Case Report: Diffuse Polymicrogyria Associated With a Novel ADGRG1 Variant

Abstract

Pathogenic variants of the ADGRG1 gene are associated with bilateral frontoparietal polymicrogyria, defined radiologically by polymicrogyria with an anterior-posterior gradient, pontine and cerebellar hypoplasia and patchy white matter abnormalities. We report a novel homozygous ADGRG1 variant with atypical features. The patient presented at 8 months of age with motor delay, esotropia, hypotonia with hyporeflexia and subsequently developed refractory epilepsy. At the last assessment, aged 12 years, head control, sitting and language were not acquired. Magnetic resonance imaging revealed diffuse polymicrogyria with relative sparing of the anterior temporal lobes, without an anterior-posterior gradient, diffuse hypomyelination and pontine and cerebellar hypoplasia. A panel targeting brain morphogenesis defects yielded an unreported homozygous ADGRG1 nonsense variant (dbSNP rs746634404), present in the heterozygous state in both parents. We report a novel ADGRG1 variant associated with diffuse polymicrogyria without an identifiable anterior-posterior gradient, diffuse hypomyelination and a severe motor and cognitive phenotype. Our case highlights the phenotypic diversity of ADGRG1 pathogenic variants and the clinico-anatomical overlap between recognized polymicrogyria syndromes.

Keywords: ADGRG1; GPR56; bilateral frontoparietal polymicrogyria; bilateral generalized polymicrogyria; case report; polymicrogyria.

Figure 1

Timeline of symptoms and signs.

Figure 2

MRI findings at age 11 years. (A) Coronal T2-weighted images showing PMG without an anterior-posterior gradient of involvement, including frontal cortex (closed arrow), parietal cortex (arrowhead) and occipital cortex (open arrow). There is relative sparing of the temporal lobes (asterisk). (B) Axial T2 image displaying diffuse white matter hypomyelination. (C) Sagittal T1 image highlighting pontine and cerebellar hypoplasia.

Figure 3

(A) Sanger sequencing chromatograms of the patient and parents. The patient is a homozygous carrier of the nonsense variant c.1504C>T. The variant was present in the heterozygous state in both parents. (B,C) Schematic of the ADGRG1 protein, showcasing the novel variant in the 7TM domain of the protein (p.Arg502*). 7TM, 7 transmembrane domain; GAIN, GPCR-Autoproteolysis-INducing domain; GPS, GPCR proteolysis site motif; PLL, Pentraxin/Laminin/neurexin/sex-hormone-binding-globulin-Like domain.