Vici syndrome in Israel: Clinical and molecular insights

Abstract

Introduction: Vici Syndrome is a rare, severe, neurodevelopmental/neurodegenerative disorder with multi-systemic manifestations presenting in infancy. It is mainly characterized by global developmental delay, seizures, agenesis of the corpus callosum, hair and skin hypopigmentation, bilateral cataract, and varying degrees of immunodeficiency, among other features. Vici Syndrome is caused by biallelic pathogenic variants in EPG5, resulting in impaired autophagy. Thus far, the condition has been reported in less than a hundred individuals.Objective and Methods: We aimed to characterize the clinical and molecular findings in individuals harboring biallelic EPG5 variants, recruited from four medical centers in Israel. Furthermore, we aimed to utilize a machine learning-based tool to assess facial features of Vici syndrome.Results: Eleven cases of Vici Syndrome from five unrelated families, one of which was diagnosed prenatally with subsequent termination of pregnancy, were recruited. A total of five disease causing variants were detected in EPG5: two novel: c.2554-5A>G and c.1461delC; and 3 previously reported: c.3447G>A, c.5993C>G, and c.1007A>G, the latter previously identified in several patients of Ashkenazi-Jewish (AJ) descent. Amongst 140,491 individuals screened by the Dor Yeshorim Program, we show that the c.1007A>G variant has an overall carrier frequency of 0.45% (1 in 224) among AJ individuals. Finally, based on two-dimensional facial photographs of individuals with Vici syndrome (n = 19), a composite facial mask was created using the DeepGestalt algorithm, illustrating facial features typical of this disorder.Conclusion: We report on ten children and one fetus from five unrelated families, affected with Vici syndrome, and describe prenatal and postnatal characteristics. Our findings contribute to the current knowledge regarding the molecular basis and phenotypic features of this rare syndrome. Additionally, the deep learning-based facial gestalt adds to the clinician’s diagnostic toolbox and may aid in facilitating identification of affected individuals.

Clinical impact of exome sequencing in the setting of a general pediatric ward for hospitalized children with suspected genetic disorders

“… Abbreviations: AV, atrioventricular; CNS, central nervous system; CRMO, chronic recurrent multifocal osteomyelitis; CVS, copy number variation; DN, de novo ; ES, exome sequencing; FTT, failure to thrive; F, female; M, male; PKU, phenylketonuria; RTA, renal tubular acidosis; WPW, wolf parkinson white. a These cases have been previously published ( Chorin et al, 2022 ; Pode-Shakked et al, 2022 ). …”

“…Elucidating the molecular diagnosis, in this case, prevented treatment with bisphosphonates for CRMO which could have These cases have been previously published (Chorin et al, 2022;Pode-Shakked et al, 2022).…”

Mutations in EPG5 are associated with a wide spectrum of neurodevelopmental and neurodegenerative disorders

“…Eight patients were homozygous for the EPG5 p.Gln336Arg variant, a likely Ashkenazi founder variant 9 and had a relatively milder/attenuated phenotype, whereas those compound heterozygous for p.Gln336Arg and another more deleterious EPG5 variant (n=3) had a more severe disorder intermediate between classic VS and milder phenotypes.…”

“…Based on histopathological evidence for a mitochondrial cytopathy as well as stalled mitophagy flux in epg-5 knockdown worms, we investigated for mitochondrial abnormalities in fibroblasts from patients with milder EPG5-RDs, homozygous for p.Gln336Arg and p.Arg1621Gln, respectively, both previously reported 9,11 . p62/SQSTM1, NDP52 and LC3-II immunoblotting showed higher levels of these proteins in patient fibroblasts under basal condition (Figure 5A) that increased even further following treatment with rapamycin (prompting autophagy flux) and bafilomycin (blocking autophagy flux) (Figure 5B and Supplementary File 5A-B), confirming the reported role of EPG5 in autophagosome-lysosome fusion 4 .…”

“…Most genotypes associated with classic VS have at least one truncating EPG5 variant, whereas the few reported milder cases carried at least one EPG5 missense variant at compound heterozygous or homozygous state 7,8 . The most common recurrent variant is the p.Gln336Arg founder variant prevalent in Ashkenazi populations 9,10 that was originally identified in homozygosity in a patient with learning difficulties, epilepsy and a myopathy but no other features of classic VS 11 .…”