The landscape of genetic diseases in Saudi Arabia based on the first 1000 diagnostic panels and exomes

被引：232

作者：

Monies, Dorota ^{[1
,30
]}

Abouelhoda, Mohamed ^{[1
,30
]}

AlSayed, Moeenaldeen ^{[2
,16
]}

Alhassnan, Zuhair ^{[2
,16
]}

Alotaibi, Maha ^{[3
]}

Kayyali, Husam ^{[4
]}

Al-Owain, Mohammed ^{[2
,16
]}

Shah, Ayaz ^{[4
]}

Rahbeeni, Zuhair ^{[2
]}

Al-Muhaizea, Mohammad A. ^{[12
,16
]}

Alzaidan, Hamad I. ^{[2
,16
]}

Cupler, Edward ^{[4
]}

Bohlega, Saeed ^{[12
]}

Faqeih, Eissa ^{[24
]}

Faden, Maha ^{[3
]}

Alyounes, Banan ^{[1
,30
]}

Jaroudi, Dyala ^{[1
,30
]}

Goljan, Ewa ^{[1
,30
]}

Elbardisy, Hadeel ^{[1
]}

Akilan, Asma ^{[1
]}

Albar, Renad ^{[30
]}

Aldhalaan, Hesham ^{[12
]}

Gulab, Shamshad ^{[26
]}

Chedrawi, Aziza ^{[12
]}

Al Saud, Bandar K. ^{[7
,16
]}

Kurdi, Wesam ^{[9
,16
]}

Makhseed, Nawal ^{[8
]}

Alqasim, Tahani ^{[12
]}

El Khashab, Heba Y. ^{[5
,21
]}

Al-Mousa, Hamoud ^{[7
,16
]}

Alhashem, Amal ^{[16
,18
]}

Kanaan, Imaduddin ^{[12
]}

Algoufi, Talal ^{[19
]}

Alsaleem, Khalid ^{[7
]}

Basha, Talal A. ^{[26
]}

Al-Murshedi, Fathiya ^{[17
]}

Khan, Sameena ^{[12
,16
]}

Al-Kindy, Adila ^{[17
]}

Alnemer, Maha ^{[9
]}

Al-Hajjar, Sami ^{[7
]}

Alyamani, Suad ^{[12
]}

Aldhekri, Hasan ^{[7
]}

Al-Mehaidib, Ali ^{[7
]}

Arnaout, Rand ^{[7
]}

Dabbagh, Omar ^{[12
]}

Shagrani, Mohammad ^{[16
,19
]}

Broering, Dieter ^{[16
,19
]}

Tulbah, Maha ^{[9
]}

Alqassmi, Amal ^{[3
]}

Almugbel, Maisoon ^{[9
]}

机构：

[1] King Faisal Specialist Hosp & Res Ctr, Deparment Genet, Riyadh, Saudi Arabia

[2] King Faisal Specialist Hosp & Res Ctr, Dept Med Genet, Riyadh, Saudi Arabia

[3] Childrens Hosp, King Saud Med City, Riyadh, Saudi Arabia

[4] King Faisal Specialist Hosp & Res Ctr, Dept Neurosci, Jeddah, Saudi Arabia

[5] Ain Shams Univ, Childrens Hosp, Dept Pediat, Cairo, Egypt

[6] King Saud Bin Abdulaziz Univ Hlth Sci, Div Med Genet, Dept Pediat, King Abdullah Int Med Res Ctr,King Abdulaziz Med, King, WI, Saudi Arabia

[7] King Faisal Specialist Hosp & Res Ctr, Dept Pediat, Riyadh, Saudi Arabia

[8] Al Jahra Hosp, Dept Pediat, Minist Hlth, Kuwait, Kuwait

[9] King Faisal Specialist Hosp & Res Ctr, Dept Obstet & Gynecol, Riyadh, Saudi Arabia

[10] Natl Res Ctr, Clin Genet Div Human Genet & Genome Res, Giza, Egypt

[11] Taif Childrens Hosp, At Taif, Saudi Arabia

[12] King Faisal Specialist Hosp & Res Ctr, Dept Neurosci, Riyadh, Saudi Arabia

[13] King Saud Univ, Dept Pediat, Coll Med, Riyadh, Saudi Arabia

[14] Secur Forces Hosp, Dept Pediat, Riyadh, Saudi Arabia

[15] King Faisal Specialist Hosp & