Thursday, March 14, 2024

ADGRG1 mutations

Inspired by a patient

Note: ADGRG1 and GPR56 are interchangeable. See:

Kuo CY, Tsai MH, Lin HH, Wang YC, Singh AK, Chang CC, Lin JJ, Hung PC, Lin KL. 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. Epilepsia Open. 2023 Mar;8(1):154-164. doi: 10.1002/epi4.12685. Epub 2023 Jan 11. PMID: 36524291; PMCID: PMC9977754.


Objective: Bilateral frontoparietal polymicrogyria (BFPP) is a rare genetic-related 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.

Significance: Sleep EEG findings of high-amplitude rhythmic activity in our BFPP cases were only noted during infancy and childhood. We also confirmed that the missense variant (p.Leu290Pro) led to loss of function due to a reduction in cell surface GPR56 expression.

Izzo G, Toto V, Faiola S, Cattaneo E, Cavallari U, Passarini A, Gladin CR, Scelsa B, Parazzini C, Righini A. Cobblestone-like brain malformation with a new bi-allelic ADGRG1 (GPR-56) mutation: Fetal imaging-pathology correlation. J Neuroimaging. 2023 Jul-Aug;33(4):527-533. doi: 10.1111/jon.13130. Epub 2023 May 31. PMID: 37259271.


Background and purpose: Autosomal recessive cobblestone-like cortical malformation of the brain, with no eye or muscle involvement, has been reported in patients with biallelic mutations in ADGRG1 (formerly GPR56) and in other brain surface defects (eg, variants in COL3A1). We reported the intra-uterine brain MRI (iu-MRI), post-mortem MRI (pm-MRI), and neuropathology findings of a new ADGRG1 mutation in a fetus at early gestation. Imaging findings were compared with those of the sibling harboring the same mutation, to provide insights about the evolving morphology of such malformation.

Methods: A 21-week fetus underwent iu-MRI for a suspected cortical anomaly on ultrasound. After the MRI results, the termination of the pregnancy was carried out. A pm-MRI scan and autopsy were performed. A neuropathology-imaging correlation was achieved. The 5-year old sibling affected by developmental impairment also underwent a brain MRI. Both subjects underwent a genetic investigation.

Results: Two patterns of abnormality of the cerebral surface were identified on both fetal MRI: one at the vertex resembling a cobblestone-cortex due to neuronal overmigration into the subarchnoid space and the other in the occipital areas resembling polymicrogyria. These details closely matched the neuropathology findings. MRI findings of the sibling consisted of typical ADGRG1/GPR56-related brain findings showing a polymicrogyric-like cortex, also reported as bilateral frontal-parietal polymicrogyria. A flattened pons and small cerebellar vermis were present in both cases. Genetic testing demonstrated a novel homozygous variant c.1484T>C in the c gene in both cases.

Conclusion: Our findings provide further evidence of the overlap of ADGRG1/GPR56-related brain dysgenesis with cobblestone-like cortical malformation of the brain.

Jha R, Kovilapu UB, Devgan A, Sondhi V. Two Novel Compound Heterozygous ADGRG1/GPR56 Mutations Associated with Diffuse Cerebral Polymicrogyria. J Pediatr Genet. 2020 Jul 29;11(1):74-80. doi: 10.1055/s-0040-1714716. PMID: 35186395; PMCID: PMC8847064.


Background Polymicrogyria (PMG) has environmental or genetic etiologies. We report a 8-year-old boy with diffuse PMG and two novel adhesion G protein-coupled receptor G1 ( ADGRG1 ) / G protein-coupled receptor 56 ( GPR56 ) mutations. Case Report The proband has intellectual disability, spastic quadriparesis, and intractable epilepsy without antenatal or perinatal insults. Brain magnetic resonance imaging revealed PMG involving fronto-polar, parietal and occipital lobes with decreasing antero-posterior gradient, and a thinned-out brain stem. Targeted exome sequencing identified two novel compound heterozygote ADGRG1/GPR56 mutations (c.C209T and c.1010dupT), and each parent carries one of these mutations. Subsequent pregnancy was terminated because the fetus had the same mutations. Conclusion The detected mutations expanded the genetic etiology of PMG and helped the family to avoid another child with this devastating condition.

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