PIGN mutation multiple congenital anomalies-hypotonia-seizures syndrome 1: A case report

INTRODUCTION

Multiple congenital anomalies-hypotonia-seizures syndrome 1 (MCAHS1) associated with mutations ingene, is an autosomal recessive disease featured as epilepsy, stunting, hypotonica, and various congenital disorders. This was initially described in 2011[1]. Mutation in thegene involved in GPI-anchor pathway have been identified cause varied neurological abnormalities[1-4].The authors report on a 16 years old girl who was presented with epilepsy, developmental delay and cerebellar atrophy. She harbors a compound heterozygous variant in thegene, include a nonsense splice site mutation (c.2557A>C) which was inherited from her mother, and a novel site mutation (c.980del) which was inherited from her father.

CASE PRESENTATION

Chief complaints

A female, 16 years old, was presented with epilepsy, developmental delay and cerebellar atrophy.

History of present illness

Clinical examination documented the eyes were deep set with nystagmus, a small nose with nasalbridge (Figure 1).

The authors will keep on to follow the patient’s disease development. This diagnosis allowed permitted appropriate genetic counseling with related risk evaluation.

History of past illness

柬埔寨留學生和本土學生漢語學習的目標需求對比研究…………………………………………………王睿昕（123）

Personal and family history

The patient was the second child of the family (non-consanguineous), her mother was 33 years old. She was born at full term with normal birth parameters, the pregnancy was normal, there was no known teratogenic exposure.

The parents does not have a personal history of seizures, nor is there a family history seizures.

Physical examination

Weakness of muscles was noticed at age 2 years old. At 1 year of age, she developed clinical seizures. Her seizure types include twitching movements, starting episodes, cluster seizures, and spasms. At a year and a half, there was only partial response to anti-convulsive therapy. Subsequently, global developmental delay was noted by 2 years old of age, there was no speech, and she needed assistance with daily life activities.

Laboratory examinations

Whole exome sequencing (WES) was performed commercially at Berrygenomics on the patient and her parents. Sequencing was performed on Illumina Novaseq 6000 (Illumina, San Diego, United States), using the Nano WES Human Exome V1.0 (Berrygenomics, Beijing, China) kit with 200 bp paired-end read, according to the manufacturer’s instructions. Annotation of variants was performed using GATK (https://software.broadinstitute.org/gatk/), gnomAD (http://gnomad.broadinstitute.org/), 1000genomes (http://browser.1000genomes.org), SIFT (http://sift.jcvi.org), FATHMM (http://fathmm.biocompute.org.uk), MutationAssessor (http://mutationassessor.org), OMIM (http://www.omim.org), ClinVar (http://www.ncbi.nlm.nih.gov/clinvar), HGMD (http:// www.hgmd.org).

Sanger sequening

出露的地層主要有泥盆系上統安格爾音烏拉組、石炭系上統寶力高廟組，白堊系下統白音高老組、梅勒圖組，以及新近系上新統寶格達烏拉組。（1）安格爾音烏拉組（D3a）為一套淺變質沉積地層，巖性為灰綠色粉砂質板巖；（2）寶力高廟組（C2bl）為一套淺變質的火山巖，主要巖性為安山質角礫凝灰巖、安山巖等，是礦區的主要含礦層位；（3）白音高老組（K1b）為一套酸性火山巖，主要巖性為流紋質玻屑凝灰巖、流紋質熔結凝灰巖、石泡流紋巖等；（4）梅勒圖組（K1m）主要巖性為安山玄武巖；（5）寶格達烏拉組（N2b）主要巖性為棕褐色泥巖、泥質砂巖等，分布于草原地勢低平處。

Imaging examinations

Neuropsychological testing demonstrated moderate intellectual disability. Brain imaging showed the progression of mild global cerebral volume loss and cerebellar atrophy. The parents could not provide the results of previous test, including brain magnetic resonance imaging, various metabolic tests.

