Single gene disorders are caused by defects in a single gene. Although they are rare, they affect approximately 1 % of the population. These can be dominant, recessive or X-linked. On the other hand, trinucleotide repeat or CGG expanding repeat disorders are characterized by the repetition of the trinucleotide sequence is certain genes leading to gene defects and disorders. Examples of trinucleotide repeat disorders include Fragile X syndrome, Huntington’s disorder, and Spinocerebellar ataxia.
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Image: “A 9 year, 8-month-old full mutation fragile X boy with the Prader-Willi phenotype. He was referred to the Medical Genetics Clinic where Prader-Willi syndrome was ruled out through methylation testing. A karyotype showed a normal male, 46, XY. Fragile X testing was done and came back abnormal with mosaicism for a full mutation and a low level 105 repeat premutation. Notice the round face and prominent ears (Fig. 1A), short fingers (Fig. 1B), and truncal obesity (Fig. 1C).” by McLennan Y, Polussa J, Tassone F, Hagerman R – Curr. Genomics (2011). License: CC BY 2.5

Single Gene Disorders

Disorders which are caused as a result of DNA alterations in one specific gene are defined as single gene disorders. These constitute approximately 1% of the general population. It is easy to detect these disorders, track their inheritance through the generations of the same family and one can also predict the risk of their inheritance as only one single gene is responsible.

Although a single gene causes these conditions, they can also be caused by different mutations leading to varying phenotypic manifestations and severity due to variations in the individual’s environment and other genetic variations. Single gene disorders can be classified as, dominant, recessive or X-linked and can be diagnosed with genetic tests.

Dominant disorders e.g. Huntington’s disease

In these disorders, the affected individual inherits one mutant gene and one normal gene and is therefore heterozygous. As the mutant gene is dominant over the normal gene, clinical manifestations of the disease are observed in every generation of the family and transmitted from parent to their progeny. If an individual inherits two copies of the mutant gene, they are considered “homozygous” and have more severe manifestations of the disorder.

Recessive disorders e.g. Sickle cell disease

The manifestations of the disorder are observed only when an individual inherits two copies of the mutant genes i.e. homozygous. The presence of a single healthy gene is sufficient to mask the effects of the mutant gene but if both genes are abnormal, then symptoms of the disease become manifest.  Recessive disorders are likely to occur in consanguineous relationships i.e. if the parents are related.

They are more difficult to detect as their features may not be manifested and as a result, they may appear in a genealogical tree to have skipped a generation.

X-linked disorders e.g. Hemophilia

These are single gene disorders that occur due to the mutant gene being located on the X chromosome and can be inherited in either dominant or recessive pattern.   Hemophilia and Duchenne’s muscular dystrophy are examples of an X-linked recessive disorder that are seen more frequently in males. The mutant gene is passed by the mother to her male progeny who manifests the clinical features of the condition.

Women, who are carriers of the mutant gene, develop symptoms only if they have an associated chromosomal disorder or their other X chromosome is inactivated.  X- linked dominant single gene disorders are rare. e.g. Rett syndrome and have identical incidence in males as well as females.

Trinucleotide Repeat Expansions (TRE)

Several human disorders are caused by trinucleotide repeat expansion which occurs in various cells and is dependent on the gender of the parent transmitting the mutation. There are almost 14 disorders which have been reported due to TRE. Of the 14, 6 disorders are unlike each other or to the other 8 conditions while 8 disorders share the identical codon, CAG, as their underlying cause. CAG codes for the amino acid, glutamine and hence these disorders are called “polyglutamine diseases”.

However, these repeats are located on different chromosomes and hence the 8 diseases are different, although their major clinical manifestations are similar – progressive neurological degeneration beginning in mid-life or early adulthood. Examples of these 8 disorders are Huntington’s disease, Spinobulbar muscular atrophy, and Spinocerebellar ataxia type 1 to type 7.

The non-polyglutamine trinucleotide repeat disorders include Fragile X syndrome, Fragile XE mental retardation, Friedrich’s ataxia, Myotonic dystrophy, Spinocerebellar ataxia type 8 and type 12.

Huntington’s Disease

This is a polyglutamine trinucleotide repeat expansion disorder due to CAG repeats. The onset of symptoms typically starts between the age of 30 and 50 years of men and women being equally affected.  The clinical manifestations of the disease can be classified as cognitive, movement disorders and psychiatric features.

The cognitive symptoms include difficulty learning anything new, communication difficulties, problems with multitasking, planning, and inability to perceive space with respect to tables and walls. Movement symptoms include tics, muscle spasms, rigidity, dysarthrias, dysphagia, chorea, and athetosis. Increased irritability, obsessive traits like repeated hand washing, anxiety, apathy, personality changes, mania, and delirium constitute the psychiatric symptoms.

Fragile X Syndrome

This is a non-polyglutamine trinucleotide repeat expansion disorder involving the CGG codon which causes moderate intellectual disability and is considered to be an autism spectrum disorder. Excessive methylation of cytosine within the FMR1 promoter region leads to condensation of the chromatin with resultant gene silencing. The FMR1 gene is located on the X chromosome and therefore the name of the condition.

Affected individuals can have more than 200 and up to 1000 repeats while asymptomatic individuals have between 53 to 230 CGG copies. Clinical features of the syndrome include long, prominent pinnae, mental retardation, stereotypical movements of the hands and hyperactivity. It typically affects males.

Mitochondrial Disorders

These are disorders which are inherited from the mother as the mitochondria are part of the ovum during fertilization. A father who has a mitochondrial mutation cannot transmit the mutation to his progeny. The mitochondria have their own DNA which mutates at a rate greater than 20 times that of nuclear DNA.

Inheritance of mitochondrial disorders includes autosomal dominant, autosomal recessive and X-linked recessive and mitochondrial inheritance patterns. They can affect different organ systems; their onset can be at any age, and they affect males and females equally. Their phenotypic expression can differ in individuals of the same family and depends on the type of mutation, the prevalence of mutant mitochondria (whether homoplasmy or heteroplasmy) and the organ which is involved.

Examples of mitochondrial disorders include Leber optic atrophy and MERRF syndrome.

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