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

Daniel G. Calame, Somayeh Bakhtiari, Rachel Logan, Zeynep Coban-Akdemir, Haowei Du, Tadahiro Mitani, Jawid M. Fatih, Jill V. Hunter, Isabella Herman, Davut Pehlivan, Shalini N. Jhangiani, Richard Person, Rhonda E. Schnur, Sheng Chih Jin, Kaya Bilguvar, Jennifer E. Posey, Sookyong Koh, Saghar G. Firouzabadi, Elham Alehabib, Abbas TafakhoriSahra Esmkhani, Richard A. Gibbs, Mahmoud M. Noureldeen, Maha S. Zaki, Dana Marafi, Hossein Darvish, Michael C. Kruer, James R. Lupski

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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.

Original languageEnglish
Pages (from-to)2455-2460
Number of pages6
JournalGenetics in Medicine
Volume23
Issue number12
DOIs
StatePublished - Dec 2021

Fingerprint

Dive into the research topics of 'Biallelic loss-of-function variants in the splicing regulator NSRP1 cause a severe neurodevelopmental disorder with spastic cerebral palsy and epilepsy'. Together they form a unique fingerprint.

Cite this