NGLY1 deficiency: estimated incidence, clinical features, and genotypic spectrum from the NGLY1 Registry

Stanclift et al. Orphanet Journal of Rare Diseases (2022) 17:440 https://doi.org/10.1186/s13023-022-02592-3 Open Access RESEARCH NGLY1 deficiency: estimated incidence, clinical features, and genotypic spectrum from the NGLY1 Registry Caroline R. Stanclift1, Selina S. Dwight1, Kevin Lee1, Quirine L. Eijkenboom1, Matt Wilsey1, Kristen Wilsey1, Erica Sanford Kobayashi2, Sandra Tong1* and Matthew N. Bainbridge2*    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 < 1.96E−11). Caregivers reported global developmental delay, movement disorder, and alacrima in over 85% of patients. Some phenotypic differences were noted between males and females. Regression was reported for all patients over 14 years old by their caregivers. The calculated U.S. incidence of NGLY1 Deficiency was ~ 12 individuals born per year. Conclusion: The estimated U.S. incidence of NGLY1 indicates the disease may be more common than the number of patients reported in the literature suggests. Given the low frequency of most variants and proportion of compound heterozygotes, genotype/phenotype correlations were not distinguishable. Keywords: NGLY1 deficiency, Congenital disorder of deglycosylation, Incidence, Rare diseases, Patient registry Introduction N-glycanase 1 (NGLY1) Deficiency (MIM #615273) is an ultra-rare, autosomal recessive disorder caused by loss of function variants in NGLY1 [1]. The disorder is characterized by five core features: (1) global developmental delay and/or intellectual disability, (2) a primarily hyperkinetic movement disorder (3) transient elevation of liver transaminases (4) hypo- or alacrima and (5) peripheral *Correspondence: ; 1 Grace Science Foundation, P.O. Box 114, Menlo Park, CA, USA Rady Children’s Institute for Genomic Medicine, 3020 Children’s Way, San Diego, CA, USA 2 neuropathy [1–3]. Additional signs and symptoms of the disease may include epilepsy, feeding difficulties, failure to thrive, hypotonia, central and/or obstructive sleep apnea, microcephaly, non-specific findings on brain MRI (delayed myelination; small corpus callosum, anterior commissure, and/or cerebellar atrophy; prominent cisterna magna and/or enlarged ventricles) [3], and orthopedic complications such as progressive scoliosis and joint contractures [4]. Caregivers commonly report regression of motor and/or cognitive function [2]. As NGLY1 Deficiency presents with a complex neurologic phenotype, the differential diagnosis is broad and may include congenital disorders of glycosylation (CDG), mitochondrial © The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativeco mmons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Stanclift et al. Orphanet Journal of Rare Diseases (2022) 17:440 disorders, MECP2-related disorders, and neurotransmitter disorders. Patients may be given a non-specific diagnosis of cerebral palsy. The constellation of symptoms and the range of severity varies between patients, making diagnosis and prognosis challenging [2, 3]. NGLY1 encodes the enzyme N-glycanase 1 (NGLY1). This 654 amino acid long protein consists of three major domains: the N-terminus PUB domain (present in PNGase/UBA or UBX-containing proteins and known to bind VCP, the C-terminus PAW domain (a high mannose-type glycan-binding domain that recognizes oligosaccharide substrates), and the transglutaminase-like domain (enzymatic domain) in the center of the protein. The enzymatic domain can be further subdivided into the transglutaminase core and the Rad4 transglutaminase-like domain. NGLY1 cleaves N-glycans from other proteins and is the only known cytosolic enzyme known to catalyze hydrolysis of the amide bond between an N-linked glycan and the asparagine of a protein [5]. As such, the underlying biology of NGLY1 Deficiency is distinct from that of congenital disorders of glycosyation (CDG) [6]. NGLY1 function is critical for the endoplasmic reticulum-associated protein degradation (ERAD) pathway that recognizes and eliminates unfolded or incorrectly processed glycoproteins [7]. Loss of NGLY1 function leads to accumulation of aspartylglucosamine (abbreviated GlcNAc-Asn or GNA) that can be detected in patient urine, plasma, and dried blood spots [5, 8]. In addition to affecting the ERAD pathway, loss of NGLY1 function impacts numerous cellular processes such as proteasomal homeostasis, mitophagy, BMP signaling, AMP kinase signaling, and ferroptosis, which may explain the multisystemic effects seen in patients with the disorder [6, 9]. Deglycosylation is critical for protein recycling and in vitro evidence suggests that misfolded products of the endoplasmic reticulum (ER) aggregate within the cells of NGLY1 patients and cause deleterious effects on the cytoplasm, ER, and mitochondria, leading to disease [10]. NGLY1 is located on chromosome 3p24.2. To date, 46 pathogenic variants in NGLY1 have been described in the literature [2]. Pathogenic variants include missense variants, truncations, small deletions, and splice-site variants. Truncating variants have been identified in each of the twelve exons of the gene [6]. With the exception of a slightly more common European allele, p.Arg401*, (MAF: 0.04% in gnomAD), the majority of known deleterious alleles are either extremely rare or have no known minor allele frequency. Until recently, the la (...truncated)