The role of chance using a stochastic single gene model has been shown to generate a continuous liability curve resembling that obtained from a multifactorial threshold model. Segregation of some malformations may be explained by a single defective gene that predisposes to, but does not necessarily result in, the malformation. Low penetrance and remarkably variable expressivity that characterize a number of presumed autosomal dominant malformation syndromes are possibly reflections of specific stochastic influences that are intrinsic to the embryonic process itself. Gene analysis is discussed and illustrated. Using polymorphic
DNA probes to study
cleft palate and
ankyloglossia in males and
ankyloglossia only in females in a large Icelandic family, the responsible gene was found to be located on the long arm of the X chromosome in the Xq21.1 region. In addition to gene analysis, some of the implications of transgenic analysis using mice are discussed. Among disorders of
collagen metabolism, both the osteogenesis imperfectas and the Ehlers-Danlos syndromes are shown to represent genetically heterogeneous groups of connective tissue disorders. The days of thinking about
osteogenesis imperfecta as one disorder and the
Ehlers-Danlos syndrome as another are a thing of the past; persistence of such thinking is erroneous and misleading. Of the many disorders affecting bone
mineral, the complexities of
hypophosphatasia and
pseudohypoparathyroidism are singled out for discussion. For lysosomal storage disorders, an overview of the
mucopolysaccharidoses is provided. Finally, the recently delineated
peroxisomal disorders--
hyperpipecolic acidemia, rhizomelic chondrodysplasia,
neonatal adrenoleukodystrophy,
Zellweger syndrome, and
infantile Refsum disease--are known to share a distinctive biochemical phenotype, although fibroblast complementation analysis suggests that some of these disorders are etiologically distinct.