What is the most likely explanation if two offspring have tuberous sclerosis complex (TSC) when their parents are normal: germline mosaicism, variable expressivity, or incomplete penetrance?

From the Guidelines

The most likely explanation for two offspring having tuberous sclerosis complex (TSC) when both parents appear normal is germline mosaicism. This condition occurs when one parent has a mutation in the TSC1 or TSC2 gene in a portion of their germline cells (eggs or sperm), but not in other body tissues, as noted in a recent study 1. As a result, the parent shows no clinical signs of TSC but can transmit the mutation to multiple offspring. Key points to consider include:

• Germline mosaicism can result in a parent having some degree of germ cell mosaicism without displaying TSC manifestations themselves 1.
• The risk of TSC in subsequent pregnancies for parents of a child with seemingly sporadic TSC is estimated at ~1–2% due to potential germ cell mosaicism 1.
• Variable expressivity or incomplete penetrance would typically result in at least one parent showing some clinical features of TSC, even if mild, making germline mosaicism a more plausible explanation in cases where both parents are asymptomatic.
• Genetic counseling is crucial for families in this situation to understand the potential recurrence risk in future pregnancies despite the parents appearing normal. Some important considerations in genetic counseling for TSC include:
• Determining the mosaic allele frequency in germ cells, which can be relatively easy in male patients through sperm analysis but is not feasible in female patients 1.
• Advising parents of the estimated risk of TSC in subsequent pregnancies, which is significant even if the parents do not show any symptoms of TSC themselves.

From the Research

Explanation for Tuberous Sclerosis in Offspring of Normal Parents

The most likely explanation for two offspring having tuberous sclerosis complex (TSC) when their parents are normal is:

• Germline mosaicism: This occurs when a parent has a mixture of normal and mutated cells in their reproductive cells (germline), which can increase the risk of passing the mutation to their offspring 2, 3, 4. Some key points to consider:
• Germline mosaicism can result in multiple affected offspring, even if the parents are clinically unaffected 3, 4.
• The risk of recurrence is higher in cases of germline mosaicism, with estimates ranging from 20 to 37% 2.
• Molecular genetic analysis can confirm germline mosaicism by identifying the same mutation in multiple affected offspring, even if the parents do not carry the mutation in their somatic cells 3, 4.

Comparison with Other Explanations

In contrast to germline mosaicism:

• Variable expressivity refers to the range of symptoms and severity of a disease, but it does not explain the occurrence of TSC in multiple offspring of normal parents.
• Incomplete penetrance refers to the failure of a disease-causing mutation to manifest in an individual, but it is less likely to explain the occurrence of TSC in multiple offspring of normal parents 2, 3. Studies have shown that germline mosaicism is a more likely explanation for the occurrence of TSC in multiple offspring of normal parents, rather than variable expressivity or incomplete penetrance 2, 3, 4. Additionally, the use of sensitive technologies such as deep panel sequencing and droplet digital polymerase chain reaction can help detect low-level mosaic TSC1/TSC2 mutations in parents, which can inform reproductive counseling 5.