Characterization of Two Novel PNKP Splice-Site Variants in a Proband With Microcephaly, Intellectual Disability, and Multiple Malformations.

IF 1.6 3区 医学 Q3 GENETICS & HEREDITY American Journal of Medical Genetics Part B: Neuropsychiatric Genetics Pub Date : 2024-10-17 DOI:10.1002/ajmg.b.33013
Ugo Sorrentino, Elisa Baschiera, Maria Andrea Desbats, Orsetta Zuffardi, Leonardo Salviati, Matteo Cassina
{"title":"Characterization of Two Novel PNKP Splice-Site Variants in a Proband With Microcephaly, Intellectual Disability, and Multiple Malformations.","authors":"Ugo Sorrentino, Elisa Baschiera, Maria Andrea Desbats, Orsetta Zuffardi, Leonardo Salviati, Matteo Cassina","doi":"10.1002/ajmg.b.33013","DOIUrl":null,"url":null,"abstract":"<p><p>Polynucleotide kinase phosphatase (PNKP), encoded by the PNKP gene, is a DNA processing enzyme involved in double-strand break and single-strand break repair pathways, which are essential for genome stability and for the correct development and maintenance of human nervous system. PNKP biallelic loss-of-function variants have been associated with a broad spectrum of neurological anomalies, ranging from congenital microcephaly with intellectual disability and seizures (MCSZ), to later onset forms of ataxia-oculomotor apraxia (AOA4) or peripheral neuropathy (CMT2B2). We report the atypical clinical manifestations of a patient with severe microcephaly, short stature, developmental delay, conductive hearing loss, and tracheoesophageal malformation, in the absence of seizures. Whole exome sequencing analysis identified two novel, compound heterozygous splice-site variants in the PNKP gene (NM_007254.4): c.1448+1G > A and c.199-8_199-5del. To demonstrate the effect of both variants on the splicing process and prove their pathogenicity, we performed a hybrid minigene assay, which successfully highlighted a deleterious impact on the transcript, particularly regarding the c.199-8_199-5del variant. The uncommon clinical features of the proband and the identification of two newly associated pathogenic variants add further evidence to the allelic and phenotypic heterogeneity of the PNKP locus.</p>","PeriodicalId":7673,"journal":{"name":"American Journal of Medical Genetics Part B: Neuropsychiatric Genetics","volume":null,"pages":null},"PeriodicalIF":1.6000,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"American Journal of Medical Genetics Part B: Neuropsychiatric Genetics","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1002/ajmg.b.33013","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"GENETICS & HEREDITY","Score":null,"Total":0}
引用次数: 0

Abstract

Polynucleotide kinase phosphatase (PNKP), encoded by the PNKP gene, is a DNA processing enzyme involved in double-strand break and single-strand break repair pathways, which are essential for genome stability and for the correct development and maintenance of human nervous system. PNKP biallelic loss-of-function variants have been associated with a broad spectrum of neurological anomalies, ranging from congenital microcephaly with intellectual disability and seizures (MCSZ), to later onset forms of ataxia-oculomotor apraxia (AOA4) or peripheral neuropathy (CMT2B2). We report the atypical clinical manifestations of a patient with severe microcephaly, short stature, developmental delay, conductive hearing loss, and tracheoesophageal malformation, in the absence of seizures. Whole exome sequencing analysis identified two novel, compound heterozygous splice-site variants in the PNKP gene (NM_007254.4): c.1448+1G > A and c.199-8_199-5del. To demonstrate the effect of both variants on the splicing process and prove their pathogenicity, we performed a hybrid minigene assay, which successfully highlighted a deleterious impact on the transcript, particularly regarding the c.199-8_199-5del variant. The uncommon clinical features of the proband and the identification of two newly associated pathogenic variants add further evidence to the allelic and phenotypic heterogeneity of the PNKP locus.

查看原文
分享 分享
微信好友 朋友圈 QQ好友 复制链接
本刊更多论文
一个患有小头畸形、智力障碍和多种畸形的婴儿体内两个新的 PNKP 片段位点变异的特征。
多核苷酸激酶磷酸酶(PNKP)由 PNKP 基因编码,是一种 DNA 处理酶,参与双链断裂和单链断裂修复途径,对基因组稳定性以及人类神经系统的正确发育和维护至关重要。PNKP 双重功能缺失变异与多种神经系统异常有关,包括先天性小头畸形伴智力障碍和癫痫发作(MCSZ),以及迟发性共济失调-运动障碍(AOA4)或周围神经病变(CMT2B2)。我们报告了一名患者的非典型临床表现,该患者患有严重小头畸形、身材矮小、发育迟缓、传导性听力损失和气管食管畸形,但没有癫痫发作。全外显子组测序分析在PNKP基因(NM_007254.4)中发现了两个新型复合杂合剪接位点变异:c.1448+1G > A和c.199-8_199-5del。为了证明这两个变异位点对剪接过程的影响并证明其致病性,我们进行了杂交微型基因检测,结果成功地突出了对转录本的有害影响,尤其是对 c.199-8_199-5del 变异位点的影响。该患者不常见的临床特征和两个新发现的相关致病变异为 PNKP 基因座的等位基因和表型异质性提供了进一步的证据。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 去求助
来源期刊
CiteScore
5.90
自引率
7.10%
发文量
40
审稿时长
4-8 weeks
期刊介绍: Neuropsychiatric Genetics, Part B of the American Journal of Medical Genetics (AJMG) , provides a forum for experimental and clinical investigations of the genetic mechanisms underlying neurologic and psychiatric disorders. It is a resource for novel genetics studies of the heritable nature of psychiatric and other nervous system disorders, characterized at the molecular, cellular or behavior levels. Neuropsychiatric Genetics publishes eight times per year.
期刊最新文献
Issue Information - TOC Contribution of Rare and Potentially Functionally Relevant Sequence Variants in Schizophrenia Risk-Locus Xq28,distal. Optimizing the Prediction of Depression Remission: A Longitudinal Machine Learning Approach. New Insights Into TRMT10A Syndrome: Case Report and Literature Review. Characterization of Two Novel PNKP Splice-Site Variants in a Proband With Microcephaly, Intellectual Disability, and Multiple Malformations.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
已复制链接
已复制链接
快去分享给好友吧!
我知道了
×
扫码分享
扫码分享
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1