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Exome sequencing identifies novel missense and deletion variants in RTN4IP1 associated with optic atrophy, global developmental delay, epilepsy, ataxia, and choreoathetosis.

ABSTRACT: Inherited optic neuropathies (IONs) are neurodegenerative disorders characterized by optic atrophy with or without extraocular manifestations. Optic atrophy-10 (OPA10) is an autosomal recessive ION recently reported to be caused by mutations in RTN4IP1, which encodes reticulon 4 interacting protein 1 (RTN4IP1), a mitochondrial ubiquinol oxydo-reductase. Here we report novel compound heterozygous mutations in RTN4IP1 in a male proband with developmental delay, epilepsy, optic atrophy, ataxia, and choreoathetosis. Workup was notable for transiently elevated lactate and lactate-to-pyruvate ratio, brain magnetic resonance imaging with optic atrophy and T2 signal abnormalities, and a nondiagnostic initial genetic workup, including chromosomal microarray and mitochondrial panel testing. Exome sequencing identified a paternally inherited missense variant (c.263T>G, p.Val88Gly) predicted to be deleterious and a maternally inherited deletion encompassing RTN4IP1. To our knowledge, this is the first report of a non-single nucleotide pathogenic variant associated with OPA10. This case highlights the expanding phenotypic spectrum of OPA10, the association between "syndromic" cases and severe RTN4IP1 mutations, and the importance of nonbiased genetic testing, such as ES, to analyze multiple genes and variants types, in patients suspected of having genetic disease.

SUBMITTER: D'Gama AM

PROVIDER: S-EPMC8388561 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Exome sequencing identifies novel missense and deletion variants in RTN4IP1 associated with optic atrophy, global developmental delay, epilepsy, ataxia, and choreoathetosis.

D'Gama Alissa M AM England Eleina E Madden Jill A JA Shi Jiahai J Chao Katherine R KR Wojcik Monica H MH Torres Alcy R AR Tan Wen-Hann WH Berry Gerard T GT Prabhu Sanjay P SP Agrawal Pankaj B PB

American journal of medical genetics. Part A 20201009 1

Inherited optic neuropathies (IONs) are neurodegenerative disorders characterized by optic atrophy with or without extraocular manifestations. Optic atrophy-10 (OPA10) is an autosomal recessive ION recently reported to be caused by mutations in RTN4IP1, which encodes reticulon 4 interacting protein 1 (RTN4IP1), a mitochondrial ubiquinol oxydo-reductase. Here we report novel compound heterozygous mutations in RTN4IP1 in a male proband with developmental delay, epilepsy, optic atrophy, ataxia, and ...[more]

PMID: 33037779

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Project description:BackgroundThe Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS) is an autosomal-dominant disorder (OMIM615722) mostly characterized by optic atrophy and/or hypoplasia, mild intellectual disability, hypotonia, seizures/infantile epilepsy. This disorder is caused by loss-of-function alterations of NR2F1 (i.e., either whole gene deletions or single nucleotide variants) and, to date, 40 patients have been identified with deletions or mutations in this gene. Here we describe two monozygotic twins harboring a de novo missense variant in the DNA-binding domain of NR2F1 (c.313G>A, p.Gly105Ser), with well-characterized features associated to BBSOAS.MethodsPatients' DNA was analyzed by exome sequencing identifying the missense variant c.313G>A in NR2F1 (NM_005654.4). Furthermore, molecular modeling was performed to evaluate putative differences in DNA binding between wild-type and mutated NR2F1.ResultsThe missense variant is predicted to be likely pathogenetic following the ACMG (American College of Medical Genetics and Genomics)/AMP (Association for Molecular Pathology) guidelines. Indeed, dynamic simulation experiments highlighted that the Gly105Ser substitution let the formation of a hydrogen bond between the S105 side chain and R142 and a base (G5) of the DNA sequence, allowing us to hypothesize that the G105 residue might be evolutionary conserved due to the absence of a side chain, besides glycine conformational features. Therefore, the G105S variation seems to cause a stiffening and a possible deformation in the protein-DNA complex due to the interaction of residues R142-S105 and G5 on the DNA, compared to the wild-type.ConclusionIn summary, we described two monozygotic twins harboring a novel Gly105Ser mutation in NR2F1 DNA binding domain, displaying the classical phenotype of BBSOAS-affected patients. Our computational data suggest a dominant negative effect of this newly characterized missense variant. To date, this is the first genetic report analyzing in silico structural consequences of NR2F1 Gly105Ser substitution.

Project description:Purpose: The Oxidation Resistance 1 gene (OXR1) confers neuroprotection against oxidative stress. Oxr1 deficiency in mice resulted in cerebellar neurodegeneration. Genetic causes account for the most proportion of neurodegenerative disorders (early) onset in children. However, the pathological consequence of Oxr1 deficiency in human remains unclear. To assess the effect of OXR1 on the whole transcriptome during neuronal differentiation, we conducted RNA-sequencing of iPS cells, neural aggregates and neurons derivated from OXR1 deficient patient fibroblast and compared with healthy control. Methods: The iPS cells (iPSC) were generated from fibroblast cells of health control (WT) and OXR1 deficient patient (OX), and induced 2 days to form neural aggregate (NA) following to be differentiated into neuron cells in day 20. Total RNA was pooled from triplicate samples in each group and performed RNA sequencing on an Illumina HiSeq2500 platform. The sequence reads that passed quality filters were analyzed at gene level. The GOseq program was used to generate gene ontology (GO) annotation of differentially expressed genes (DEGs). The pathway enrichments were identified by KEGG Pathway Enrichment Analysis. qRT–PCR validation was performed using SYBR Green assays. Results:Totally 1595 DEGs were identified at neuron stage due to Oxr1 disruption, 874 DEGs at iPSC stage and 388 DEGs at NA stage. Among them, there are 61 DEGs commonly regulated by Oxr1 throughout all of the three stages . Further gene oncology (GO) analysis of biological process showed there was a significant enrichment for DEGs related to cell adhesion and extracellular matrix organization (ECM), cell development, cell differentiation, organ development caused by Oxr1 deficiency throughout all developmental stages. Especially neurogenesis and differentiation, axonogensis and guidance, brain and nerves system development were among the top of 50 items when entering neuron stage. In addition, a set of DEGs was significantly enriched in positive regulation of intrinsic apoptotic signaling pathway and regulation of cellular response to stress. Conclusions: Oxr1 regulates transcriptional networks required for modulating oxidative stress, apoptosis and neurogenesis during neuronal differentiation of iPS cells.

Dataset Information

Exome sequencing identifies novel missense and deletion variants in RTN4IP1 associated with optic atrophy, global developmental delay, epilepsy, ataxia, and choreoathetosis.

Publications

Exome sequencing identifies novel missense and deletion variants in RTN4IP1 associated with optic atrophy, global developmental delay, epilepsy, ataxia, and choreoathetosis.

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