What is the likely cause of a de novo mutation in a newly diagnosed patient?

Causes of De Novo Mutations in Newly Diagnosed Patients

De novo mutations are most commonly caused by spontaneous errors during DNA replication, with environmental factors like advanced parental age, exposure to mutagens, and ionizing radiation playing significant contributing roles. 1, 2

Primary Causes of De Novo Mutations

Spontaneous Errors in DNA Replication

• De novo mutations occur at a rate of approximately 1.29 × 10^-8 per base pair per generation, resulting in approximately 70 de novo mutations genome-wide in each individual 1
• In the protein-coding exome, approximately 1 de novo mutation occurs against a background of ~50,000 inherited variants 1
• These mutations arise during gametogenesis and early embryonic development, creating a complex mixture of mutations through different biological processes 3

Parental Age Effects

• Advanced parental age at conception is strongly associated with increased risk for de novo mutations 2
• The recurrence probability of a de novo mutation decreases by 2.27% per year for paternal mutations and 1.78% per year for maternal mutations 4
• Paternal age has a stronger effect due to continuous spermatogenesis throughout life, leading to more DNA replication cycles and opportunities for errors 3

Environmental Exposures

• Several established mutagens have been linked to increased risk of de novo mutations, including: 2
  • Mercury
  • Cadmium
  • Nickel
  • Trichloroethylene
  • Vinyl chloride
• Occupational exposure to pesticides, petroleum products, and ionizing radiation are known risk factors that can cause DNA damage leading to de novo mutations 1

Vitamin D Deficiency

• Factors associated with decreased sun exposure (urban residence, higher latitudes, high precipitation areas) contribute to vitamin D deficiency 2
• Vitamin D plays important roles in DNA repair and protection against oxidative stress, which is a key cause of DNA damage 2
• Vitamin D deficiency may impair DNA repair mechanisms, potentially increasing mutation rates 2

Clinical Implications and Detection

Diagnostic Considerations

• De novo mutations account for a significant proportion of positive diagnoses from clinical genetic testing 1
• Candidate de novo mutations require careful scrutiny as they are rare events compared to inherited variants 1
• Manual review of sequence alignments is recommended to identify false-positive variant calls that may slip past automated filters 1

Validation Methods

• De novo mutations should be queried against public databases of genome variation, such as gnomAD 1
• A candidate de novo mutation with appreciable frequency in the population (MAF > 0.0001) is more likely to represent a germline variant 1
• Visual review using tools like Integrative Genomics Viewer (IGV) should be used to exclude both artifactual calls and variants with supporting evidence in one or both parents 1

Recurrence Risk

• The recurrence risk for de novo mutations is generally low, which is important for genetic counseling and reproductive planning 5
• Prenatal diagnosis can be offered for reassurance in subsequent pregnancies 5
• In rare cases, germline mosaicism may lead to recurrence in subsequent pregnancies 5

Disease-Specific Considerations

Neurodevelopmental Disorders

• De novo mutations play a prominent role in rare and common forms of neurodevelopmental diseases, including intellectual disability, autism, and schizophrenia 6
• These mutations provide a mechanism by which early-onset reproductively lethal diseases remain frequent in the population 6

Genetic Disorders

• In disorders like Wilson Disease, de novo mutations remain difficult to diagnose due to the large numbers of disease-specific mutations 1
• For conditions like Hypertrophic Cardiomyopathy (HCM), de novo mutations can initiate new familial disease 1
• Sporadic cases of genetic disease often reflect a de novo mutation rather than incomplete penetrance in family members 1

Myeloid Disorders

• In myelodysplastic syndromes, somatic mutations can accumulate over time and may be influenced by environmental exposures 1
• Novel variant and gene discovery is an important cause of positive diagnosis in previously undiagnosed cases 1

By understanding the causes of de novo mutations, clinicians can better assess risk factors, provide appropriate genetic counseling, and develop strategies for prevention and management of genetic disorders.