Deleterious mutation in GPR88 is associated with chorea, speech delay, and learning disabilities

Area of Science:

• Genetics
• Neurodevelopmental Disorders
• Molecular Biology

Background:

• Familial developmental disorders present complex diagnostic challenges.
• Understanding the genetic underpinnings of neurodevelopmental conditions is crucial.

Purpose of the Study:

• To elucidate the molecular basis of a developmental disorder affecting four sisters.
• To identify the specific gene responsible for chorea, speech delay, and learning difficulties.

Main Methods:

• Whole-exome sequencing was performed on affected individuals.
• Sanger sequencing confirmed the identified mutation in all family members.

Main Results:

• A homozygous deleterious mutation (p.C291X) was identified in the GPR88 gene.
• This GPR88 mutation segregated with the disease phenotype within the family.
• The mutation was absent in a large control cohort.

Conclusions:

• Homozygous GPR88 mutations are associated with a distinct human developmental disorder.
• The disorder is characterized by speech delay, learning disabilities, and chorea, typically manifesting around 8-9 years of age.
• This finding highlights GPR88's role in motor control and learning, supported by its expression in the striatum and effects in knockout mice.