首先，電力公司要抓好電力生產的安全管理動態評價，落實各級生產部門的安全職責。要從各個方面對電力系統安全生產過程進行監督，根據實際情況完善生產管理的監督體制，要確立行政責任制度，明確各個部門的第一負責人。按照電力公司的安全生產計劃表，將供電線路和電力設備進行逐級分配，將責任嚴格落實到個人。此外，各級安全監督負責人還要做好電力安全生產事故的匯報和總結工作，舉一反三，深刻吸取事故中的經驗和教訓。電力公司還要組織工作人員進行安全工作的教育和培訓，例舉出一些典型的安全事故，提高員工安全生產的意識。還要建立公司內部電力系統安全生產事故責任制度，對已發生或者未遂事故的負責人進行確定。

FINAL DIAGNOSIS

Whole Exome sequencing was performed commercially at BerryGenomics on the patient and her parents. Compound heterozygous mutations ingene were found, maternally inherited c.2557A>C and paternally inherited c.980del. The mutations were validated by sanger sequencing in the patient and her parents (Figure 2).

The authors also examined several small insertion/deletion variants (Indels), but none of these had an apparent connection to the clinical phenotype.

TREATMENT

The present therapies for patients withgene associated illnesses are mainly supportive, which were aimed to reduce the development of epileptic seizures.

OUTCOME AND FOLLOW-UP

改革開放以來，中國找鉀工作有了很大發展。進入1985年，為了迅速改變中國嚴重缺鉀狀況，地質部專門安排了中國柴達木盆地西部和北部鉀鹽的普查項目，為日后鉀鹽資源的重大發現，打下了堅實基礎。在國家政策指引和各項科研資金支持下，國投新疆羅布泊鉀鹽有限責任公司研發的“含鉀硫酸鎂亞型鹵水制取硫酸鉀”工藝 ，在新疆羅布泊鹽湖建成120萬噸/年硫酸鉀成套裝置，使我國擁有了世界領先的利用硫酸鹽型鹵水制取硫酸鉀的技術和產能世界第一的硫酸鉀大型裝置，該項目獲得2013年國家科技進步一等獎。

通過計算得到在邊坡開挖后，其安全系數為Fs=1.052<1.25，破壞概率PL1為25.02%，可靠性指數為0.663(見圖5)，不滿足規范要求，故邊坡需進行整體加固處理。

DISCUSSION

There are more than 20 genes that participated in GPI-anchor biosynthesis pathway.is responsible for supplement of phosphoethanolamine to the primary mannose in GPI[2]. Mutations in thegene involved in GPI biosynthesis, have been identified associated with MCAHS1[1,5,6]. The authors report a patient with epilepsy, global delay, cerebellar atrophy with amutation. The maternally inherited variant (c.2557A>C) has not been seen observed in the gnomAD and 1000genomes, which was called variants of unknown significance. The original mutation c.980del (paternally inherited) discovered in the prohand was estimated as “probably damaging”. The novel mutation changes the gene’s open reading frameshift, support the conclusion that the novel mutation detected in the patient cause major damage to the GPI-anchored protein, finally leading to the disorder.

Unlike previous reports[1,5,6], the patient did not have other visceral congenital anomalies of urinary, cardiac or gastrointestinal systems. Gastro-esophageal reflux, diaphragmatic hernia, brachycephaly, flat face, hypoplasia of distal parts of all fingers, open mouth, drooling have not been seen in the patient. Evaluation for mutations incausingassociated epilepsy or MCAHS1 should be considered in patients of all ethnicities with epilepsy. These phenotypic differences may be explained as allele specific effects.

Sequence analysis of exon 28 and 12 ofusing genomic DNA from the patient and her parents were performed by amplification of a 438 bp and 239 bp fragment containing the putative mutation identifiedexome sequencing. The sense primer sequence was 5’-TAAGTCAGTTTCATCACCGTTCTAT-3’ and the antisense primer sequence was 5’-ATTTCCTCTAATGACAAGCAACAC-3’ for exon 28. The sense primer sequence was 5’-TCTAGCAAATGACACTTTTAGAGA-3’, and the antisense primer sequence was 5’-TTCCTTACCACTGAGTTAAGAGG-3’ for exon 12.

