Two Novel Compound Heterozygous ADGRG1/GPR56 Mutations Associated with Diffuse Cerebral Polymicrogyria.

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.

Clinical and molecular spectrum associated with Polymerase-γ related disorders.

BACKGROUND: POLG pathogenic variants are the commonest single-gene cause of inherited mitochondrial disease. However, the data on clinicogenetic associations in POLG-related disorders are sparse. This study maps the clinicogenetic spectrum of POLG-related disorders in the pediatric population. METHODS: Individuals were recruited across 6 centers in India. Children diagnosed between January 2015 and August 2020 with pathogenic or likely pathogenic POLG variants and age of onset <15 years were eligible. Phenotypically, patients were categorized into Alpers-Huttenlocher syndrome; myocerebrohepatopathy syndrome; myoclonic epilepsy, myopathy, and sensory ataxia; ataxia-neuropathy spectrum; Leigh disease; and autosomal dominant / recessive progressive external ophthalmoplegia. RESULTS: A total of 3729 genetic reports and 4256 hospital records were screened. Twenty-two patients with pathogenic variants were included. Phenotypically, patients were classifiable into Alpers-Huttenlocher syndrome (8/22; 36.4%), progressive external ophthalmoplegia (8/22; 36.4%), Leigh disease (2/22; 9.1%), ataxia-neuropathy spectrum (2/22; 9.1%), and unclassified (2/22; 9.1%). The prominent clinical manifestations included developmental delay (n = 14; 63.7%), neuroregression (n = 14; 63.7%), encephalopathy (n = 11; 50%), epilepsy (n = 11; 50%), ophthalmoplegia (n = 8; 36.4%), and liver dysfunction (n = 8; 36.4%). Forty-four pathogenic variants were identified at 13 loci, and these were clustered at exonuclease (18/44; 40.9%), linker (13/44; 29.5%), polymerase (10/44; 22.7%), and N-terminal domains (3/44; 6.8%). Genotype-phenotype analysis suggested that serious outcomes including neuroregression (odds ratio [OR] 11, 95% CI 2.5, 41), epilepsy (OR 9, 95% CI 2.4, 39), encephalopathy (OR 5.7, 95% CI 1.4, 19), and hepatic dysfunction (OR 4.6, 95% CI 21.3, 15) were associated with at least 1 variant involving linker or polymerase domain. CONCLUSIONS: We describe the clinical subgroups and their associations with different POLG domains. These can aid in the development of follow-up and management strategies of presymptomatic individuals.