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Abstract Purpose NGLY1 Deficiency is an ultra-rare, multisystemic disease caused by biallelic pathogenic NGLY1 variants. The aims of this study were to (1) characterize the variants and clinical features of the largest cohort of NGLY1 Deficiency patients reported to date, and (2) estimate the incidence of this disorder. Methods The Grace Science Foundation collected genotypic data from 74 NGLY1 Deficiency patients, of which 37 also provided phenotypic data. We analyzed NGLY1 variants and clinical features and estimated NGLY1 disease incidence in the United States (U.S.). Results Analysis of patient genotypes, including 10 previously unreported NGLY1 variants, showed strong statistical enrichment for missense variants in the transglutaminase-like domain of NGLY1 (p

N-glycanase 1 (NGLY1) Deficiency is a progressive, ultra-rare, autosomal recessive disorder with no approved therapy and five core clinical features: severe global developmental delay, hyperkinetic movement disorder, elevated liver transaminases, alacrima, and peripheral neuropathy. Here, we confirmed and characterized the Ngly1-/-/ rat as a relevant disease model. GS-100, a gene therapy candidate, is a recombinant, single-stranded adeno-associated virus (AAV) 9 vector designed to deliver a functional copy of the human NGLY1 gene. Using the Ngly1-/- rat, we tested different administration routes for GS-100: intracerebroventricular (ICV), intravenous (IV), or the dual route (IV + ICV). ICV and IV + ICV administration resulted in widespread biodistribution of human NGLY1 DNA and corresponding mRNA and protein expression in CNS tissues. GS-100 delivered by ICV or IV + ICV significantly reduced levels of the substrate biomarker N-acetylglucosamine-asparagine (GlcNAc-Asn or GNA) in CSF and brain tissue compared with untreated Ngly1-/- rats. ICV and IV + ICV administration of GS-100 resulted in behavioral improvements in rotarod and rearing tests, whereas IV-only administration did not. IV + ICV did not provide additional benefit compared with ICV administration alone. These data provide evidence that GS-100 could be an effective therapy for NGLY1 Deficiency using the ICV route of administration.

Abstract Background Identification of clinically significant genetic alterations involved in human disease has been dramatically accelerated by developments in next-generation sequencing technologies. However, the infrastructure and accessible comprehensive curation tools necessary for analyzing an individual patient genome and interpreting genetic variants to inform healthcare management have been lacking. Results Here we present the ClinGen Variant Curation Interface (VCI), a global open-source variant classification platform for supporting the application of evidence criteria and classification of variants based on the ACMG/AMP variant classification guidelines. The VCI is among a suite of tools developed by the NIH-funded Clinical Genome Resource (ClinGen) Consortium and supports an FDA-recognized human variant curation process. Essential to this is the ability to enable collaboration and peer review across ClinGen Expert Panels supporting users in comprehensively identifying, annotating, and sharing relevant evidence while making variant pathogenicity assertions. To facilitate evidence-based improvements in human variant classification, the VCI is publicly available to the genomics community. Navigation workflows support users providing guidance to comprehensively apply the ACMG/AMP evidence criteria and document provenance for asserting variant classifications. Conclusions The VCI offers a central platform for clinical variant classification that fills a gap in the learning healthcare system, facilitates widespread adoption of standards for clinical curation, and is available at https://curation.clinicalgenome.org