Abstract Details

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

Topic Child Neurology and Developmental Neurology

Presentation(s) Child Neurology and Developmental Neurology Posters (7:00 AM-5:00 PM)

Poster/Presentation
Number 030

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.

Authors/Disclosures
Daniel Calame, MD, PhD (Baylor College of Medicine, Child Neurology) PRESENTER	Dr. Calame has nothing to disclose.
	No disclosure on file
	No disclosure on file
	No disclosure on file
Rachel Logan	Rachel Logan has nothing to disclose.
	No disclosure on file
Isabella Herman, MD (Boystown National Research Hospital)	Dr. Herman has nothing to disclose.
Davut Pehlivan, MD	Dr. Pehlivan has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Ionis Pharmaceuticals.
	No disclosure on file
	No disclosure on file
Danah Marafie, MD (Baylor College of Medicine)	Dr. Marafie has received research support from United States National Institute of Health.
Michael Kruer, MD (Sanford Children's Speciality Clinic)	Dr. Kruer has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for PTC Therapeutics. The institution of Dr. Kruer has received research support from NIH NINDs. The institution of Dr. Kruer has received research support from Medtronic . Dr. Kruer has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant with NHRSA.
James R. Lupski, MD, PhD (Baylor College of Medicine)	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.

�鶹��ýӳ��

�鶹��ýӳ��

Abstract Details