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.
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.
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.
We establish NSRP1 as a gene for a severe autosomal recessive neurodevelopmental disease trait characterized by developmental delay, epilepsy, microcephaly, and spastic cerebral palsy.
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All data described in this study are provided within the article and Supplementary Material. Raw sequencing data and de-identified clinical data is available from the corresponding authors upon request.
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This study was supported in part by the US National Human Genome Research Institute (NHGRI) and National Heart Lung and Blood Institute (NHLBI) to the Baylor-Hopkins Center for Mendelian Genomics (BHCMG, UM1 HG006542, J.R.L); NHGRI grant to Baylor College of Medicine Human Genome Sequencing Center (U54HG003273 to R.A.G.), NHGRI grant to the Yale-NIH Center for Mendelian Genomics (U54 HG006504-01); U.S. National Institute of Neurological Disorders and Stroke (NINDS) (R35NS105078 to J.R.L. and R01NS106298 to M.C.K.), Muscular Dystrophy Association (MDA) (512848 to J.R.L.), and Spastic Paraplegia Foundation Research Grant to J.R.L. S.B. is supported by a Cerebral Palsy Alliance Research Foundation Career Development Award (#CDG01318). D.M. is supported by a Medical Genetics Research Fellowship Program through the United States National Institute of Health (T32 GM007526-42). T.M. is supported by the Uehara Memorial Foundation. D.P. is supported by a fellowship award from International Rett Syndrome Foundation (IRSF grant #3701‐1). J.E.P. was supported by NHGRI K08 HG008986. D.G.C. is supported by NIH - Brain Disorders and Development Training Grant (T32 NS043124-19) and MDA Development Grant (873841).
This study adheres to the principles in the Declaration of Helsinki. The study was reviewed by Baylor College of Medicine Institutional Review Board (IRB) protocol H-29697. Written informed consent was obtained from all participants including consent for publication of photographs as required by the IRB. Consent forms are archived and available upon request.
J.R.L. has stock ownership in 23andMe, is a paid consultant for Regeneron Genetics Center, and is a co-inventor on multiple United States and European patents related to molecular diagnostics for inherited neuropathies, eye diseases, and bacterial genomic fingerprinting. The Department of Molecular and Human Genetics at Baylor College of Medicine receives revenue from clinical genetic testing conducted at Baylor Genetics (BG) Laboratories. M.C.K. is a paid consultant for PTC Therapeutics and Aeglea. R.P. and R.E.S. are employees of GeneDx. The other authors have no competing interests.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Calame, D.G., Bakhtiari, S., Logan, R. et al. Biallelic loss-of-function variants in the splicing regulator NSRP1 cause a severe neurodevelopmental disorder with spastic cerebral palsy and epilepsy. Genet Med 23, 2455–2460 (2021). https://doi.org/10.1038/s41436-021-01291-x