome. If the mother is a carrier and the father is normal, 50% of male children will be affected while 100% of females will be normal.

Fig: Pattern of Inheritance in Colourblindness

ii. Haemophilia: Also known as the royal disease, it is also an X -linked recessive trait that affects males. A single mutation in a clotting protein affects a person’s ability to clot blood, even for a minor cut. The gene is present on the X chromosome. The possibility of a female becoming haemophilic is extremely rare because the mother of such a female has to be at least carrier, and the father should be haemophilic.

Fig: Inability to Clot Blood in Haemophilia

(c) Sex-Linked Dominant Disease

Sex-linked dominant traits are those present on the sex chromosome (X or Y). Since it is sex-linked, it has a different impact on different gender. For example, If the father carries the abnormal X gene, there is a 100% chance that the daughter will be affected, but none of his sons will be affected. And, if the mother carries the abnormal X gene, there is a 50% chance that the child, male or female, will be affected. Example: Rett syndrome

(d) Autosomal Dominant Disease

Autosomal dominant traits are those where a single copy of a mutated gene located in autosomes is required to affect an individual. If one of the parents is affected with autosomal dominant traits, there is a 50% chance that the child will be affected too. Example: Huntington’s disease, Myotonic dystrophy, Achondroplasia.

2. Chromosomal Abnormality

Chromosomal abnormality includes any change in the number or structure of the chromosome. Chromosomal abnormality can cause various kinds of diseases. 

Change in structure: It includes a change in the structure of the chromosome. Structural modification may include deletion of a portion of chromosome, Inversion, duplication, translocation, or deletion. Inversion is a condition where a segment of the chromosome breaks away and inverts itself. Duplication is a condition where a segment of the chromosome is duplicated and attached to the chromosome. In Translocation, a segment of chromosome breaks away and reattaches itself to another location, and in deletion, a segment of the chromosome is deleted. Example: Cri-du-Chat Syndrome, Prader-Willi syndrome.

Fig: Types of Structural Change in Chromosome

Change in number: The number of chromosomes may increase or decrease. There are mainly two kinds of changes observed in chromosomes – Aneuploidy and polyploidy

Aneuploidy:  It is defined as the condition where the number of chromosomes is increased or decreased in its haploid set. This condition is caused due to failure of segregation during anaphase of meiosis, also called nondisjunction. It is common among humans.

Polyploidy:  It is defined as the condition when a completely new set of chromosomes get added. It results due to chromosomal nondisjunction. These are rare in humans. Triticum aestivum (wheat) is an example of natural polyploidy.

Disease caused due to change in chromosome number:

(A) Down’s syndrome

i. Incidence: 1 in every 800 newborns is affected by this condition.
ii. Chromosomal Basis: This disease is caused due to trisomy of 21. The karyotype of Down syndrome can be written as (47, XX + 21) (females) and (47, XY +21) (males). The trisomy condition occurs due to the inability of chromosomes to separate at the time of cell division, also called nondisjunction.

Fig: Idiogram of Downs Syndrome

iii. Symptoms: Symptoms include the flat face, slanting eye, smallmouth, protruding tongue, flattened nose, short neck, short arms and legs, single deep crease across the palm, low IQ, stunted growth, muscular hypotonia, underdeveloped gonads. Down’s syndrome babies also show breathing, heart, or hearing problems.
iv. Diagnosis and Treatment: This is diagnosed by identifying the presence of an extra 21st chromosome in the karyotype. There is no standard treatment procedure discovered yet. This disease can be managed with the help of counselling, speech therapy, and nutritional supplements.

(B) Turner’s Syndrome

i. Incidence: It occurs in 1 in 2,500 newborns. It is frequently observed in miscarriages and stillbirths.
ii. Chromosomal basis: Genotype- (45, X). This disease is caused due to absence of an extra X chromosome in females. The affected individual has 45 chromosomes, i.e., 22 pairs + XO.
iii. Symptoms: Symptoms include short stature, webbed neck, small breasts, low set ears, swollen hands and feet, rudimentary ovary, sterility, and absence of secondary sexual characteristics.

Fig: Symptoms of Turner’s Syndrome

iv. Diagnosis and Treatment: This is diagnosed by the absence of barr body in the karyotype. There is no standard procedure for treatment. Hormone therapy like the administration of androgen and estrogen can be prescribed for feminine development, and counselling is helpful in managing the condition.

(C) Klinefelter’s Syndrome

i. Incidence: It occurs in approximately 1 out of every 1000 newborns.
ii. Chromosomal basis: Genotype: (47, XXY). This condition is caused due to the presence of an additional copy of the X chromosome. These individuals have 47 chromosomes, i.e., 22 pairs + XXY.
iii. Symptoms: Symptoms include Tall stature, reduced facial and body hair, coarse voice, smaller testes, Gynaecomastia( Breast development), and sterility.

