ADGRG1

Inheritance Pattern: AR

Disease ID:MONDO:0011738

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0017091

Submitter: Natera

Inheritance Pattern: AR

Disease ID:MONDO:0011738

Submitter: Ambry Genetics

Inheritance Pattern: AR

Disease ID:MONDO:0011738

Submitter: ClinGen

Bilateral Frontoparietal Polymicrogyria with linkage to chromosome 16 was initially described in 2003 by Chang et al. (PMID: 12730993) in 19 affected members from ten consanguineous families. Bilateral frontoparietal polymicrogyria (BFPP) manifests as increased gyral frequency with anterior predominance, cerebral white matter signal abnormalities, and cerebellar signal abnormalities on brain MRI; though originally described as polymicrogyria, subsequent histopathology has demonstrated that the increased gyral frequency actually represents a cobblestone malformation (PMID: 20929962). The disorder presents with hypotonia, developmental delay, moderate to severe intellectual disability, pyramidal signs, epileptic seizures, non progressive cerebellar ataxia, dysconjugate gaze and/or strabismus. First genotype-phenotype association was obtained in 2004 by Piao et al. (PMID:15044805) when all affected probands from PMID: 12730993 were found to carry homozygous variants of the ADGRG1 gene. ADGRG1 is a G protein-coupled receptor involved in cell-cell and cell-extracellular matrix interactions with a key role in cortical development. Structurally, it contains an ectodomain (ECD) with multiple protein motifs implicated in protein-protein interaction and glycosylation sites that mediate the adhesion function; a seven-pass transmembrane domain (7TM) responsible for signaling and a proteolysis site (GPS) crucial for the self-catalytic reaction. This reaction takes place in the ER and splits the receptor into an adhesion and a signaling (in the cell surface) subunit. The mechanism of pathogenicity is biallelic inherited loss-of-function (PMID: 21349848) variants. Seventeen missense, nine nonsense, six frameshift, one non frameshift and two splice site variants were reported in sixty-eight patients and two affected fetuses from forty-one families across twelve publications (PMIDs: 15044805, 16240336, 25642806, 35186395, 19016831, 20929962, 21723461, 23981349, 23274687, 29707406, 30982090, 36524291). Not all variants from the aforementioned PMIDs were scored because maximum genetic evidence points were reached. Additionally, a single report (PMID: 24531968) for autosomal recessive bilateral perisylvian polymicrogyria (associated with a 15-bp homozygous deletion located upstream of the transcriptional site of noncoding exon 1 of ADGRG1 gene) in three consanguineous families was not included for the purposes of this curation. The gene-disease relationship is supported by experimental evidence demonstrating preferential expression gene expression in neuronal progenitor cells of the cerebral cortical ventricular and subventricular zones during periods of neurogenesis but no expression in the cortical plate or intermediate zone (PMID: 15044805); the altered function in engineered cells with candidate pathogenic missense variants (PMID: 21349848); and neuropathological findings of an affected fetus terminated at 35 weeks of pregnancy which showed cobblestone-like and polymicrogyric cortex (PMID: 20929962). In summary, ADGRG1 is definitively associated with autosomal recessive Bilateral frontoparietal polymicrogyria. This has been repeatedly demonstrated and has been upheld over time. This was approved by the ClinGen Brain Malformation GCEP on October 24th, 2023.

Inheritance Pattern: AR

Disease ID:MONDO:0011738

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0011738

Submitter: Labcorp Genetics (formerly Invitae)