<i>EPG5</i> c.1007A &gt; G mutation in a sibling pair with rapidly progressing Vici syndrome

Vojcek, Eszter; Keszthelyi, Magdolna; Jávorszky, Eszter; Balogh, Lídia; Tory, Kálmán

doi:10.1111/ahg.12337

Cited by 6 publications

(10 citation statements)

References 32 publications

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“…Furthermore, it has been shown that this substitution maintains the overall structure, thermal stability and binding capacities of the proteins to GABARAP-y (Nam et al, 2021). The remaining functioning isoform may explain the previously reported milder phenotype with prolonged survival (Byrne et al, 2016a;Vojcek et al, 2020). In accordance with prior reports, this patient developed mild dilated cardiomyopathy, and currently receives no treatment and visual involvement developed at ~12 months of age.…”

Section: Discussionsupporting

confidence: 86%

Vici syndrome in Israel: Clinical and molecular insights

Chorin

Hirsch²,

Rock³

et al. 2022

Front. Genet.

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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.

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Section: Discussionsupporting

confidence: 86%

Vici syndrome in Israel: Clinical and molecular insights

Chorin

Hirsch²,

Rock³

et al. 2022

Front. Genet.

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“…Interestingly, the homozygous nonsense variant p.R2483* was detected in three unrelated Turkish patients and one Iranian patient. Vojcek et al (2020) showed two siblings carrying the p.Q336R sequence variant exhibited severe phenotypes, which deviated from patients with the same sequence variant described by Byrne, Jansen, et al (2016), who had longer survival times. However, Vojcek et al (2020) hypothesized that the interfamilial variability in prognosis was presumably the result of differential splicing.…”

Section: Discussionmentioning

confidence: 73%

“…Vojcek et al (2020) showed two siblings carrying the p.Q336R sequence variant exhibited severe phenotypes, which deviated from patients with the same sequence variant described by Byrne, Jansen, et al (2016), who had longer survival times. However, Vojcek et al (2020) hypothesized that the interfamilial variability in prognosis was presumably the result of differential splicing. Most of the sequence variants reported to date are private; however, Byrne et al in 2015 identified 39 different EPG5 variants in 50 VICIS individuals and found three recurrent sequence variants p.M2242Cfs*5, p.R417* and p.Q336R, which may be hotspot sequence variants of VICIS (Byrne, Jansen, et al, 2016).…”

Section: Discussionmentioning

confidence: 73%

“…As a rare and severe progressive disorder affecting multiple systems, Vici syndrome (VICIS) (OMIM 242840) is mainly characterized by agenesis of the corpus callosum, cardiomyopathy, oculocutaneous hypopigmentation, cataracts and combined immunodeficiency (Moirangthem et al, 2019). Additional clinical features include microcephaly, nystagmus, sensorineural hearing loss, facial dysmorphism, myopathy, idiopathic thrombocytopenic purpura, hypotonia, maculopapular rashes and seizures (Hizal et al, 2020;Vojcek et al, 2020). In 2020, Abidi et al described that the estimated incidence of VICIS is one case per million individuals worldwide (Abidi et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

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The first Chinese case of Vici syndrome with novel compound heterozygous sequence variants in EPG5

Dong

Zhang

et al. 2021

Intl J of Devlp Neuroscience

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Background: Vici syndrome (VICIS) refers to a clinical spectrum of multiple organ systems characterized by corpus callosum agenesis, hypopigmentation, cataracts, cardiomyopathy and immunodeficiency. The aims of this study were to describe detailed clinical and molecular features of two Chinese female siblings and to review several previous findings. Methods: Targeted sequencing panel involving all known disease-causing genes of monogenic disorders combined with Sanger sequencing validation were performed to identify the likely pathogenic sequence variants of the proband with VICIS.Results: The proband diagnosed as VICIS presented with neonatal pneumonia, myocardial damage, hypotonia, maxillofacial malformations, hearing impairment, failure to thrive and died 40 days after birth. Two novel missense variants in ectopic P-granules autophagy protein 5 homologue (EPG5, NM_020964.3) were identified in this proband. The two likely pathogenic variants c.1609G > A (p.(E537K)) and c.5764C>G (p.(P1922A)) were assessed as damaging by bioinformatic analysis. As these variants were absent in 150 unrelated Chinese normal controls and inherited from asymptomatic parents in the co-segregation analysis, the compound heterozygous EPG5 variants were responsible for the clinical features of this patient. Finally, she was genetically diagnosed with VICIS.Conclusions: To our knowledge, this is the first Chinese case of VICIS. Our report identified novel compound heterozygous EPG5 sequence variants in the proband with VICIS, highlighting the rarity and high mortality rate of VICIS and emphasizing on the importance of high-throughput sequencing in confirmed diagnosis of monogenic diseases, which could further facilitate the development of genetic counselling and prenatal diagnosis.

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“…A common missense mutation discovered from studies on two large cohorts of Vici syndrome is a nucleotide mutation at position 1007 of the epg5 gene. This mutation results in single residue change (Gln336Arg; Q336R) in hEPG5 protein 22,24,[50][51][52] . We decided to first focus on this disease mutation and examine its effect on the hEPG5 protein.…”

Section: Resultsmentioning

confidence: 99%

Insights on autophagosome–lysosome tethering from structural and biochemical characterization of human autophagy factor EPG5

et al. 2021

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Pivotal to the maintenance of cellular homeostasis, macroautophagy (hereafter autophagy) is an evolutionarily conserved degradation system that involves sequestration of cytoplasmic material into the double-membrane autophagosome and targeting of this transport vesicle to the lysosome/late endosome for degradation. EPG5 is a large-sized metazoan protein proposed to serve as a tethering factor to enforce autophagosome–lysosome/late endosome fusion specificity, and its deficiency causes a severe multisystem disorder known as Vici syndrome. Here, we show that human EPG5 (hEPG5) adopts an extended “shepherd’s staff” architecture. We find that hEPG5 binds preferentially to members of the GABARAP subfamily of human ATG8 proteins critical to autophagosome–lysosome fusion. The hEPG5–GABARAPs interaction, which is mediated by tandem LIR motifs that exhibit differential affinities, is required for hEPG5 recruitment to mitochondria during PINK1/Parkin-dependent mitophagy. Lastly, we find that the Vici syndrome mutation Gln336Arg does not affect the hEPG5’s overall stability nor its ability to engage in interaction with the GABARAPs. Collectively, results from our studies reveal new insights into how hEPG5 recognizes mature autophagosome and establish a platform for examining the molecular effects of Vici syndrome disease mutations on hEPG5.

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EPG5 c.1007A > G mutation in a sibling pair with rapidly progressing Vici syndrome

Cited by 6 publications

References 32 publications

Vici syndrome in Israel: Clinical and molecular insights

Vici syndrome in Israel: Clinical and molecular insights

The first Chinese case of Vici syndrome with novel compound heterozygous sequence variants in EPG5

Insights on autophagosome–lysosome tethering from structural and biochemical characterization of human autophagy factor EPG5

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