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Novel RAB3GAP1 Mutations Causing Warburg Micro Syndrome in Two Italian Sisters.

ABSTRACT: This report details two novel RAB3GAP1 mutations causing Warburg Micro syndrome, a rare autosomal recessive disorder characterized by multiple organ abnormalities involving the ocular, nervous, and endocrine systems. Two Italian sisters were referred to our department for the assessment of congenital bilateral cataracts. They also presented with microphthalmia, postnatal microcephaly, severe developmental delay, and hypotony. Perinatal investigations were negative for any toxins or infectious diseases during pregnancy, including toxoplasmosis, rubella, cytomegalovirus, and herpes virus. Genetic tests were performed on samples from probands and their parents, targeting a total of 114 genes. After sequence analysis of RAB3GAP1, two heterozygous changes were identified in both sisters: C.519G>A, p.(Trp173Ter) and c.2486T>A, p.(Leu829Ter). The identified mutations have not previously been described in the literature, but they affect critical regions of the gene, suggesting a legitimate causal relationship between the genetic alterations and the clinical features of the patients.

SUBMITTER: Loiudice P

PROVIDER: S-EPMC5890559 | biostudies-literature | 2017 Oct-Dec

REPOSITORIES: biostudies-literature

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Novel <i>RAB3GAP1</i> Mutations Causing Warburg Micro Syndrome in Two Italian Sisters.

Loiudice Pasquale P Napoli Debora D Ragone Maria Cristina MC Nardi Marco M Casini Giamberto G

Journal of pediatric neurosciences 20171001 4

This report details two novel <i>RAB3GAP1</i> mutations causing Warburg Micro syndrome, a rare autosomal recessive disorder characterized by multiple organ abnormalities involving the ocular, nervous, and endocrine systems. Two Italian sisters were referred to our department for the assessment of congenital bilateral cataracts. They also presented with microphthalmia, postnatal microcephaly, severe developmental delay, and hypotony. Perinatal investigations were negative for any toxins or infect ...[more]

PMID: 29675078

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Project description:BackgroundEpileptic encephalopathies are a group of childhood epilepsies that display high phenotypic and genetic heterogeneity. The recent, extensive use of next-generation sequencing has identified a large number of genes in epileptic encephalopathies, including UBA5 in which biallelic mutations were first described as pathogenic in 2016 (Colin E et al., Am J Hum Genet 99(3):695-703, 2016. Muona M et al., Am J Hum Genet 99(3):683-694, 2016). UBA5 encodes an activating enzyme for a post-translational modification mechanism known as ufmylation, and is the first gene from the ufmylation pathway that is linked to disease.Case presentationWe sequenced the genomes of two sisters with early-onset epileptic encephalopathy along with their unaffected parents in an attempt to find a genetic cause for their condition. The sisters, born in 2004 and 2006, presented with infantile spasms at six months of age, which later progressed to recurrent, treatment-resistant seizures. We detected a compound heterozygous genotype in UBA5 in the sisters, a genotype not seen elsewhere in an Icelandic reference set of 30,067 individuals nor in public databases. One of the mutations, c.684G > A, is a paternally inherited exonic splicing mutation, occuring at the last nucleotide of exon 7 of UBA5. The mutation is predicted to disrupt the splice site, resulting in loss-of-function of one allele of UBA5. The second mutation is a maternally inherited missense mutation, p.Ala371Thr, previously reported as pathogenic when in compound heterozygosity with a loss-of-function mutation in UBA5 and is believed to produce a hypomorphic allele. Supportive of this, we have identified three adult Icelanders homozygous for the p.Ala371Thr mutation who show no signs of neurological disease.ConclusionsWe describe compound heterozygous mutations in the UBA5 gene in two sisters with early-onset epileptic encephalopathy. To our knowledge, this is the first description of mutations in UBA5 since the initial discovery that pathogenic biallelic variants in the gene cause early-onset epileptic encephalopathy. We further provide confirmatory evidence that p.Ala371Thr is a hypomorphic mutation, by presenting three adult homozygotes who show no signs of neurological disease.

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Novel RAB3GAP1 Mutations Causing Warburg Micro Syndrome in Two Italian Sisters.

Publications

Novel <i>RAB3GAP1</i> Mutations Causing Warburg Micro Syndrome in Two Italian Sisters.

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