Low‐level expression of EPG5 leads to an attenuated Vici syndrome phenotype

Abstract

Vici syndrome is a multisystem disorder characterized by agenesis of the corpus callosum, oculocutaneous hypopigmentation, cataracts, cardiomyopathy, combined immunodeficiency, failure to thrive, profound developmental delay, and acquired microcephaly. Most individuals are severely affected and have a markedly reduced life span. Here we describe an 8-year-old boy with a history of developmental delay, agenesis of the corpus callosum, failure to thrive, myopathy, and well-controlled epilepsy. He was initially diagnosed with a mitochondrial disorder, based in part upon nonspecific muscle biopsy findings, but mitochondrial DNA mutation analysis revealed no mutations. Whole exome sequencing revealed compound heterozygosity for two EPG5 variants, inherited in trans. One was a known pathogenic mutation in exon 13 (c.2461C > T, p.Arg821X). The second was reported as a variant of unknown significance found within intron 16, six nucleotides before the exon 17 splice acceptor site (c.3099-6C > G). Reverse transcription-polymerase chain reaction of the EPG5 mRNA showed skipping of exon 17-which maintains an open reading frame-in 77% of the transcript, along with 23% expression of wild-type mRNA suggesting that intronic mutations may affect splicing of the EPG5 gene and result in symptoms. However, the expression of 23% wild-type mRNA may result in a significantly attenuated Vici syndrome phenotype.

Diagnostic Utility of Whole Exome Sequencing in the Neuromuscular Clinic

“…19 Patients 2 and 3 were siblings with a classic Vici phenotype and one pathogenic variant and one likely pathogenic variant, while patient 4 was previously reported due to one pathogenic variant and one variant of unknown significance causing a novel splice site mutation which resulted in a significantly attenuated phenotype, investigated and reported in detail elsewhere. 20 In light of our identification of three Vici patients in a single center, it is very possible that patients with a milder phenotype may be undiagnosed in the broader patient population. In the absence of WES, patient 4 would not have been identified as a potential Vici syndrome candidate and would have remained undiagnosed.…”

The epg5 knockout zebrafish line: a model to study Vici syndrome

“…Severity of the pathological features differs among Vici's patients, and this was suggested to depend on the residual amount of functional EPG5 protein [12,13]. Interestingly, a recent paper [35], describes a young boy with an attenuated Vici syndrome phenotype, presenting only four of the eight diagnostic features of the syndrome. This patient bears compound heterozygous mutations in the EPG5 gene, with one of these allowing reduced expression of WT EPG5 that possibly allowed him to acquire motor and communicative skills.…”

EPG5 Variants with Modest Functional Impact Result in an Ameliorated and Primarily Neurological Phenotype in a 3.5-Year-Old Patient with Vici Syndrome

“…Vici syndrome has been proposed to be underdiagnosed, 1 and we propose that these missed cases may be partly due to milder phenotypes, as in this proband and another recent report. 8 With an increasing ability to perform molecular diagnostics, it will be necessary to perform functional studies on novel variants to confirm pathogenicity.…”

“…In support of this hypothesis, recent reports have presented patients with a milder Vici syndrome phenotype who carry biallelic variants in the causative gene, ectopic p-granules protein 5 (EPG5). [6][7][8] The gene EPG5 encodes ectopic p-granules protein 5 (EPG5), a key protein in autophagy. 9 The vast majority of reported EPG5 mutations are null alleles, many of them unique to individual families.…”