The landscape of genetic diseases in Saudi Arabia based on the first 1000 diagnostic panels and exomes.
The landscape of genetic diseases in Saudi Arabia based on the first 1000 diagnostic panels and exomes.
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DOI：
10.1007/s00439-017-1821-8
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发表时间：
2017-08
期刊：
影响因子：
5.3
通讯作者：
Alkuraya FS
中科院分区：
文献类型：
--
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
在这项研究中，我们报告了沙特阿拉伯唯一的参考临床下一代测序实验室的经验，其中前1000个家庭跨越了广泛的疑似孟德尔表型。在2016年3月至2016年12月期间，共进行了1019次检测，包括972次单独检测（仅索引），14次二人检测（仅父母或受影响的兄弟姐妹）和33次三人检测（索引和父母）。多基因面板占672个测试，而全外显子组测序（WES）代表其余347个测试。解释临床适应症的致病性或可能致病性变体在34%中被鉴定（27%在面板中，43%在外显子组中），跨越279个基因，包括165个新变体。虽然隐性突变在已解决的病例中占主导地位（71%的突变，其中97%是纯合子），但也有相当一部分（27%）是在显性突变的基础上解决的。研究人群的高度血缘性质也促进了许多私人突变的纯合性（只有32.5%的隐性突变是创始人），以及先前假定的严格显性疾病（涉及ITPR 1，VAMP 1，MCTP 2和TBP）的隐性遗传的第一个实例。然而，令人惊讶的是，仅在1.5%的病例中观察到双重分子诊断。最后，我们在75个基因中发现了候选变异体，（ABHD 6、ACY 3、ADGRB 2、ADGRG 7、AGTPBP1、AHNAK 2、AKAP 6、ASB 3、ATXN1L、C17orf62、CABP 1、CCDC 186、CCP 110、CLSTN2、CNTN 3、CNTN 5、CTNNA 2、CWC22、DMAP1、DMKN、DMXL1、DSCAM、DVL 2、ECI1、EP 400、EPB41L5、FBXL22、GAP 43、GEMIN 7、GIT 1、GRIK4、GRSF1、GTRP1、HID1、IFNL1、KCNC4、LRRC52、MAP7D3、MCTP 2、MED26、MPP7、MRPS35、MTDH、MTMR 9、NECAP 2、NPAT、NRAP、PAX7、PCNX、PLCH 2、PLEKHF 1、PTPN 12、QKI、RILPL 2、RIMKLA、RIMS 2、RNF213、ROBO 1、SEC 16A、SIAH1、SIRT 2、SLAIN 2、SLC22A20、SMDT 1、SRRT、SSTR 1、ST 20、SYT9、TSPAN 6、UBR 4、VAMP 4、VPS 36、WDR 59、WDYHV 1和WHSC 1）之前未与人类表型关联，并且这些被呈现以加速出版后匹配。其中两个基因在一个以上具有相似表型的家族中独立突变，这证实了它们与人类疾病的联系（智力残疾中的AKAP 6和早期痴呆中的UBR 4）。如果该队列中的新候选疾病基因得到独立确认，WES的产率将增加到83%，这表明大多数“阴性”临床外显子组测试由于解释而不是技术限制而未解决。本文的在线版本（doi：10.1007/s 00439 -017-1821-8）包含补充材料，可供授权用户使用。
In this study, we report the experience of the only reference clinical next-generation sequencing lab in Saudi Arabia with the first 1000 families who span a wide-range of suspected Mendelian phenotypes. A total of 1019 tests were performed in the period of March 2016–December 2016 comprising 972 solo (index only), 14 duo (parents or affected siblings only), and 33 trio (index and parents). Multigene panels accounted for 672 tests, while whole exome sequencing (WES) represented the remaining 347 tests. Pathogenic or likely pathogenic variants that explain the clinical indications were identified in 34% (27% in panels and 43% in exomes), spanning 279 genes and including 165 novel variants. While recessive mutations dominated the landscape of solved cases (71% of mutations, and 97% of which are homozygous), a substantial minority (27%) were solved on the basis of dominant mutations. The highly consanguineous nature of the study population also facilitated homozygosity for many private mutations (only 32.5% of the recessive mutations are founder), as well as the first instances of recessive inheritance of previously assumed strictly dominant disorders (involving ITPR1, VAMP1, MCTP2, and