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

Caroline R Stanclift, Selina S Dwight, Kevin Lee, Quirine L Eijkenboom, Matt Wilsey, Kristen Wilsey, Erica Sanford Kobayashi, Sandra Tong, Matthew N Bainbridge, Caroline R Stanclift, Selina S Dwight, Kevin Lee, Quirine L Eijkenboom, Matt Wilsey, Kristen Wilsey, Erica Sanford Kobayashi, Sandra Tong, Matthew N Bainbridge

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: Congenital disorder of deglycosylation; Incidence; NGLY1 deficiency; Patient registry; Rare diseases.

Conflict of interest statement

CRS, ST, SD, MW are employees of Grace Science, LLC. MNB is an advisor to Grace Science, LLC. KW has financial interest in Grace Science, LLC. ESK and QE have no conflicts of interest to disclose.

© 2022. The Author(s).

Figures

Fig. 1
Fig. 1
Frequency of NGLY1 Deficiency Related Symptoms by Caregiver Report. Frequency of symptoms reported in our NGLY1 Deficiency cohort for whom phenotypic data was available (N = 37; 19 males, 18 females). This bar chart demonstrates the number of patients affected by each clinical feature surveyed in the questionnaire. Males are colored in turquoise and females are colored in orange. The percentage represents the proportion of males or females with relevant symptoms compared to the whole cohort
Fig. 2
Fig. 2
Height and Weight by Caregiver Report. Growth Curves. Height (panel A, males, C, females) and weight (panel B, males, D females) for each individual NGLY1 patient aged 2 to 20 years old compared to CDC child growth standards (50th-tile solid line, 3rd and 97th-tile dashed line). Each black dot represents a single measurement for one individual
Fig. 3
Fig. 3
Lollipop Plot of Variants in NGLY1. 56 pathogenic variants and their frequency. Pathogenic variants (orange, nonsense; red, frameshift; purple, splice; green, indel; blue, missense) indicated by circles, with pathogenic variant count (n > 1) and pathogenic variant label (n > 2). Protein domains PAW (red) and transglutaminase-like (light blue), exon-exon boundaries (dotted) lines are shown across the protein (box). Amino acid count is given at top

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Source: PubMed

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