What is the inheritance pattern of Wilson's disease?

Wilson's Disease Inheritance Pattern

Wilson's disease is inherited in an autosomal recessive pattern, requiring two copies of the mutated ATP7B gene on chromosome 13 for disease manifestation. 1

Genetic Basis

• Wilson's disease results from mutations in the ATP7B gene located on chromosome 13q14.3, which encodes a copper-transporting P-type ATPase (ATP7B) 1
• More than 500 distinct mutations have been described in the ATP7B gene, with approximately 380 confirmed to play a role in disease pathogenesis 1
• The gene frequency is estimated at 1 in 90-150, with an incidence that may be as high as 1 in 30,000 1

Inheritance Characteristics

• As an autosomal recessive disorder, both parents must be carriers (heterozygotes) for a child to develop the disease 2, 3
• When both parents are carriers:
  • 25% chance that a sibling of an affected individual will be homozygous and develop the disease 1
  • 50% chance of being a carrier (heterozygote) 1
  • 25% chance of inheriting two normal alleles 1
• The risk of offspring of an affected individual developing Wilson's disease is only 0.5%, unless the other parent is a carrier 1

Family Screening Implications

• Family screening is essential due to the 25% risk of siblings being affected 1
• Genetic testing is the only reliable method to distinguish between heterozygote carriers and homozygotes 1
• Options for genetic screening include:
  • Direct mutation analysis when the specific mutations in the index case are known 1
  • Haplotype analysis using polymorphisms surrounding the ATP7B gene when mutations cannot be identified 1

Clinical Relevance of Inheritance Pattern

• Early identification of presymptomatic family members through genetic screening is crucial as treatment can prevent disease progression 1
• The autosomal recessive inheritance pattern means that the disease can appear to skip generations, making family history sometimes unreliable 1
• Despite having the same mutations, there can be significant variability in disease presentation even within families, suggesting the influence of other genetic or environmental modifiers 4

Diagnostic Considerations

• Genetic testing should be considered for:
  • Asymptomatic siblings of affected patients 1
  • Children of affected individuals, despite their lower risk 1
  • Confirmation of diagnosis in clinically suspected cases 1

The autosomal recessive inheritance pattern has important implications for genetic counseling and family planning, as carriers (heterozygotes) do not develop the disease but can pass the mutation to their offspring 3, 5.