How Autosomal Dominant Disease Occurs Without Affected Parents
An individual can develop an autosomal dominant disease despite having unaffected parents through three primary mechanisms: de novo mutations (new mutations arising in the egg or sperm), parental germline or somatic mosaicism (where a parent carries the mutation in only some cells), or incomplete penetrance (where a parent carries the mutation but never manifests disease). 1
De Novo Mutations: The Most Common Explanation
De novo mutations represent the most frequent cause of autosomal dominant disease in children of unaffected parents. These are new genetic changes that occur spontaneously during the formation of parental egg or sperm cells, or very early in embryonic development. 1, 2
Key characteristics of de novo mutations:
All humans carry approximately 44-82 de novo single nucleotide variants, of which 1-2 are expected to be in protein-coding regions. 1 This means new mutations are a normal part of human reproduction, though most are harmless.
The mutation is present in every cell of the affected child but in neither parent's blood or tissue samples. 1 This explains why genetic testing of parents returns negative results.
Confirmation requires documented maternity and paternity, the variant must be in a gene associated with the patient's phenotype, and there should be no family history of disease. 1 These criteria establish strong evidence (PS2 level) for pathogenicity in variant interpretation.
Most cases of autosomal dominant early-onset Alzheimer disease (EOAD) and congenital central hypoventilation syndrome (CCHS) arise through de novo mutations. 1 In CCHS specifically, most parents of affected children do not carry any mutation at all, indicating a high de novo mutation rate. 1
Parental Mosaicism: The Hidden Carrier State
Parental mosaicism occurs when one parent carries the disease-causing mutation in only a subset of their cells—either throughout their body (somatic mosaicism) or exclusively in their reproductive cells (germline mosaicism). 1 This parent appears unaffected because the mutation is absent or present at very low levels in most tissues.
Critical features of mosaicism:
Somatic mosaicism can be detected when the mutant allele represents significantly less than 50% of total alleles in genetic testing. 1 For example, in CCHS, mosaic parents may show the expanded allele at only 9-35% rather than the expected 50%. 1
Germline mosaicism may be completely undetectable in standard blood or tissue testing but still present in eggs or sperm. 1 This explains rare cases where unaffected parents have multiple affected children.
The recurrence risk for mosaic parents can be up to 50% for subsequent pregnancies, depending on the proportion of germ cells carrying the mutation. 1 This is substantially higher than the general population risk.
Mosaic individuals always have a new mutation—mosaicism cannot be inherited—so only their children (not other family members) are at risk. 1
Even when both parents test negative, germline mosaicism cannot be completely ruled out, and prenatal testing should be considered for subsequent pregnancies. 1
Incomplete Penetrance: Carrying Without Manifesting
Incomplete penetrance means a parent carries the disease-causing mutation in all their cells but never develops clinical manifestations of the disease. 1 This is distinct from mosaicism because the mutation is present at full (50%) levels but simply doesn't cause disease in that individual.
Important aspects of incomplete penetrance:
Certain mutations in autosomal dominant conditions show reduced penetrance, meaning not everyone with the mutation will develop disease. 1 For example, PSEN2 mutations in Alzheimer disease show 95% penetrance, meaning 5% of carriers never develop symptoms. 1
In CCHS, the 20/24 and 20/25 genotype mutations may be found in asymptomatic parents and family members, suggesting dominant inheritance with incomplete penetrance. 1 These family members may show other related phenotypes or remain presymptomatic.
Autosomal dominant inheritance patterns can be masked by small families, premature death from other causes, or incomplete penetrance. 1 This can make a true autosomal dominant condition appear sporadic.
Variable expressivity means that even when penetrant, the severity and specific features can vary dramatically within the same family. 1 A mildly affected parent might not have been diagnosed, making the family history appear negative.
Clinical Implications and Genetic Counseling
When evaluating a patient with apparent autosomal dominant disease and unaffected parents, both parents should undergo genetic testing to distinguish between de novo mutation, mosaicism, and incomplete penetrance. 1
Practical considerations:
Standard genetic testing may miss low-level mosaicism; high-sensitivity analysis capable of detecting pathogenic alleles at frequencies as low as 1% is recommended when initial testing is negative. 1
For families with one affected child and negative parental testing, the empirical recurrence risk is approximately 1-2% due to the possibility of undetected germline mosaicism. 1, 3
Improved sequencing techniques are facilitating better detection of mosaic variants, and some previously reported de novo mutations have been revealed to be inherited from mosaic parents. 1
Accurate segregation analysis requires thorough phenotypic evaluation of family members, which can be complicated by issues of penetrance, expressivity, age of onset, and ascertainment bias. 1