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Case Reports
. 2021 Jan;185(1):203-207.
doi: 10.1002/ajmg.a.61910. Epub 2020 Oct 9.

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

Alissa M D'Gama  1   2   3   4 , Eleina England  4 , Jill A Madden  3 , Jiahai Shi  5 , Katherine R Chao  4 , Monica H Wojcik  1   2   3   4 , Alcy R Torres  6 , Wen-Hann Tan  1 , Gerard T Berry  1   3 , Sanjay P Prabhu  7 , Pankaj B Agrawal  1   2   3   4
Affiliations
Case Reports

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

Alissa M D'Gama et al. Am J Med Genet A. 2021 Jan.

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.

Keywords: OPA10; RTN4IP1; epilepsy; exome sequencing; optic atrophy.

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Figures

Figure 1:
Figure 1:. Compound heterozygous RTN4IP1 variants identified in the proband.
(A) MRI Brain at 10 months: Axial T2-weighted image shows mild T2 hyperintensity in the globi pallidi (arrowheads) and parietooccipital white matter (thin arrows). (B) MRI Brain at 29 months: Axial T2-weighted image shows abnormal T2 hyperintensity and decreased size of the bilateral thalami (block arrows), T2 hyperintensity in the globi pallidi (arrowheads) and parietooccipital white matter (thin arrows), and mild sulcal prominence in the bilateral frontal and temporal lobes (curved arrows). Coronal T2-weighted image shows small prechiasmatic segments of the optic nerves (black arrows). (C) The RTN4IP1 (NM_032730) missense variant (c.263T>G, p.Val88Gly) is present in the proband (01) and his father (03) and not his mother (02). (D) The deletion (hg19 chr6:106987026-107077832) is present in the proband (blue line) and his mother (purple line) with copy number (CN) = 1 and not present in his father (green line) with CN = 2. (E) Val88 is fairly conserved across species. (F) Pedigree of the proband and his family with variants as described above. (G) 3D RTN4IP1 modeling (green with secondary structures) shows that (H) Val88 (red) is located near the NADPH binding site (blue) and forms hydrophobic interactions with Phe379 and Val382 (purple) while (I) Val88Gly (orange) removes the hydrophobic side chain and likely reduces hydrophobic interactions with the surrounding area.
See this image and copyright information in PMC

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