Fig: Symptoms of Klinefelter’s Syndrome

iv. Diagnosis and treatment: This condition is diagnosed by the identification of extra X chromosomes in the karyotypic study. There is no standard treatment procedure. Some people opt for hormone therapy (testosterone) to develop a masculine appearance. Counselling is required to manage aggression and depression associated with it.

3. Multifactorial Inheritance

Multifactorial inheritance is also known as polygenic inheritance.  It is a condition caused due to mutation in multiple genes in combination with environmental factors. For example,

i. Diabetes mellitus: A common example of multifactorial inheritance, which is an important example of polygenic disease. It is a heterogeneous group of disorders that is characterised by persistent high blood sugar levels or hyperglycemia. India has the largest number of patients worldwide. This condition can not be permanently cured. However, insulin injections can keep the sugar level in check.
ii. Breast cancer: It is associated with genes on chromosomes 6, 11, 13, 14, 15, 17, and 22. Other examples: Cancer, Obesity, Diabetes, heart disease, etc.

4. Mitochondrial Inheritance

Mitochondria is a cell organelle associated with ATP production. Mitochondria possess their own genome made up of roughly 37 genes. Most of these genes are associated with enzyme production involved in ATP synthesis. Defects in mitochondrial genes can lead to genetic disorders. Mitochondrial genes can only be transferred from the mother to the progeny. Example- Leber’s Hereditary Optic Atrophy (LHON), Myoclonic epilepsy, Mitochondrial encephalopathy, and Lactic acidosis, etc.

Fig: Mitochondrial Inheritance

Management of Genetic Disease

Genetic conditions can not be cured permanently, but these can be managed. The management of different diseases requires different approaches. Inborn metabolic conditions like PKU can be managed by enzyme replacement therapy. This can help in reducing the symptoms and help prevent future complications. Genetic conditions with defective blood cell formation like Thalassemia can be managed with bone marrow transplantation if performed at an early stage of life. Some genetic conditions which may affect later parts of life, like cancer, etc., can be prevented by frequent tests and preventative surgeries.  Few difficult diseases like adenosine deaminase (ADA) deficiency can be managed by gene therapy.

Although we have various methods to manage many genetic conditions, sadly, not all conditions can be prevented or treated. Genetic counselling can be used to predict the chances of occurrence of a genetic condition in a baby or the age of onset of disease in an individual. Proper diagnosis, genetic counselling, and a cautious lifestyle can make it easy to deal with genetic conditions.

Summary

Genetic disorders are inborn errors that occur due to defects in the genome. The genetic condition can be broadly classified into four types: single-gene, chromosomal, multifactorial, or mitochondrial. Single gene disorders are caused due to mutation in one gene. Single gene disorders follow Mendelian patterns, and they can be autosomal dominant, autosomal recessive, X- linked dominant, or X-linked recessive. Examples of single-gene disorders are haemophilia, Sickle cell anaemia, Thalassemia, colour blindness, etc. Chromosomal disorders occur due to change in structure or number of chromosomes.

Down’s syndrome, Klinefelter’s syndrome, and Turner’s syndrome, etc., are examples of chromosomal disorders. Multifactorial disorders occur due to multiple genes in combination with environmental conditions. Examples of multifactorial disorders include cancer, heart disease, etc. Mitochondrial disorders occur due to mutation in mitochondrial genes. Examples include Leber’s Hereditary Optic Atrophy (LHON), Myoclonic epilepsy, Mitochondrial encephalopathy, Lactic acid-osis, etc. Genetic conditions can not be cured, but they can be managed with a proper approach, genetic counselling, and an adequate lifestyle.

Frequently Asked Questions (FAQs) on Genetic Disorders

Q.1. Are all genetic disorders inherited?
Ans: No! Not all genetic conditions can be inherited. Some genetic conditions can occur spontaneously at the time of birth or during embryonic conditions. Chromosomal abnormalities can not be passed onto another generation.

Q.2. What is the rarest genetic disorder?
Ans: According to the Journal of Molecular Medicine, Ribose-5 phosphate isomerase deficiency, or RPI Deficiency, is the rarest disease in the world. To date, there has been only one reported case.

Q.3. What is the most common inherited genetic disorder?
Ans: Sickle cell anaemia is the most common genetic disease.

Q.4. Can genetic disorders be cured?
Ans: Most genetic conditions can not be cured. Only some conditions like cleft pallet or congenital heart disease can be fully cured. Gene therapy has shown some promising results, but there are so many genetic conditions that can only be managed to reduce its effect.

Q.5. How common are genetic abnormalities?
Ans: According to an estimate, one in every 250 adults are affected by genetic conditions.

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