Dataset Information

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

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.

SUBMITTER: Calame DG

PROVIDER: S-EPMC8633036 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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Publications

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

Calame Daniel G DG Bakhtiari Somayeh S Logan Rachel R Coban-Akdemir Zeynep Z Du Haowei H Mitani Tadahiro T Fatih Jawid M JM Hunter Jill V JV Herman Isabella I Pehlivan Davut D Jhangiani Shalini N SN Person Richard R Schnur Rhonda E RE Jin Sheng Chih SC Bilguvar Kaya K Posey Jennifer E JE Koh Sookyong S Firouzabadi Saghar G SG Alehabib Elham E Tafakhori Abbas A Esmkhani Sahra S Gibbs Richard A RA Noureldeen Mahmoud M MM Zaki Maha S MS Marafi Dana D Darvish Hossein H Kruer Michael C MC Lupski James R JR

Genetics in medicine : official journal of the American College of Medical Genetics 20210812 12

<h4>Purpose</h4>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.<h4>Methods</h4>Exome sequencing and rare variant family-based genomics was performed a ...[more]

PMID: 34385670

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Dataset Information

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

Purpose

Methods

Results

Conclusion

Publications

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

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