Case Report: Diffuse Polymicrogyria Associated With a Novel ADGRG1 Variant

Fábio Carneiro,Francisco Laranjeira,Maria José Fonseca,Júlia Duarte,María-Luz Couce,Sofia Barbosa-Gouveia

doi:10.3389/fped.2021.728077

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.

Highlights

Polymicrogyria (PMG) is a cortical malformation characterized by supernumerary, small gyri with abnormal cortical lamination
BFPP is radiologically defined by the presence of PMG with an anterior to posterior gradient, bilateral patchy white matter signal changes and brainstem and cerebellar hypoplasia or dysplasia [3]
At the time of publication, ADGRG1 pathogenic variants have been described in a total of 77 patients from 47 pedigrees and 34 different corresponding variants [2, 3, 7,8,9,10,11,12,13,14,15,16,17,18,19,20]

Summary

INTRODUCTION

Polymicrogyria (PMG) is a cortical malformation characterized by supernumerary, small gyri with abnormal cortical lamination. The clinical phenotype consists of early onset hypotonia with subsequent motor and cognitive developmental delay, seizures and eye abnormalities (strabismus and/or nystagmus) [3]. Global development was reportedly normal until 6 months of age, when hypotonia and failure to achieve motor milestones were first noticed and the patient was referred to our Child Neurology outpatient clinic (Figure 1). Genetic analysis with a next-generation sequencing panel targeting brain morphogenesis defects yielded a homozygous ADGRG1 nonsense variant (rs746634404), caused by a nucleotide change [(NM_001145771.2: c.1504C>T) (NP_ 005673.3: p.Arg502Ter)] in exon 12. This variant is not present homozygously in GnomAD. The level of evidence of pathogenicity was classified as “very strong” according to American College of Medical Genetics criteria [6], as the nonsense variant was identified in a gene for which loss-of-function is a known mechanism of disease

DISCUSSION

CONCLUSIONS

Findings

DATA AVAILABILITY STATEMENT