Deleterious mutation in GPR88 is associated with chorea, speech delay, and learning disabilities.
OBJECTIVE
To identify the underlying molecular basis of a familial developmental disorder characterized by chorea, marked speech delay, and learning difficulties in 4 sisters from a consanguineous family.


METHODS
Whole-exome analysis of DNA of the 2 older patients followed by Sanger sequencing of the mutated exon in all family members.


RESULTS
A homozygous deleterious mutation, p.C291X, was identified in the GPR88 gene in both exome analyses. The mutation segregated with the disease in the family and was absent from a large cohort of controls.


CONCLUSIONS
Homozygous deleterious mutation in GPR88 in humans is associated with marked speech delay, learning disabilities, and chorea, which manifest at 8-9 years of age. The finding is consistent with the reported abundant expression of GPR88 in the striatum and the hyperkinetic activity and learning impairment observed in GPR88 knockout mice. Although further functional characterization is needed, the finding underscores the importance of GPR88 in movement control and learning.
Department of Neurosciences (F.A.) and Department of Pediatrics (B.A.-L.), Al-Makassed Islamic Hospital, Jerusalem, Israel; and Monique and Jacques Roboh Department of Genetic Research (A.S., O.E.), Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
Fadi
F
Alkufri
Department of Neurosciences (F.A.) and Department of Pediatrics (B.A.-L.), Al-Makassed Islamic Hospital, Jerusalem, Israel; and Monique and Jacques Roboh Department of Genetic Research (A.S., O.E.), Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
Avraham
A
Shaag
Department of Neurosciences (F.A.) and Department of Pediatrics (B.A.-L.), Al-Makassed Islamic Hospital, Jerusalem, Israel; and Monique and Jacques Roboh Department of Genetic Research (A.S., O.E.), Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
Bassam
B
Abu-Libdeh
Department of Neurosciences (F.A.) and Department of Pediatrics (B.A.-L.), Al-Makassed Islamic Hospital, Jerusalem, Israel; and Monique and Jacques Roboh Department of Genetic Research (A.S., O.E.), Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
Orly
O
Elpeleg