Inheritance is X-linked dominant with the gene locus on the short arm of the X chromosome at Xp22.2-p22.1. A woman who has CLS herself has a 50% chance of having a child with CLS, depending on which of her X chromosomes are inherited by the child. In about 70-80% of cases, there is no family history - this is known as a spontaneous mutation. In the absence of any physical signs or mental impairment, the mother of a child with CLS with no known family history is probably at low risk of being a carrier.   20-30% have more than one additional affected family member. There are no recorded cases of an affected male producing offspring, so the ability of CLS males to father affected children is not known. The father of an affected male will not have the mutation nor will he be a carrier of the mutation. 

In families with more than one affected individual, the mother of an affected male is an obligate carrier.

	In males with the CLS-causing mutation: 100% will be affected
	In females with the CLS-causing mutation are carriers and are at high risk for developmental delay and mild physical signs of CLS

Germline mosaicism has also been reported in CLS. "Mosaicism" means that the person's body is made up of a combination of cells with and cells without a mutation, like a mosaic with some blue pieces, and some red pieces. "Germline" refers to the presence of cells with mutations in the egg or sperm cell supply. Germline mosaicism is relatively rare, and this explanation does not apply to most families with a spontaneous mutation. The chances of a mother with germline mosaicism having another child with CLS is higher than the average population. There is no simple way to determine if the mother has germline mosaicism, and no one knows how often it occurs. Therefore, the absence of a mutation in the mother of a sporadic Coffin-Lowry patient does not rule out a recurrence risk for future pregnancies, and prenatal diagnosis should be offered. [Jacquot, Merienne, Pannetier et al 1998; Horn et al 2001]

About 70-80% have no family history of Coffin-Lowry syndrome and 20-30% have more than one affected family member. [Delaunoy et al 2001].

The risk to the siblings depends upon the carrier status of the mother.  If the mother has the CLS mutation, the chance of transmitting it in each pregnancy is 50%. Male siblings who inherit the mutation will be affected; female sibs who inherit the mutation will be at high risk for at least some developmental delay and mild physical signs of CLS. A mildly affected woman may have a severely affected daughter [Simensen et al 2002].

In the absence of any physical signs or mental impairment, the mother with no known family history of Coffin-Lowry syndrome is probably at low risk of having another CLS child. However, germline mosaicism has been demonstrated in this condition. Thus, even if the CLS mutation has not been identified in the mother's DNA, siblings are still at increased risk of inheriting the mutation [Jacquot, Merienne, Pannetier et al 1998 ; Horn et al 2001].