Dataset Information

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

ABSTRACT:

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.

SUBMITTER: Calame DG

PROVIDER: S-EPMC10054521 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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Publications

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

Calame Daniel G DG Herman Isabella I Maroofian Reza R Marshall Aren E AE Donis Karina Carvalho KC Fatih Jawid M JM Mitani Tadahiro T Du Haowei H Grochowski Christopher M CM Sousa Sergio B SB Gijavanekar Charul C Bakhtiari Somayeh S Ito Yoko A YA Rocca Clarissa C Hunter Jill V JV Sutton V Reid VR Emrick Lisa T LT Boycott Kym M KM Lossos Alexander A Fellig Yakov Y Prus Eugenia E Kalish Yosef Y Meiner Vardiella V Suerink Manon M Ruivenkamp Claudia C Muirhead Kayla K Saadi Nebal W NW Zaki Maha S MS Bouman Arjan A Barakat Tahsin Stefan TS Skidmore David L DL Osmond Matthew M Silva Thiago Oliveira TO Murphy David D Karimiani Ehsan Ghayoor EG Jamshidi Yalda Y Jaddoa Asaad Ghanim AG Tajsharghi Homa H Jin Sheng Chih SC Abbaszadegan Mohammad Reza MR Ebrahimzadeh-Vesal Reza R Hosseini Susan S Alavi Shahryar S Bahreini Amir A Zarean Elahe E Salehi Mohammad Mehdi MM Al-Sannaa Nouriya Abbas NA Zifarelli Giovanni G Bauer Peter P Robson Simon C SC Coban-Akdemir Zeynep Z Travaglini Lorena L Nicita Francesco F Jhangiani Shalini N SN Gibbs Richard A RA Posey Jennifer E JE Kruer Michael C MC Kernohan Kristin D KD Morales Saute Jonas A JA Houlden Henry H Vanderver Adeline A Elsea Sarah H SH Pehlivan Davut D Marafi Dana D Lupski James R JR

Annals of neurology 20220528 2

<h4>Objective</h4>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).<h4>Methods</h4>Individuals with biallelic ENTPD1 varian ...[more]

PMID: 35471564

Similar Datasets

Project description:Hereditary spastic paraplegias (HSPs) are a heterogeneous group of genetic disorders with spastic paraparesis as the main clinical feature. Complex forms may co-occur with other motor, sensory, and cognitive impairment. A growing number of loci and genes are being identified, but still more than 50% of the patients remain without molecular diagnosis. We present a Spanish family with autosomal dominant HSP and intellectual disability (ID) in which we found a possible dual genetic diagnosis with incomplete penetrance and variable expressivity in the parents and three siblings: a heterozygous duplication of 15q11.2-q13.1 found by array CGH and a novel missense heterozygous change in REEP1 [c.73A>G; p.(Lys25Glu)] found by whole exome sequencing (WES). Following the standard genetic diagnosis approach in ID, array CGH analysis was first performed in both brothers affected by spastic paraparesis and ID from school age, and a heterozygous duplication of 15q11.2-q13.1 was found. Subsequently, the duplication was also found in the healthy mother and in the sister, who presented attention deficit/hyperactivity disorder (ADHD) symptoms from school age and pes cavus with mild pyramidal signs at 22 years of age. Methylation analysis revealed that the three siblings carried the duplication unmethylated in the maternal allele, whereas their mother harbored it methylated in her paternal allele. Functional studies revealed an overexpression of UBE3A and ATP10A in the three siblings, and the slightest cognitive phenotype of the sister seems to be related to a lower expression of ATP10A. Later, searching for the cause of HSP, WES was performed revealing the missense heterozygous variant in REEP1 in all three siblings and the father, who presented subtle pyramidal signs in the lower limbs as well as the sister. Our findings reinforce the association of maternally derived UBE3A overexpression with neurodevelopmental disorders and support that a spectrum of clinical severity is present within families. They also reveal that a dual genetic diagnosis is possible in patients with presumed complex forms of HSP and cognitive impairment.

Dataset Information

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

Objective

Methods

Results

Interpretation

Publications

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

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