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Abstract Details

Bi-allelic variants in the ectonucleotidase ENTPD1 cause a complex neurological disease consisting of intellectual disability, brain abnormalities, and spastic paraplegia
Child Neurology and Developmental Neurology
Child Neurology and Developmental Neurology Posters (7:00 AM-5:00 PM)
031
To describe a cohort of patients with bi-allelic variants in ENTPD1, highlighting the spectrum of ENTPD1-related neurological disease.
Exome sequencing (ES) has markedly improved molecular diagnostic rates in rare Mendelian disorders by accelerating novel “disease gene” discovery. For example, hereditary spastic paraplegia (HSP), a neurodegenerative disorder affecting 1 in 10,000 individuals, is caused by 82 unique genes. HSP is characterized by upper motor neuron degeneration, leading to progressive spasticity, motor weakness, and loss of ambulation. Complex HSP can also involve other neurological features such as intellectual disability, epilepsy, and ataxia. Due to its genetic heterogeneity, pathogenic variants in many HSP-related genes, including ENTPD1, have only been described in a few affected individuals, and detailed disease phenotype and molecular studies are lacking.  ENTPD1 is a widely expressed plasma membrane protein involved in the catalysis of ATP, but its role in human disease is not well established. 

Through family-based ES with rare variant analysis, we identified a family with deleterious bi-allelic variants in ENTPD1. Additional subjects were recruited via the online gene matchmaking tool GeneMatcher.

We report 14 patients from 9 unrelated families with bi-allelic variants in ENTPD1 with a complex neurological phenotype of intellectual disability, cerebral abnormalities, progressive spastic paraplegia, epilepsy, and musculoskeletal abnormalities.  Molecular analysis identified 8 different deleterious variants, of which 6 represent novel variants: c.434_435delGCinAA, c.576delT, c.769_770delGG, c.574-8_574-5delTCTT, c.676delC, c.1145T>A, c.1006C>T (previously reported), and c.422T>G (previously reported).

We establish ENTPD1 as the molecular cause of a complex neurological disease characterized by intellectual disability, cerebral abnormalities, and spastic paraplegia. Functional studies to examine the effect of variants are ongoing. This study highlights the importance of establishing detailed phenotypic cohorts in rare neurological disease to capture/characterize the full disease spectrum and develop novel treatments for rare and complex neurological diseases.

Authors/Disclosures
Daniel Calame, MD, PhD (Baylor College of Medicine, Child Neurology)
PRESENTER 		Dr. Calame has nothing to disclose.
Isabella Herman, MD (Boystown National Research Hospital) Dr. Herman has nothing to disclose.
Danah Marafie, MD (Baylor College of Medicine) Dr. Marafie has received research support from United States National Institute of Health.
No disclosure on file
No disclosure on file
No disclosure on file
No disclosure on file
Michael Kruer, MD (Sanford Children's Speciality Clinic) Dr. Kruer has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for PTC Therapeutics. The institution of Dr. Kruer has received research support from NIH NINDs. The institution of Dr. Kruer has received research support from Medtronic . Dr. Kruer has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant with NHRSA.
Alexander Lossos, MD (Hadassah Hospital) Dr. Lossos has nothing to disclose.
No disclosure on file
No disclosure on file
No disclosure on file
No disclosure on file
No disclosure on file
Davut Pehlivan, MD Dr. Pehlivan has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Ionis Pharmaceuticals.
No disclosure on file
James R. Lupski, MD, PhD (Baylor College of Medicine) Dr. Lupski has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Novartis. Dr. Lupski has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Regeneron Genetics Center.