Multifactorial Inheritance

Some conditions do not appear to be linked to a single gene defect, but are more complex, perhaps representing the effects of more than one gene and also interaction with environmental influences or embryogenesis. Two such disorders are cleft lip and diabetes mellitus. Both conditiions occur more frequently when there is a family history, but without a clear pattern of inheritance.

Of babies born with congenital anomalies, many (perhaps 40 to 50%) fall into a cagetory of "multiple congenital anomalies " without a defined syndrome or without an identifiable genetic or chromosomal defect. Many syndromes still do not have a defined genetic basis. Research continues to turn up new genes linked to disorders, so in the future more congenital anomalies may be explained by specific defects. Be aware that a normal karyotype or the absence of a family history of a genetic disease does not reduce the risk of birth defects to 0.

The recurrence risk for such conditions is probably above the standard 3% risk, but is not as high as the 25% risk for autosomal recessive conditions. The often quoted recurrence risk for anomalies of unknown cause is 5-8%, indicating that there is an increased risk, but not a greatly increased risk.

A condition, though multifactorial, may have a "threshold of liability " above which the disease is manifested -- more genetic risks are present. The disease pyloric stenosis, which causes bowel obstruction with vomiting in babies about 1 month old, exhibits this pattern. The incidence in males is 1/200 and in females 1/1000, reflecting the fact that more risks must be present in females for the disease to occur. Estimating the recurrence risk when there is a sex ratio difference is counter-intuitive. If males are more likely to have the disease, then the risk is increased if a female child is born with the condition. This is because more risks must be present in the family in order for a girl to have the disease, and thus the threshold of liability will be exceeded more easily for males born into such a family.