Genetic disorder

Genetic disorders constitute a broad category of health conditions arising from abnormalities within the human genome. These abnormalities may involve single genes, multiple genes, or entire chromosomes, and they can originate spontaneously or be inherited from one or both parents. Although polygenic disorders represent the most common type, the term ‘genetic disorder’ is frequently applied to single-gene or chromosomal anomalies that follow recognisable inheritance patterns. The study of these disorders is central to medical genetics, clinical diagnosis, population health, and the understanding of hereditary disease transmission.
Genetic disorders are present before birth and contribute significantly to congenital and lifelong health problems. While many conditions are rare individually, their combined prevalence makes them a major component of global disease burden. Advances in molecular genetics, reproductive technologies, and genomic screening have expanded knowledge of their causes, inheritance mechanisms, and clinical management.

Background and Classification

Genetic disorders arise through alterations in DNA that impair normal biological functions. These alterations may be small-scale mutations confined to a single gene or large-scale structural changes in chromosomes. More than 6,000 genetic disorders have been identified in medical literature, and new disorders continue to be described as sequencing technologies improve. Of these, over 600 are considered treatable through targeted therapies, metabolic management, or symptomatic interventions.
Genetic disorders may be classified into several broad categories:

• Single-gene (monogenic) disorders: caused by mutations in a specific gene.
• Polygenic or multifactorial disorders: involving the combined effect of multiple genes, often interacting with environmental factors.
• Chromosomal disorders: arising from numerical or structural abnormalities in chromosomes.
• Mitochondrial disorders: caused by mutations in mitochondrial DNA.

Although polygenic conditions such as hypertension or type 2 diabetes are common, monogenic and chromosomal disorders serve as key models for understanding inheritance patterns in human genetics.

Prevalence and Public Health Context

Approximately 1 in 50 individuals is affected by a known single-gene disorder. In contrast, chromosomal disorders affect roughly 1 in 263 people. It is estimated that around two-thirds of the population will experience some health effect attributable to congenital genetic mutations. Due to the vast number of rare conditions, around 1 in 21 people lives with a disorder classified as a rare disease, defined as affecting fewer than 1 in 2,000 individuals.
Most cancers involve somatic mutations rather than inherited changes, making them acquired disorders. Nevertheless, the presence of hereditary cancer syndromes such as BRCA-associated breast and ovarian cancers demonstrates that inherited mutations can predispose individuals to malignancy.

Single-Gene Disorders

Single-gene disorders follow defined inheritance patterns, making them central to the study of medical genetics. Their transmission may be influenced by mechanisms such as genomic imprinting, in which gene expression depends on parental origin, or uniparental disomy, where both copies of a chromosome derive from one parent.
Examples of major monogenic disorders include:

• Achondroplasia, typically inherited in a dominant pattern but lethal in homozygous form.
• Sickle cell disease, recessive in inheritance but providing heterozygous carriers with increased resistance to malaria, a classic example of the heterozygote advantage.
• Inborn errors of metabolism, including phenylketonuria and medium-chain acyl-CoA dehydrogenase deficiency.

Couples who are carriers or affected by monogenic disorders may utilise in vitro fertilisation with preimplantation genetic diagnosis to detect the presence of specific mutations in embryos.

Autosomal Dominant Inheritance

Autosomal dominant disorders require only one mutated allele for the phenotype to be expressed. Affected individuals typically have one affected parent, and each child of an affected parent has a 50 per cent likelihood of inheriting the mutation. Some disorders exhibit reduced penetrance, where not all mutation carriers develop symptoms.
Common autosomal dominant conditions include:

• Huntington’s disease
• Neurofibromatosis types 1 and 2
• Marfan syndrome
• Hereditary non-polyposis colorectal cancer
• Tuberous sclerosis
• Von Willebrand disease

Structural protein disorders often follow an autosomal dominant pattern due to dominant-negative effects, where a defective protein disrupts normal function despite the presence of a normal allele. Examples include osteogenesis imperfecta and several forms of Ehlers–Danlos syndrome.

Autosomal Recessive Inheritance

Autosomal recessive disorders occur when both alleles of a gene are mutated. Affected individuals usually have unaffected carrier parents. Each pregnancy between two carriers has:

• 25% probability of producing an affected child
• 50% probability of producing a carrier child
• 25% probability of producing an unaffected, non-carrier child

Well-known autosomal recessive disorders include:

• Albinism
• Cystic fibrosis
• Tay–Sachs disease
• Niemann–Pick disease
• Spinal muscular atrophy
• Roberts syndrome

Some recessive traits, such as wet versus dry earwax, represent benign genetic variations rather than disease. In several populations, carrier states have been maintained due to selective advantages, as seen in thalassaemia traits conferring protection against malaria.

X-Linked Dominant Inheritance

X-linked dominant disorders stem from mutations on the X chromosome. Both sexes may be affected, although males often exhibit more severe symptoms due to possessing only one X chromosome. Conditions include:

• X-linked hypophosphataemic rickets
• Rett syndrome
• Incontinentia pigmenti type 2
• Aicardi syndrome

Some disorders in this class are typically fatal in males, resulting in their predominance among females. Rare exceptions may occur in boys with additional X chromosomes, such as in Klinefelter syndrome (XXY), who survive with attenuated symptoms.
Transmission patterns differ between sexes:

• Affected fathers pass the condition to all daughters but no sons.
• Affected mothers have a 50 per cent chance of transmitting the mutation to each child.

X-Linked Recessive Inheritance

X-linked recessive conditions manifest predominantly in males due to their single X chromosome. Carrier females may be asymptomatic or mildly affected, particularly if skewed X-inactivation occurs.
Key X-linked recessive disorders include:

• Haemophilia A
• Duchenne muscular dystrophy
• Lesch–Nyhan syndrome
• Red–green colour blindness
• Male-pattern baldness

Inheritance patterns are predictable:

• Affected fathers produce carrier daughters and unaffected sons.
• Carrier mothers have a 50 per cent risk of having affected sons and a 50 per cent risk of having carrier daughters.

Y-Linked Inheritance

Y-linked disorders, transmitted exclusively from father to son, are rare owing to the limited number of genes on the Y chromosome. These conditions often involve male infertility or anomalies in male sexual development. Natural transmission is restricted to males, and reproduction in affected individuals may require medical intervention such as assisted reproductive technologies.

Mitochondrial Inheritance

Mitochondrial or maternal inheritance involves mutations in mitochondrial DNA, which is transmitted solely through the egg cell. As a result, both male and female offspring of an affected mother can inherit the disorder, but only daughters will transmit it to the next generation. Mitochondrial disorders typically affect high-energy tissues, including muscle and nerve cells, due to the central role of mitochondria in cellular energy production.
Mitochondrial mutations contribute to a range of clinical syndromes involving metabolic dysfunction, neurodegeneration, and multi-system involvement.