Biallelic loss-of-function variants in the splicing regulator NSRP1 cause a severe neurodevelopmental disorder with spastic cerebral palsy and epilepsy

• Authors: Daniel G Calame, Baylor College of Medicine; Somayeh Bakhtiari, Phoenix Childrens Hosp; Rachel Logan, Childrens Healthcare Atlanta; Zeynep Coban-Akdemir, Baylor College of Medicine; Haowei Du, Baylor College of Medicine; Tadahiro Mitani, Baylor College of Medicine; Jawid M Fatih, Baylor College of Medicine; Jill V Hunter, Baylor College of Medicine; Isabella Herman, Texas Childrens Hospital; Davut Pehlivan, Baylor College of Medicine; Shalini N Jhangiani, Human Genome Sequencing Center,; Richard Person, GeneDX, Gaithersburg; Rhonda E Schnur, GeneDX, Gaithersburg; Sheng C Jin, Washington University School of Medicine; Kaya Bilguvar, Yale University; Jennifer E Posey, Baylor College of Medicine; Sookyong Koh, Emory University; Saghar G Firouzabadi, University of Social Welfare and Rehabilitation Sciences; Elham Alehabib, Shahid Beheshti University Medical Sciences; Abbas Tafakhori, Tehran University of Medical Sciences; Sahra Esmkhani, Istanbul University; Richard A Gibbs, Baylor College of Medicine; Mahmoud M Noureldeen, Beni Suef University; Maha S Zaki, Kuwait University; Dana Marafi, Baylor College of Medicine; Hossein Darvish, Golestan University of Medical Sciences, Gorgan; Michael C Kruer, Phoenix Children’s Hospital; James R Lupski, Texas Children’s Hospital, Houston
• Journal Title: GENETICS IN MEDICINE
• Volume: Volume 23, Number 12
• Publisher: SPRINGERNATURE | 2021-08-12, Pages 2455-2460
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1038/s41436-021-01291-x
• Subjects: Health Sciences, Oncology; Biology, Genetics
• Keywords: Science & Technology; Life Sciences & Biomedicine; Genetics & Heredity; SPECKLE-RELATED PROTEIN; ORGANIZATION; MECHANISMS

Abstract

Purpose: Alternative splicing plays a critical role in mouse neurodevelopment, regulating neurogenesis, cortical lamination, and synaptogenesis, yet few human neurodevelopmental disorders are known to result from pathogenic variation in splicing regulator genes. Nuclear Speckle Splicing Regulator Protein 1 (NSRP1) is a ubiquitously expressed splicing regulator not known to underlie a Mendelian disorder. Methods: Exome sequencing and rare variant family-based genomics was performed as a part of the Baylor-Hopkins Center for Mendelian Genomics Initiative. Additional families were identified via GeneMatcher. Results: We identified six patients from three unrelated families with homozygous loss-of-function variants in NSRP1. Clinical features include developmental delay, epilepsy, variable microcephaly (Z-scores −0.95 to −5.60), hypotonia, and spastic cerebral palsy. Brain abnormalities included simplified gyral pattern, underopercularization, and/or vermian hypoplasia. Molecular analysis identified three pathogenic NSRP1 predicted loss-of-function variant alleles: c.1359_1362delAAAG (p.Glu455AlafsTer20), c.1272dupG (p.Lys425GlufsTer5), and c.52C>T (p.Gln18Ter). The two frameshift variants result in a premature termination codon in the last exon, and the mutant transcripts are predicted to escape nonsense mediated decay and cause loss of a C-terminal nuclear localization signal required for NSRP1 function. Conclusion: We establish NSRP1 as a gene for a severe autosomal recessive neurodevelopmental disease trait characterized by developmental delay, epilepsy, microcephaly, and spastic cerebral palsy.