|Title||Biallelic loss-of-function variants in the splicing regulator NSRP1 cause a severe neurodevelopmental disorder with spastic cerebral palsy and epilepsy.|
|Publication Type||Journal Article|
|Year of Publication||2021|
|Authors||Calame, DG, Bakhtiari, S, Logan, R, Coban-Akdemir, Z, Du, H, Mitani, T, Fatih, JM, Hunter, JV, Herman, I, Pehlivan, D, Jhangiani, SN, Person, R, Schnur, RE, Jin, SChih, Bilguvar, K, Posey, JE, Koh, S, Firouzabadi, SG, Alehabib, E, Tafakhori, A, Esmkhani, S, Gibbs, RA, Noureldeen, MM, Zaki, MS, Marafi, D, Darvish, H, Kruer, MC, Lupski, JR|
|Date Published||2021 Dec|
|Keywords||Cerebral Palsy, Epilepsy, Humans, Microcephaly, Neurodevelopmental Disorders, Nuclear Proteins, Pedigree, RNA Splicing|
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.
|Alternate Journal||Genet Med|
|PubMed Central ID||PMC8633036|
|Grant List||U54HG003273 / HG / NHGRI NIH HHS / United States |
UM1 HG006504 / HG / NHGRI NIH HHS / United States
T32 GM007526 / GM / NIGMS NIH HHS / United States
UL1 TR001863 / TR / NCATS NIH HHS / United States
R35 NS105078 / NS / NINDS NIH HHS / United States
U54 HG006504 / HG / NHGRI NIH HHS / United States
T32 NS043124 / NS / NINDS NIH HHS / United States
R01 NS106298 / NS / NINDS NIH HHS / United States
UM1 HG006542 / HG / NHGRI NIH HHS / United States
U54 HG003273 / HG / NHGRI NIH HHS / United States
R00 HL143036 / HL / NHLBI NIH HHS / United States
K08 HG008986 / HG / NHGRI NIH HHS / United States