Identification of a Rare Exon 19 Skipping Mutation in ALMS1 Gene in Alström Syndrome Patients From Two Unrelated Saudi Families.
Identification of a Rare Exon 19 Skipping Mutation in ALMS1 Gene in Alström Syndrome Patients From Two Unrelated Saudi Families.
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DOI：
10.3389/fped.2021.652011
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发表时间：
2021
影响因子：
2.6
通讯作者：
Elango R
中科院分区：
文献类型：
--
作者：
Saadah OI;Banaganapalli B;Kamal NM;Sahly AN;Alsufyani HA;Mohammed A;Ahmad A;Nasser KK;Al-Aama JY;Shaik NA;Elango R
背景：阿尔斯特伦综合征(Alström综合征，AS)是一种罕见的儿童疾病，以心肌病、进行性听力损失和失明为特征。ALMS1基因的遗传变异是该病的已知分子病因。本研究的目的是确定沙特强直性脊柱炎患者的遗传基础，并了解其基因-表型关系。方法：对来自两个无血缘关系的沙特家系的6例AS患者进行临床表型和全外显子组测序分析。Sanger测序用于确定ALMS1变异在一级家系亲属中的遗传方式，并确保其在100名健康人群对照中罕见的患病率。结果：我们发现这两个家系的阿尔斯特伦患者都有一个非常罕见的ALMS1，3‘-剪接位点受体(c.11873−2 A>；T)变异，该变异跳过了整个外显子19，并将蛋白质缩短了80个氨基酸。这种疾病变异是由AS患者以常染色体隐性模式遗传的，目前还没有在任何群体特有的遗传数据库中报道。由于携带该突变的患者在临床表现上表现出异质性。对突变的ALMS1mRNA质心结构的计算分析表明，外显子19的跳跃扩大了发夹环，降低了自由能，最终影响了其折叠模式、稳定性和功能。因此，我们建议在沙特阿拉伯将c.11873-2a作为致病的潜在创始人突变，因为它在两个缺乏共同血统的家庭中被发现。结论：WES分析可能有助于临床表现不同的阿尔斯特伦患者的临床表型、早期诊断和更好的临床处理。
Background: Alström syndrome (AS) is a very rare childhood disorder characterized by cardiomyopathy, progressive hearing loss and blindness. Inherited genetic variants of ALMS1 gene are the known molecular cause of this disease. The objective of this study was to characterize the genetic basis and understand the genotype–phenotype relationship in Saudi AS patients. Methods: Clinical phenotyping and whole-exome sequencing (WES) analysis were performed on six AS patients belonging to two unrelated consanguineous Saudi families. Sanger sequencing was performed to determine the mode of inheritance of ALMS1 variant in first-degree family relatives and also to ensure its rare prevalence in 100 healthy population controls. Results: We identified that Alström patients from both the families were sharing a very rare ALMS1, 3′-splice site acceptor (c.11873−2 A>T) variant, which skips entire exon-19 and shortens the protein by 80 amino acids. This disease variant was inherited by AS patients in autosomal recessive mode and is not yet reported in any population-specific genetic databases. AS patients carrying this mutation showed heterogeneity in clinical presentations. Computational analysis of the mutant centroid structure of ALMS1 mRNA revealed that exon-19 skipping enlarges the hairpin loop and decreases the free energy, eventually affecting its folding pattern, stability, and function. Hence, we propose c.11873–2A as an AS causative potential founder mutation in Saudi Arabia because it is found in two families lacking a common lineage. Conclusions: We conclude that WES analysis potentially helps in clinical phenotyping, early diagnosis, and better clinical management of Alström patients showing variable clinical expressivity.
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影响因子：
5.3
作者：
Monies D;Abouelhoda M;AlSayed M;Alhassnan Z;Alotaibi M;Kayyali H;Al-Owain M;Shah A;Rahbeeni Z;Al-Muhaizea MA;Alzaidan HI;Cupler E;Bohlega S;Faqeih E;Faden M;Alyounes B;Jaroudi D;Goljan E;Elbardisy H;Akilan A;Albar R;Aldhalaan H;Gulab S;Chedrawi A;Al Saud BK;Kurdi W;Makhseed N;Alqasim T;El Khashab HY;Al-Mousa H;Alhashem A;Kanaan I;Algoufi T;Alsaleem K;Basha TA;Al-Murshedi F;Khan S;Al-Kindy A;Alnemer M;Al-Hajjar S;Alyamani S;Aldhekri H;Al-Mehaidib A;Arnaout R;Dabbagh O;Shagrani M;Broering D;Tulbah M;Alqassmi A;Almugbel M;AlQuaiz M;Alsaman A;Al-Thihli K;Sulaiman RA;Al-Dekhail W;Alsaegh A;Bashiri FA;Qari A;Alhomadi S;Alkuraya H;Alsebayel M;Hamad MH;Szonyi L;Abaalkhail F;Al-Mayouf SM;Almojalli H;Alqadi KS;Elsiesy H;Shuaib TM;Seidahmed MZ;Abosoudah I;Akleh H;AlGhonaium A;Alkharfy TM;Al Mutairi F;Eyaid W;Alshanbary A;Sheikh FR;Alsohaibani FI;Alsonbul A;Al Tala S;Balkhy S;Bassiouni R;Alenizi AS;Hussein MH;Hassan S;Khalil M;Tabarki B;Alshahwan S;Oshi A;Sabr Y;Alsaadoun S;Salih MA;Mohamed S;Sultana H;Tamim A;El-Haj M;Alshahrani S;Bubshait DK;Alfadhel M;Faquih T;El-Kalioby M;Subhani S;Shah Z;Moghrabi N;Meyer BF;Alkuraya FS
通讯作者：
Alkuraya FS
Alström综合征：遗传学和临床概述。
影响因子：
2.6
作者：
Marshall JD;Maffei P;Collin GB;Naggert JK
通讯作者：
Naggert JK
影响因子：
3
作者：
Magnus, Marcin;Kappel, Kalli;Bujnicki, Janusz M.
通讯作者：
Bujnicki, Janusz M.
影响因子：
0.6
作者：
Abu Safieh, Leen;Al-Otaibi, Humoud M.;Kozak, Igor
通讯作者：
Kozak, Igor
影响因子：
3.9
作者：
Marshall, Jan D.;Hinman, Elizabeth G.;Naggert, Juergen K.
通讯作者：
Naggert, Juergen K.