Review Question - QID 102720

Achondroplasia is a homozygous-lethal, autosomal-dominant condition. Therefore, 67% of offspring can be expected to have the achondroplasia phenotype, and 33% will be of average height.

In a homozygous-lethal, autosomal-dominant condition, one can assume that each affected parent is heterozygous for the condition, since the homozygous condition is incompatible with life. Of the zygotes these two heterozygotes create, 25% will be homozygous recessive (average height); 50% will be heterozygous (achondroplasia phenotype), and 25% will be homozygous dominant (usually lethal in utero). Therefore, of the children that two parents with achondroplasia have that result in a live birth, it can be expected that 2/3 (66%) will have the achondroplasia phenotype and 1/3 (33%) will be of average height. Note that the homozygous individual AA would die in utero and is not considered a live birth and would not be a part of the calculation.

Achondroplasia is due to a mutation in the fibroblast growth factor receptor 3 (FGFR3). The mutated gene can be inherited, or it can occur sporadically. Unrelated individuals usually carry the same mutation because a particular sequence in this gene prone to specific mutation. In other words, this gene houses a mutation "hotspot." This particular hotspot has an observed 0.6-1.4*10^-5 frequency of the Gly380Arg mutation, which is much higher than what would be expected by chance alone.

Illustration A shows a patient with achondroplasia as well as a characteristic radiograph.

Illustration B shows a Punnett square depicting a typical homozygous-lethal autosomal-dominant condition, like achondroplasia.

Incorrect Answers:
Answer 1: If achondroplasia were not a homozygous-lethal condition and both parents were heterozygotes, one could expect that 25% of offspring would be of average height.
Answer 3: If the patient's husband was of average height, one could expect 50% of their offspring to be of average height.
Answer 4: If achondroplasia were not a homozygous-lethal condition and both parents were heterozygotes, one could expect 75% of offspring to have the achondroplasia phenotype.
Answer 5: Achondroplasia is an autosomal dominant condition, however there is 1 possibility (aa) out of three total possibilities (aa, aA, Aa) that could be of normal height.