Biallelic Variants in the Ectonucleotidase ENTPD1 Cause a Complex Neurodevelopmental Disorder with Intellectual Disability, Distinct White Matter Abnormalities, and Spastic Paraplegia

Abstract

ObjectiveHuman genomics established that pathogenic variation in diverse genes can underlie a single disorder. For example, hereditary spastic paraplegia is associated with >80 genes, with frequently only few affected individuals described for each gene. Herein, we characterize a large cohort of individuals with biallelic variation in ENTPD1, a gene previously linked to spastic paraplegia 64 (Mendelian Inheritance in Man # 615683).MethodsIndividuals with biallelic ENTPD1 variants were recruited worldwide. Deep phenotyping and molecular characterization were performed.ResultsA total of 27 individuals from 17 unrelated families were studied; additional phenotypic information was collected from published cases. Twelve novel pathogenic ENTPD1 variants are described (NM 001776.6): c.398_399delinsAA; p.(Gly133Glu), c.540del; p.(Thr181Leufs*18), c.640del; p.(Gly216Glufs*75), c.185 T > G; p.(Leu62*), c.1531 T > C; p.(*511Glnext*100), c.967C > T; p.(Gln323*), c.414‐2_414‐1del, and c.146 A > G; p.(Tyr49Cys) including 4 recurrent variants c.1109 T > A; p.(Leu370*), c.574‐6_574‐3del, c.770_771del; p.(Gly257Glufs*18), and c.1041del; p.(Ile348Phefs*19). Shared disease traits include childhood onset, progressive spastic paraplegia, intellectual disability (ID), dysarthria, and white matter abnormalities. In vitro assays demonstrate that ENTPD1 expression and function are impaired and that c.574‐6_574‐3del causes exon skipping. Global metabolomics demonstrate ENTPD1 deficiency leads to impaired nucleotide, lipid, and energy metabolism.InterpretationThe ENTPD1 locus trait consists of childhood disease onset, ID, progressive spastic paraparesis, dysarthria, dysmorphisms, and white matter abnormalities, with some individuals showing neurocognitive regression. Investigation of an allelic series of ENTPD1 (1) expands previously described features of ENTPD1‐related neurological disease, (2) highlights the importance of genotype‐driven deep phenotyping, (3) documents the need for global collaborative efforts to characterize rare autosomal recessive disease traits, and (4) provides insights into disease trait neurobiology. ANN NEUROL 2022;92:304–321

Functional genomics and small molecules in mitochondrial neurodevelopmental disorders

“…In contrast, the study of rare genetic variation has only just begun. An explosion of neurodevelopmental disease-gene associations has resulted from family-based studies, next generation sequencing, and online gene matchmaking [ 4 , [111] , [112] , [113] , [114] , [115] , [116] , [117] , [118] , [119] , [120] , [121] , [122] , [123] , [124] , [125] , [126] , [127] , [128] ], but genome-wide functional annotation requires greater international integration of human genomic and phenotypic data. National programs like UK Biobank and All of Us represent an important step in this direction [ 129 , 130 ], but a wealth of genomic and phenotypic data remains locked away in data silos: research databases, clinical diagnostic laboratories, and electronic health records.…”

Movement disorders in hereditary spastic paraplegias

“…Neuroimaging shows only mild white matter changes in some cases. 36 Garcia-Berlanga et al 37 described a case of a patient with SPG76 with SPG complicated by oculomotor abnormalities, ataxia, bradykinesia, and cervical dystonia, in which brain MRI was unrevealing and mutation in the CAPN1 was found. SPG78 is another complicated form of AR SPG with intellectual disability, cognitive decline, psychosis, upward ophthalmoplegia, neuropathy, dystonia, and thin corpus callosum.…”