The clinical severity of the disease seems to correlate with the predicted functional severity of the mutations seen in[6]. Depending upon the severity of mutations, major congenial anomalies may also be present. Other hypotheses of environmental and genetic modification need to be considered. It should also be noted here that for PIGN gene-associated with disability, some tissues are more sensitive than others during body development.

CONCLUSION

This case report expands the mutation spectrum found ingene, and strengthens the association betweenmutation and MCAHS1. Mutations ingene may be an underestimated cause of epilepsy. The authors recommend that, for patients with epilepsy or prenatal diagnosis of highly suspicious fetus, gene sequencing should be the preferred detection method.

She was vigorous in the newborn period and passed her newborn disease screening, began walking around the age of 18 mo.

ACKNOWLEDGEMENTS

The authors have read the CARE Checklist (2016), and the manuscript was prepared and revised according to the CARE Checklist (2016).

FOOTNOTES

Hou F performed the research and wrote the manuscript; Shan S analyzed the data; Jin H designed the research study; all authors have read and approve the final manuscript.

The patient and her legal guardian, provided informed written consent prior to study enrollment.

The authors declare that they have no conflict of interest.

當變壓器處于理想的狀態下，會得出變壓器的參數的關系為：當空間參數處于運行的狀態時候，將其劃定為一次繞組的接電源和二次繞組的開路的狀態。此外變壓器在受到電壓的UI作用下在一次繞組的N1內所通過的電流I0將其稱之為空載電流。此外I0能夠產生磁通，可將其稱之為勵磁電流。在它的作用下，其中的二次繞組N2的兩端會感應出電動的實例，可將變壓器的變換關系式為：

Authors are grateful to the patients and their families for their collaboration. The laboratory examination and data analysis were conducted in BerryGenomics.

This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BYNC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is noncommercial. See: https://creativecommons.org/Licenses/by-nc/4.0/

我國城市人口逐年遞增，導致排放污水的數量越來越多。以往的城市排水系統，大部分都是將污水直接排放到道路的兩邊或周圍的河流里，對城市環境造成了威脅，若依舊使用這種直接排放污水的方法，將會帶來嚴重的危害。因此，需確保城市排水的有效進行，加大對排水系統的研究工作。在設計排水系統時，為防止因污水數量過于龐大導致污水不能順利地經管道排出，從而對市民的生活造成影響，需要計算污水排放量。在排放污水時，還應使用節能方式進行排水，不斷加大污水的處理力度，同時也要提高對節能的重視程度。

China

發揚風格也不是隨意發揮，上文所提到的兩位翻譯家，魯迅和周作人，他們都認為兒童文學翻譯作品的目標讀者是兒童，因此應該著重考慮兒童的閱讀習慣和心理。原文中一些晦澀難懂的詞匯應該改成簡單生動的詞匯，所以在翻譯這些作品時，譯者要做二次創作。(夏丐尊，1983)[9]

Fei Hou 0000-0001-7164-9200; Shan Shan 0000-0002-8267-2833; Hua Jin 0000-0001-8008-8257.

從回歸系數t的數值來看，出口的對外直接投資彈性系數顯著.浙江省對外直接投資與出口之間存在著互補效應，對外直接投資每增加1個百分點，浙江省的出口將會增加0.1個百分點.一個可能的解釋是：一方面，對外直接投資的增加，使得浙江省與東道國的貿易聯系增加，從而有助于出口的增加；另一方面，浙江省對外直接投資一旦進入生產階段，則促進了中間品、原材料和技術的出口.同時根據式(5)還可以看出，距離與貿易量呈顯著的負相關性，表明地理位置會影響兩個國家或地區的貿易往來，而且是重要影響因素.此外，樣本國與浙江省是否擁有共同邊界或者同屬于一個貿易集團，對出口、進口貿易的影響比較小或者不明顯.

Liu JH

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Liu JH