Identification and clinical characteristics of a novel missense ADGRG1 variant in bilateral Frontoparietal Polymicrogyria: The electroclinical change from infancy to adulthood after Callosotomy in three siblings

Abstract

Objective: Bilateral frontoparietal polymicrogyria (BFPP) is a rare geneticrelated migration disorder. It has been attributed to loss-of-function of the ADGRG1 gene, which encodes an adhesion G protein-coupled receptor, ADGRG1/GPR56. We report the EEG findings of BFPP in three Asian patients, and confirmed that change in protein function was caused by the novel missense variant (p.Leu290Pro). Methods:We reviewed the medical records of three siblings with BFPP including one elder girl and two identical twin boys from birth to adulthood. The clinical symptoms, electroencephalography (EEG), brain MRI, whole-exome sequencing, treatment including medications, neuromodulation, and epilepsy surgery, and clinical outcomes were reviewed. The protein structure of a novel missense variant (p.Leu290Pro) was predicted by in silico studies, and molecular analysis was performed via typical flow cytometry and Western blotting. Results: The elder girl (Patient 1) was 22 years old and the twin boys (Patients 2 and 3) were 20 years old at the time of publication. All of them presented with typical clinical symptoms/signs and MRI findings of BFPP. Whole-exome sequencing followed by Sanger confirmation showed that all three patients had compound heterozygous variants in the ADGRG1 gene. The missense variant (p.Leu290Pro) was confirmed to be related to a reduction in cell surface GPR56 expression. High-amplitude rhythmic activity was noted in sleep EEG during infancy, which may have been due to excessive sleep spindle, and the rhythm disappeared when they were of pre-school age. Partial callosotomy provided short-term benefits in seizure control in Patients 1 and 2, and combined vagus nerve stimulation and partial callosotomy provided longer benefits in Patient 3.

Integrating Genome Sequencing and Untargeted Metabolomics in Monozygotic Twins with a Rare Complex Neurological Disorder

“…However, certain symptoms are specific to the loss of CNTNAP1, such as respiratory distress, retrognathia (Subject 1), low-set ears (Subject 2), absent swallowing, abnormal basal ganglia, and reduced cerebral volume. It is noteworthy that subjects with an ADGRG1-related disease typically survive to adulthood, while subjects with CNTNAP1-related disease die in infancy or early childhood [ 15 , 17 , 18 ]. The early lethality seen in the twin patients further supports the pathogenicity of the identified CNTNAP1 variant.…”

Re‐routing GPR56 signalling using Gα12/13 G protein chimeras

“…GPR56/ADGRG1 is especially intriguing, as it is one of few aGPCRs with a known causative role in a monogenetic human disease, namely, bilateral frontoparietal polymicrogyria (BFPP), an autosomal recessive disorder affecting brain development 5‐8 . Various GPR56 mutations that result in impaired receptor functionality, including sub‐cellular trafficking, protein expression and auto‐proteolysis have been associated with BFPP pathology 6,7,9 . Moreover, GPR56 is strongly associated with cancer and has been proposed as a novel immune checkpoint, rendering it an attractive therapeutic target 10–12 .…”

“…[5][6][7][8] Various GPR56 mutations that result in impaired receptor functionality, including sub-cellular trafficking, protein expression and auto-proteolysis have been associated with BFPP pathology. 6,7,9 Moreover, GPR56 is strongly associated with cancer and has been proposed as a novel immune checkpoint, rendering it an attractive therapeutic target. [10][11][12] Dependent on the cancer type, GPR56 was described to be tumour-suppressive or tumour-promoting.…”