Biallelic Loss of Function Variants in SENP7 Cause Immunodeficiency with Neurologic and Muscular Phenotypes.

To evaluate a novel candidate disease gene, we engaged international collaborators and identified rare, biallelic, specifically homozygous, loss of function variants in SENP7 in four children from three unrelated families presenting with neurodevelopmental abnormalities, dysmorphism, and immunodeficiency. Their clinical presentations were characterized by hypogammaglobulinemia, intermittent neutropenia, and ultimately death in infancy for all four patients. SENP7 is a sentrin-specific protease involved in posttranslational modification of proteins essential for cell regulation, via a process referred to as deSUMOylation. We propose that deficiency of deSUMOylation may represent a novel mechanism of primary immunodeficiency.

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

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.