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Why can inheriting two achondroplasia mutations be life-threatening?

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BRCA2 tumor suppressor gene on chromosome 13 — human genetic disease Photomicrograph of the *BRCA2* tumor suppressor gene on chromosome 13 of the human genome. Inactivation of this growth-regulating gene is associated with a higher risk of developing breast cancer.

Achondroplasia is an autosomal dominant disorder caused by a specific mutation in the FGFR3 gene. While individuals who inherit one copy of the mutant gene (heterozygotes) typically exhibit the characteristic features of short-limbed dwarfism, inheriting two copies of the mutation—one from each parent—results in a homozygous condition that is lethal.1

In such cases, the homozygous fetus is much more severely affected than a heterozygote, often leading to death in utero or shortly after birth. Consequently, when two individuals with achondroplasia conceive, there is a 25 percent chance that the fetus will be homozygous for the mutation, which is fatal. This outcome highlights the severe biological impact of the homozygous state for this specific dominant mutation, as it disrupts essential developmental processes beyond the level seen in individuals with a single copy of the gene.1