|Title||Biallelic Variants in the Ectonucleotidase ENTPD1 Cause a Complex Neurodevelopmental Disorder with Intellectual Disability, Distinct White Matter Abnormalities, and Spastic Paraplegia.|
|Publication Type||Journal Article|
|Year of Publication||2022|
|Authors||Calame, DG, Herman, I, Maroofian, R, Marshall, AE, Donis, KCarvalho, Fatih, JM, Mitani, T, Du, H, Grochowski, CM, Sousa, SB, Gijavanekar, C, Bakhtiari, S, Ito, YA, Rocca, C, Hunter, JV, V Sutton, R, Emrick, LT, Boycott, KM, Lossos, A, Fellig, Y, Prus, E, Kalish, Y, Meiner, V, Suerink, M, Ruivenkamp, C, Muirhead, K, Saadi, NW, Zaki, MS, Bouman, A, Barakat, TStefan, Skidmore, DL, Osmond, M, Silva, TOliveira, Murphy, D, Karimiani, EGhayoor, Jamshidi, Y, Jaddoa, AGhanim, Tajsharghi, H, Jin, SChih, Abbaszadegan, MReza, Ebrahimzadeh-Vesal, R, Hosseini, S, Alavi, S, Bahreini, A, Zarean, E, Salehi, MMehdi, Al-Sannaa, NAbbas, Zifarelli, G, Bauer, P, Robson, SC, Coban-Akdemir, Z, Travaglini, L, Nicita, F, Jhangiani, SN, Gibbs, RA, Posey, JE, Kruer, MC, Kernohan, KD, Saute, JAMorales, Houlden, H, Vanderver, A, Elsea, SH, Pehlivan, D, Marafi, D, Lupski, JR|
|Date Published||2022 Aug|
|Keywords||Apyrase, Dysarthria, Humans, Intellectual Disability, Mutation, Paraplegia, Pedigree, Phenotype, Spastic Paraplegia, Hereditary, White Matter|
OBJECTIVE: Human 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).
METHODS: Individuals with biallelic ENTPD1 variants were recruited worldwide. Deep phenotyping and molecular characterization were performed.
RESULTS: A 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.
INTERPRETATION: The 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.
|Alternate Journal||Ann Neurol|
|Grant List||U54HG003273 / HG / NHGRI NIH HHS / United States |
T32 NS043124-19 / NH / NIH HHS / United States
UM1 HG006542 / HG / NHGRI NIH HHS / United States
T32 GM007526 / GM / NIGMS NIH HHS / United States
NIH T32 GM007526-42 / NH / NIH HHS / United States
R01DK108894 / NH / NIH HHS / United States
T32 NS043124 / NS / NINDS NIH HHS / United States
R01NS106298 / NS / NINDS NIH HHS / United States
R01 NS106298 / NS / NINDS NIH HHS / United States
R21CA164970 / NH / NIH HHS / United States
R35NS105078 / NS / NINDS NIH HHS / United States
MFE-176616 / / CIHR / Canada
K08 HG008986 / HG / NHGRI NIH HHS / United States