TBP). Surprisingly, however, dual molecular diagnosis was only observed in 1.5% of cases. Finally, we have encountered candidate variants in 75 genes (ABHD6, ACY3, ADGRB2, ADGRG7, AGTPBP1, AHNAK2, AKAP6, ASB3, ATXN1L, C17orf62, CABP1, CCDC186, CCP110, CLSTN2, CNTN3, CNTN5, CTNNA2, CWC22, DMAP1, DMKN, DMXL1, DSCAM, DVL2, ECI1, EP400, EPB41L5, FBXL22, GAP43, GEMIN7, GIT1, GRIK4, GRSF1, GTRP1, HID1, IFNL1, KCNC4, LRRC52, MAP7D3, MCTP2, MED26, MPP7, MRPS35, MTDH, MTMR9, NECAP2, NPAT, NRAP, PAX7, PCNX, PLCH2, PLEKHF1, PTPN12, QKI, RILPL2, RIMKLA, RIMS2, RNF213, ROBO1, SEC16A, SIAH1, SIRT2, SLAIN2, SLC22A20, SMDT1, SRRT, SSTR1, ST20, SYT9, TSPAN6, UBR4, VAMP4, VPS36, WDR59, WDYHV1, and WHSC1) not previously linked to human phenotypes and these are presented to accelerate post-publication matchmaking. Two of these genes were independently mutated in more than one family with similar phenotypes, which substantiates their link to human disease (AKAP6 in intellectual disability and UBR4 in early dementia). If the novel candidate disease genes in this cohort are independently confirmed, the yield of WES will have increased to 83%, which suggests that most “negative” clinical exome tests are unsolved due to interpretation rather than technical limitations. The online version of this article (doi:10.1007/s00439-017-1821-8) contains supplementary material, which is available to authorized users.
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影响因子：
5.3
作者：
Yavarna, Tarunashree;Al-Dewik, Nader;Ben-Omran, Tawfeg
通讯作者：
Ben-Omran, Tawfeg
影响因子：
8.8
作者：
Monies, Dorota;Maddirevula, Sateesh;Alkuraya, Fowzan S.
通讯作者：
Alkuraya, Fowzan S.
DOI：
10.1056/nejmoa1516767
发表时间：
2017-01-05
期刊：
The New England journal of medicine
影响因子：
--
作者：
Posey JE;Harel T;Liu P;Rosenfeld JA;James RA;Coban Akdemir ZH;Walkiewicz M;Bi W;Xiao R;Ding Y;Xia F;Beaudet AL;Muzny DM;Gibbs RA;Boerwinkle E;Eng CM;Sutton VR;Shaw CA;Plon SE;Yang Y;Lupski JR
通讯作者：
Lupski JR
临床外显子组测序：2819个样品的结果反映了1000个家庭。
DOI：
10.1038/ejhg.2016.146
发表时间：
2017-02
期刊：
European journal of human genetics : EJHG
影响因子：
--
作者：
Trujillano D;Bertoli-Avella AM;Kumar Kandaswamy K;Weiss ME;Köster J;Marais A;Paknia O;Schröder R;Garcia-Aznar JM;Werber M;Brandau O;Calvo Del Castillo M;Baldi C;Wessel K;Kishore S;Nahavandi N;Eyaid W;Al Rifai MT;Al-Rumayyan A;Al-Twaijri W;Alothaim A;Alhashem A;Al-Sannaa N;Al-Balwi M;Alfadhel M;Rolfs A;Abou Jamra R
通讯作者：
Abou Jamra R
影响因子：
9.8
作者：
Boycott KM;Rath A;Chong JX;Hartley T;Alkuraya FS;Baynam G;Brookes AJ;Brudno M;Carracedo A;den Dunnen JT;Dyke SOM;Estivill X;Goldblatt J;Gonthier C;Groft SC;Gut I;Hamosh A;Hieter P;Höhn S;Hurles ME;Kaufmann P;Knoppers BM;Krischer JP;Macek M Jr;Matthijs G;Olry A;Parker S;Paschall J;Philippakis AA;Rehm HL;Robinson PN;Sham PC;Stefanov R;Taruscio D;Unni D;Vanstone MR;Zhang F;Brunner H;Bamshad MJ;Lochmüller H
通讯作者：
Lochmüller H