Our modern concepts of genetic inheritance originated nearly a century ago. Early concepts of dominant and recessive inheritance were developed in insects and were subsequently applied to sex-linked inheritance in mammals. Years of clinical experience, however, suggest that the modern-day rules for X-linked dominant and recessive diseases do not explain why so many female carriers of X-linked 'recessive' disorders have an abnormal phenotype. In a review of 32 X-linked diseases we revealed an unexpectedly high degree of intermediate disease penetrance in females that cannot be explained by existing concepts. We recommend that the terms 'dominant' and recessive' be abandoned and that these disorders be referred to as X-linked. In this review we will present modified rules for X-linked inheritance and propose hypotheses related to the potential mechanisms that may explain differences in disease expression in females.
Conclusion: Past assumptions regarding factors that may affect phenotype in heterozygous females do not capture the extraordinarily variable expressivity of X-linked disorders in females and need to be revisited.