What causes a genetic disorder?

Causes of Genetic Disorders

Genetic disorders are caused by abnormalities in an individual's DNA, including mutations in single genes, chromosomal abnormalities, or complex interactions between multiple genetic variants and environmental factors. 1

Types of Genetic Abnormalities

Single-Gene Disorders

• Result from disruptive variants in individual genes 1
• Can be:
  • De novo (new) mutations occurring only in the affected individual
  • Inherited from parents in dominant, recessive, or X-linked patterns
  • Examples include Fragile X syndrome (most common inherited cause of intellectual disability) 1

Chromosomal Abnormalities

• Result from extra, missing, or structurally altered chromosomes 1, 2
• Include:
  • Numerical abnormalities (e.g., trisomies 13,18, and 21)
  • Structural abnormalities (deletions, duplications, inversions)
  • Down syndrome (trisomy 21) is the most common genetic cause of intellectual disability 1

Copy Number Variants

• Involve deletions or duplications of chromosomal segments 1
• Can disrupt multiple dosage-sensitive genes 2
• Often identified through molecular cytogenetic technologies like microarrays 2

Genomic Instability Disorders

• Characterized by DNA/chromosomal instability 1
• Caused by biallelic pathogenic variants in genes involved in DNA repair pathways 1
• Examples include:
  • Ataxia telangiectasia
  • Bloom syndrome
  • Fanconi anemia
  • Xeroderma pigmentosum
  • Nijmegen breakage syndrome 1, 3

Mechanisms of Genetic Damage

DNA Replication Errors

• DNA replication is error-prone and becomes less efficient with age 4
• Errors include:
  • Single-nucleotide variations
  • Insertions and deletions 4

DNA Repair Defects

• Mutations in genes responsible for DNA damage repair 1
• Lead to accumulation of genetic errors
• Associated with increased cancer risk and developmental abnormalities 1

Epigenetic Alterations

• Changes in DNA methylation patterns 4
• Can affect gene expression without changing the DNA sequence
• May be influenced by maternal age and environmental factors 4

Risk Factors for Genetic Disorders

Advanced Parental Age

• Maternal age over 35 and paternal age over 40 increase risk 4
• Associated with:
  • Increased DNA mutations
  • Chromosomal abnormalities
  • Intellectual disability in offspring 4

Environmental Exposures

• Prenatal exposures to:
  • Alcohol (leading cause of preventable developmental disabilities)
  • Drugs
  • Toxins
  • Teratogens 1

Prenatal Infections

• Can directly affect fetal development:
  • Toxoplasmosis
  • Syphilis
  • Varicella-zoster
  • Rubella
  • Cytomegalovirus
  • Herpes 1

Perinatal Events

• Asphyxia during delivery is a significant risk factor 1
• Can cause brain damage leading to intellectual disability

Clinical Implications

Diagnosis

• Modern diagnosis relies on:
  • Next-generation DNA sequencing 5
  • Chromosome studies (karyotype)
  • Microarray analysis 2
  • Specific tests for known syndromes (e.g., chromosome breakage analysis) 1

Management

• Early identification through genetic testing
• Genetic counseling for families
• Developmental screening for at-risk children
• Coordinated care within a medical home model 4

Emerging Therapies

• Genetic therapies fall into three categories:
  • Bulk replacement of affected genetic material
  • Addition of compensatory genetic material
  • Direct correction using gene editing 5

Important Considerations

• Genetic disorders vary widely in severity and presentation
• Many disorders result from complex interactions between genetic and environmental factors 1, 6
• Some genetic variants may contribute smaller amounts of risk, particularly in mild intellectual disability 1
• Family history remains a crucial clue to the presence of genetic disorders 1

Understanding the specific genetic cause is essential for proper diagnosis, genetic counseling, cancer screening when applicable, and informing treatment choices 1.