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

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

1 Citation (Scopus)


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
Publication statusPublished - Aug 2022

Bibliographical note

This study was supported by a US National Human Genome Research Institute (NHGRI) and National Heart Lung and Blood Institute grant to BHCMG (UM1 HG006542, J.R.L); an NHGRI grant to the BCM Human Genome Sequencing Center (U54HG003273, R.A.G.), the US National Institute of Neurological Disorders and Stroke (R35NS105078, J.R.L.; R01NS106298, M.C.K.), the Spastic Paraplegia Foundation (J.R.L.), and the Muscular Dystrophy Association (512848, J.R.L.). The functional studies performed for Family 20 were supported by the Care4Rare Canada Consortium, funded by Genome Canada and the Ontario Genomics Institute (OGI-147), the Canadian Institutes of Health Research, Ontario Research Fund, Genome Alberta, Genome British Columbia, Genome Quebec, and Children's Hospital of Eastern Ontario Foundation. S.B. is supported by a Cerebral Palsy Alliance Research Foundation Career Development Award. S.C.R. is supported by the NIH National of Aging (R01 DK108894; R21 CA164970, R21 CA221702) and a US Department of Defense Award (W81XWH-16-0464). D.M. was supported by a Medical Genetics Research Fellowship Program through the NIH (T32 GM007526-42). T.M. was supported by the Uehara Memorial Foundation. H.T. was supported by the European Union's Seventh Framework Programme for research, technological development and demonstration under grant agreement no. 608473. is supported by a Clinical Research Training Scholarship in Neuromuscular Disease by the American Brain Foundation and Muscle Study Group (MSG), and the International Rett Syndrome Foundation (3701-1). J.E.P. was supported by NHGRI K08 HG008986. D.G.C. is supported by an NIH Brain Disorders and Development Training Grant (T32 NS043124-19) and Muscular Dystrophy Association grant 873841. A.E.M. is supported by a Canadian Institutes of Health Research fellowship award (MFE-176616). J.A.M.S. is supported by the Brazilian National Council for Scientific and Technological Development. V.M. was supported by the Karl Kahane Foundation. A.L. was supported by an Israeli Ministry of Health (MOH) grant (5914) and the Israeli MOH/ERA-Net (4800). T.S.B. is supported by the Netherlands Organization for Scientific Research (ZonMW Veni; 91617021), a NARSAD Young Investigator Grant from the Brain & Behavior Research Foundation, Erasmus MC Fellowship 2017, and Erasmus MC Human Disease Model Award 2018.

We thank the families reported in this study for their willingness to contribute to the advancement of science and the understanding of rare neurological disease. L. Ben Avi is thanked for her technical assistance.

The initial stages of this project and preliminary data were previously presented in poster form at the American Society of Neurology Annual Meeting in April 2021 (

Publisher Copyright: © 2022 American Neurological Association.


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