TY - JOUR
T1 - Biallelic loss-of-function variants in the splicing regulator NSRP1 cause a severe neurodevelopmental disorder with spastic cerebral palsy and epilepsy
AU - Calame, Daniel G.
AU - Bakhtiari, Somayeh
AU - Logan, Rachel
AU - Coban-Akdemir, Zeynep
AU - Du, Haowei
AU - Mitani, Tadahiro
AU - Fatih, Jawid M.
AU - Hunter, Jill V.
AU - Herman, Isabella
AU - Pehlivan, Davut
AU - Jhangiani, Shalini N.
AU - Person, Richard
AU - Schnur, Rhonda E.
AU - Jin, Sheng Chih
AU - Bilguvar, Kaya
AU - Posey, Jennifer E.
AU - Koh, Sookyong
AU - Firouzabadi, Saghar G.
AU - Alehabib, Elham
AU - Tafakhori, Abbas
AU - Esmkhani, Sahra
AU - Gibbs, Richard A.
AU - Noureldeen, Mahmoud M.
AU - Zaki, Maha S.
AU - Marafi, Dana
AU - Darvish, Hossein
AU - Kruer, Michael C.
AU - Lupski, James R.
N1 - Funding Information:
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).
Publisher Copyright:
© 2021, The Author(s), under exclusive licence to the American College of Medical Genetics and Genomics.
PY - 2021/12
Y1 - 2021/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85112722188&partnerID=8YFLogxK
U2 - 10.1038/s41436-021-01291-x
DO - 10.1038/s41436-021-01291-x
M3 - Article
C2 - 34385670
AN - SCOPUS:85112722188
VL - 23
SP - 2455
EP - 2460
JO - Genetics in Medicine
JF - Genetics in Medicine
SN - 1098-3600
IS - 12
ER -