Bi-allelic loss-of-function variants in the splicing regulator NSRP1 cause a severe neurodevelopmental disorder with epilepsy

Objective: To describe a novel neurodevelopmental disorder caused by bi-allelic pathogenic variants in the splicing regulator NSRP1. Background: Alternative splicing is a major contributor to transcriptome diversity. Through selective inclusion or exclusion of exons, alternative splicing generates multiple mRNA and protein isoforms with different functional properties from single genes. Splicing patterns are tightly regulated during development by RNA-binding proteins which influence spliceosome assembly at specific splice sites. Mouse genetic studies demonstrate that these splicing regulators control neurogenesis, cortical lamination, and synaptogenesis. They also maintain CNS homeostasis by regulating neuronal excitability. Despite this, few splicing regulator genes are associated with Mendelian genetic disease. Design/Methods: We performed exome sequencing as part of Baylor-Hopkins Center for Mendelian Genomics initiative. Additional families were recruited via the online database GeneMatcher. Results: Through family-based exome sequencing and rare variant analysis, we identified six patients from three unrelated consanguineous families with homozygous loss-of-function variants in the ubiquitously expressed Nuclear Speckle Splicing Regulator Protein 1, NSRP1. Clinical features include developmental delay (6/6), epilepsy (6/6), microcephaly (5/6), axial hypotonia (5/6), and appendicular hypertonia (4/6). Brain abnormalities detected on magnetic resonance imaging include dysmorphic corpus callosum, delayed myelination, simplified gyral pattern, under opercularization, inferior vermian hypoplasia, and dysmorphic lateral ventricles. Molecular analysis identified three rare pathogenic variants: c.1357_1360delAGAA (p.Glu455Alafs*20), c.1272dupG (p.Lys425Glufs*5), and c.52C>T (p.Gln18*). The two frameshift variants occur in the last exon and are predicted to cause loss of a critical nuclear localization signal. Conclusions: Our data demonstrate that biallelic pathogenic variants in NSRP1 cause a severe autosomal recessive neurodevelopmental disorder characterized by developmental delay, epilepsy, microcephaly, and hypotonia. Furthermore, these data implicate Nuclear Speckle Splicing Regulator Protein 1 as a key splicing regulator in human CNS development. Disclosure: Dr. Calame has nothing to disclose. Somayeh Bakhtiari has nothing to disclose. Tadahiro Mitani has nothing to disclose. Jawid Fatih has nothing to disclose. Rachel Logan has nothing to disclose. Jill Hunter has received personal compensation in the range of $10,000-$49,999 for serving as an Expert Witness for VARIOUS LEGAL FIRMS. Jill Hunter has received publishing royalties from a publication relating to health care. Dr. Herman has nothing to disclose. Dr. Pehlivan has nothing to disclose. Jennifer Posey has nothing to disclose. Maha Zaki has nothing to disclose. Dr. Marafie has received research support from United States National Institute of Health. The institution of Dr. Kruer has received research support from NIH NINDs. Dr. Kruer has received research support from Cure CP. Dr. Kruer has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant with NHRSA. Dr. Lupski has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Novartis. Dr. Lupski has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Regeneron Genetics Center.