Familial diaphragmatic defects: early prenatal diagnosis and evidence for major gene inheritance.

Congenital diaphragmatic defect (CDD) is a relatively common malformation and results in neonatal death in over 50% of affected infants [Harrison and de Lorimier, 1981]. Although most cases are sporadic, familial aggregation occurs, and controversy exists as to whether this is a "multifactorial" or autosomal recessive trait. Statistical genetic analysis of affected families has not been reported. We report on two new families with multiple occurrence of CDD. In one of the families, the lesion was detected in the fetus by ultrasound at 14 weeks, the earliest reported prenatal diagnosis of CDD. Segregation analysis of our data and of 17 additional multiplex families from the literature led to the conclusion that the autosomal recessive hypothesis cannot be rejected. Multifactorial determination is rejected by the data. The analyses are complicated by several factors, including phenotypic variability, probable genetic heterogeneity, and inadequate description of defects and studies of first-degree relatives. Recurrence risk figures based on a model of multifactorial determination give an underestimate of risk in multiplex families and should not be used until the major gene model is rejected or heterogeneity is clearly demonstrated.