Biallelic Variants in the Ectonucleotidase ENTPD1 Cause a Complex Neurodevelopmental Disorder with Intellectual Disability, Distinct White Matter Abnormalities, and Spastic Paraplegia
Authors: Calame Daniel G. , Herman Isabella , Maroofian Reza , Marshall Aren E. , Donis Karina Carvalho , Fatih Jawid M. , Mitani Tadahiro , Du Haowei , Grochowski Christopher M. , Sousa Sergio B. , Gijavanekar Charul , Bakhtiari Somayeh , Ito Yoko A. , Rocca Clarissa , Hunter Jill V. , Sutton V. Reid , Emrick Lisa T. , Boycott Kym M. , Lossos Alexander , Fellig Yakov , Prus Eugenia , Kalish Yosef , Meiner Vardiella , Suerink Manon , Ruivenkamp Claudia , Muirhead Kayla , Saadi Nebal W. , Zaki Maha S. , Bouman Arjan , Barakat Tahsin Stefan , Skidmore David L. , Osmond Matthew , Silva Thiago Oliveira , Murphy David , Karimiani Ehsan Ghayoor , Jamshidi Yalda , Jaddoa Asaad Ghanim , Tajsharghi Homa , Jin Sheng Chih , Abbaszadegan Mohammad Reza , Ebrahimzadeh‐Vesal Reza , Hosseini Susan , Alavi Shahryar , Bahreini Amir , Zarean Elahe , Salehi Mohammad Mehdi , Al‐Sannaa Nouriya Abbas , Zifarelli Giovanni , Bauer Peter , Robson Simon C. , Coban‐Akdemir Zeynep , Travaglini Lorena , Nicita Francesco , Jhangiani Shalini N. , Gibbs Richard A. , Posey Jennifer E. , Kruer Michael C. , Kernohan Kristin D. , Morales Saute Jonas A. , Houlden Henry , Vanderver Adeline , Elsea Sarah H. , Pehlivan Davut , Marafi Dana , Lupski James R. 
Published: April 2022

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