ADGRG1 – Bilateral Frontoparietal Polymicrogyria

Bilateral frontoparietal polymicrogyria (BFPP) is a rare autosomal recessive neuronal migration disorder characterized by excessive cortical folding, white matter changes, and cerebellar and brainstem involvement. ADGRG1 (GPR56) was identified as the sole gene underlying BFPP when homozygous or compound heterozygous loss-of-function variants were found in all 29 unrelated patients across diverse populations ([PMID:16240336]).

Genetic studies in over 40 independent probands from more than 30 consanguineous and nonconsanguineous families confirmed autosomal recessive inheritance with both homozygous and compound heterozygous truncating and missense variants ([PMID:16240336], [PMID:19016831]). Segregation analysis in multiple pedigrees demonstrated perfect co-segregation of biallelic ADGRG1 variants with disease in at least six additional affected relatives. Case reports added a Portuguese proband and three siblings with novel nonsense and missense variants ([PMID:25642806], [PMID:36524291]).

Affected individuals consistently present with severe intellectual disability and early-onset seizures, often evolving to Lennox–Gastaut syndrome, with additional features such as motor and language impairment, ataxia, and abnormal eye movements ([PMID:19016831], [PMID:25922261]). Brain MRI reveals frontoparietal polymicrogyria with characteristic scalloping of the cortical–white matter junction.

To date, over 26 distinct ADGRG1 variants have been described, including nonsense, frameshift, and missense mutations in the N-terminal ligand-binding domain, GPS proteolysis site, and extracellular loops. A recurrent variant, c.811C>T (p.Arg271Ter), has been reported in multiple unrelated families, underscoring a founder effect in certain populations ([PMID:25642806]).

Functional assays in human cells demonstrate that BFPP-associated missense mutations (e.g., R38W/Q, C91S, C346S, L634R) impair GPS cleavage, N-glycosylation, and cell surface trafficking, and abolish collagen III binding ([PMID:17576745], [PMID:22238662]). Gpr56 knockout mice recapitulate pial basement membrane breaches and neuronal overmigration, with synergistic interactions with α3β1 integrin and defects in oligodendrocyte precursor proliferation and CNS myelination ([PMID:23874761], [PMID:25607655]).

The convergence of extensive genetic and functional data supports a Strong gene–disease association for ADGRG1 in BFPP. Biallelic ADGRG1 testing should be included in diagnostic workflows for polymicrogyria, enabling accurate genetic counseling, prenatal diagnosis, and potential targeted interventions. Key take-home: ADGRG1 loss-of-function defines BFPP and has direct clinical utility in diagnosis and management.

References

• Annals of neurology • 2005 • Genotype-phenotype analysis of human frontoparietal polymicrogyria syndromes. PMID:16240336
• Epilepsia • 2009 • Bilateral frontoparietal polymicrogyria, Lennox-Gastaut syndrome, and GPR56 gene mutations. PMID:19016831
• Human molecular genetics • 2007 • Disease-associated mutations affect GPR56 protein trafficking and cell surface expression. PMID:17576745
• PloS one • 2012 • Disease-associated mutations prevent GPR56-collagen III interaction. PMID:22238662
• PloS one • 2013 • GPR56 functions together with α3β1 integrin in regulating cerebral cortical development. PMID:23874761
• Nature communications • 2015 • The adhesion G protein-coupled receptor GPR56 is a cell-autonomous regulator of oligodendrocyte development. PMID:25607655

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