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

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Biallelic loss-of-function variants in the splicing regulator NSRP1 cause a severe neurodevelopmental disorder with spastic cerebral palsy and epilepsy
Genetics in Medicine ( IF 6.6 ) Pub Date : 2021-08-12 , DOI: 10.1038/s41436-021-01291-x
Daniel G Calame _{1,

2,

3} , Somayeh Bakhtiari _{4,

5} , Rachel Logan ₆ , Zeynep Coban-Akdemir _{3,

7} , Haowei Du ₃ , Tadahiro Mitani ₃ , Jawid M Fatih ₃ , Jill V Hunter _{8,

9} , Isabella Herman _{1,

2,

3} , Davut Pehlivan _{1,

2,

3} , Shalini N Jhangiani ₁₀ , Richard Person ₁₁ , Rhonda E Schnur ₁₁ , Sheng Chih Jin ₁₂ , Kaya Bilguvar ₁₃ , Jennifer E Posey ₃ , Sookyong Koh ₁₄ , Saghar G Firouzabadi ₁₅ , Elham Alehabib ₁₆ , Abbas Tafakhori ₁₇ , Sahra Esmkhani ₁₈ , Richard A Gibbs _{3,

10} , Mahmoud M Noureldeen ₁₉ , Maha S Zaki ₂₀ , Dana Marafi _{3,

21} , Hossein Darvish ₂₂ , Michael C Kruer _{4,

5} , James R Lupski _{2,

3,

10,

23}

Affiliation

Division of Neurology and Developmental Neuroscience, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
Texas Children's Hospital, Houston, TX, USA.
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
Pediatric Movement Disorders Program, Division of Pediatric Neurology, Barrow Neurological Institute, Phoenix Children's Hospital, Phoenix, AZ, USA.
Departments of Child Health, Neurology, and Cellular & Molecular Medicine, and Program in Genetics, University of Arizona College of Medicine-Phoenix, Phoenix, AZ, USA.
Division of Neurosciences, Children's Healthcare of Atlanta, Atlanta, GA, USA.
Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA.
Department of Radiology, Baylor College of Medicine, Houston, TX, USA.
E.B. Singleton Department of Pediatric Radiology, Texas Children's Hospital, Houston, TX, USA.
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA.
GeneDX, Gaithersburg, MD, USA.
Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA.
Department of Genetics, Yale University, New Haven, CT, USA.
Department of Pediatrics, Children's Hospital, University of Nebraska, Omaha, NE, USA.
Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran.
Student Research Committee, Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Iranian Center of Neurological Research, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran.
Department of Basic Oncology, Division of Cancer Genetics, Oncology Institute, Istanbul University, Istanbul, Turkey.
Department of Pediatrics, Faculty of Medicine, Beni-Suef University, Beni-Suef, Egypt.
Department of Clinical Genetics, Human Genetics and Genome Research Division, National Research Centre, Cairo, Egypt.
Department of Pediatrics, Faculty of Medicine, Kuwait University, Safat, Kuwait.
Neuroscience Research Center, Faculty of Medicine, Golestan University of Medical Sciences, Gorgan, Iran.
Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.

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.

中文翻译：

剪接调节因子 NSRP1 中的双等位基因功能丧失变异导致严重的神经发育障碍，伴有痉挛性脑瘫和癫痫

目的

选择性剪接在小鼠神经发育、调节神经发生、皮质分层和突触发生中起关键作用，但已知很少有人类神经发育障碍是由剪接调节基因的致病变异引起的。核斑点剪接调节蛋白 1 (NSRP1) 是一种普遍表达的剪接调节因子，不知道是孟德尔疾病的基础。

方法

外显子组测序和基于稀有变异家族的基因组学是贝勒-霍普金斯孟德尔基因组学计划中心的一部分。通过 GeneMatcher 确定了其他家族。

结果

我们从三个不相关的家族中鉴定出 6 名患者，这些患者在NSRP1中具有纯合功能丧失变异体。临床特征包括发育迟缓、癫痫、可变小头畸形（Z评分 -0.95 至 -5.60）、肌张力减退和痉挛性脑瘫。脑异常包括简化的脑回模式、鳃盖不足和/或蠕虫发育不全。分子分析确定了三种致病性NSRP1预测的功能丧失变异等位基因：c.1359_1362delAAAG (p.Glu455AlafsTer20)、c.1272dupG (p.Lys425GlufsTer5) 和 c.52C>T (p.Gln18Ter)。这两个移码变体导致最后一个外显子中的过早终止密码子，并且预计突变转录物会逃避无义介导的衰变并导致 NSRP1 功能所需的 C 末端核定位信号的丢失。