Chapter 10, Problem 1CS

A couple was referred for genetic counseling because they wanted to know the chances of having a child with dwarfism. Both the man and the woman had achondroplasia (MIM 100800), the most common form of short-limbed dwarfism. The couple knew that this condition is inherited as an autosomal dominant trait, but they were unsure what kind of physical manifestations a child would have if it inherited both mutant alleles. They were each heterozygous for the FGFR3 (MIM 134934) allele that causes achondroplasia. Normally, the protein encoded by this gene interacts with growth factors outside the cell and receives signals that control growth and development. In achrodroplasia, a mutation alters the activity of the receptor, resulting in a characteristic form of dwarfism. Because both the normal and mutant forms of the FGFR3 protein act before birth, no treatment for achrondroplasia is available.

The parents each carry one normal allele and one mutant allele of FGRF3, and they wanted information on their chances of having a homozygous child. The counsellor briefly reviewed the phenotypic features of individuals with achondroplasia. These include facial features (large head with prominent forehead; small, flat nasal bridge; and prominent jaw), very short stature, and shortening of the arms and legs. Physical examination and skeletal X-ray films are used to diagnose this condition. Final adult height is approximately 4 feet.

Because achondroplasia is an autosomal dominant condition, a heterozygote has a 1-in-2, or 50%, chance of passing this trait to his or her offspring. However, about 75% of those with achondroplasia have parents of average size who do not carry the mutant allele. In these cases, achondroplasia is due to a new mutation. In the couple being counseled, each individual is heterozygous, and they are at risk for having a homozygous child with two copies of the mutated gene. Infants with homozygous achondroplasia are either stillborn or die shortly after birth. The counselor recommended prenatal diagnosis via ultrasounds at various stages of development. In addition, a DNA test is available to detect the homozygous condition prenatally.

What is the chance that this couple will have a child with two copies of the dominant mutant gene? What is the chance that the child will have normal height?

Summary Introduction

To determine: The chances of the couple having a child with two copies of the dominant mutant gene in the given case study.

Introduction: Autosomal genetic defects are inherited from one generation to next in two patterns, either in autosomal recessive form or in autosomal dominant form. For a disease that is autosomal recessive, presence of two copies of the defective alleles (homozygous condition) is required for the development of disease. In case of autosomal dominant disease, presence of even a single copy of the defective allele (heterozygous condition) can cause development of the disease.

Explanation of Solution

Information given in the case study is as follows:

• Achondroplasia is an autosomal dominant defect.
• Both the parents carry heterozygous allelic combination for the disease.
• Phenotypic effects of the disease are short stature, shortened arms and legs, abnormal facial features, and many more.

The parents wanted to know the chances of their child having homozygous dominant state for the disease. For this, genotype of the parents can be assumed as:

A represents gene for achondroplasia and a representing a healthy gene.

Both the parents are having heterozygous genotype for the disease, so their genotype will be Aa and the gametes produced by them will be having genotype as A and a.

Possible genotypes of the child produced from these parents can be found as:

Gametes	A	a
A	AA	Aa
a	Aa	aa

It is clear that only 25% (1 out of 4) chance is there that the child will have two copies of the dominant allele (AA) for the disease.

Summary Introduction

To determine: The chances of having a child with normal height in the given case study.

Explanation of Solution

Information given in the case study is as follows:

• Achondroplasia is an autosomal dominant defect.
• Both the parents carry heterozygous allelic combination for the disease.
• Phenotypic effects of the disease are short stature, shortened arms and legs, abnormal facial features and many more.

The parents in the given case study want to know the chances of their child having homozygous dominant state for the disease. For this, genotype of the parents can be assumed as:

A represents gene for achondroplasia and a representing a healthy gene.

Both the parents are having heterozygous genotype for the disease, so their genotype will be Aa and the gametes produced by them will be having genotype as A and a.

Possible genotypes of the child produced from these parents can be found as:

	A	a
A	AA	Aa
a	Aa	aa

Achondroplasia is a heterozygous dominant disease. So, from the possible genotypes of the child, AA and Aa will give dwarfism phenotypically, whereas only aa genotype will give a normal height phenotypically.

Thus, it can be seen that the child from the parents in the given case study will only have 25% chance of having normal height (possible only in aa genotype).