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

Daniel G. Calame, Isabella Herman, Reza Maroofian, Aren E. Marshall, Karina Carvalho Donis, Jawid M. Fatih, Tadahiro Mitani, Haowei Du, Christopher M. Grochowski, Sergio B. Sousa, Charul Gijavanekar, Somayeh Bakhtiari, Yoko A. Ito, Clarissa Rocca, Jill V. Hunter, V. Reid Sutton, Lisa T. Emrick, Kym M. Boycott, Alexander Lossos, Yakov FelligEugenia Prus, Yosef Kalish, Vardiella Meiner, Manon Suerink, Claudia Ruivenkamp, Kayla Muirhead, Nebal W. Saadi, Maha S. Zaki, Arjan Bouman, Tahsin Stefan Barakat, David L. Skidmore, Matthew Osmond, Thiago Oliveira Silva, David Murphy, Ehsan Ghayoor Karimiani, Yalda Jamshidi, Asaad Ghanim Jaddoa, Homa Tajsharghi, Sheng Chih Jin, Mohammad Reza Abbaszadegan, Reza Ebrahimzadeh-Vesal, Susan Hosseini, Shahryar Alavi, Amir Bahreini, Elahe Zarean, Mohammad Mehdi Salehi, Nouriya Abbas Al-Sannaa, Giovanni Zifarelli, Peter Bauer, Simon C. Robson, Zeynep Coban-Akdemir, Lorena Travaglini, Francesco Nicita, Shalini N. Jhangiani, Richard A. Gibbs, Jennifer E. Posey, Michael C. Kruer, Kristin D. Kernohan, Jonas A. Morales Saute, Henry Houlden, Adeline Vanderver, Sarah H. Elsea, Davut Pehlivan, Dana Marafi, James R. Lupski

Research output: Contribution to journalArticlepeer-review

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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.

Original languageEnglish
Pages (from-to)304-321
Number of pages18
JournalAnnals of neurology
Issue number2
StatePublished - Aug 2022


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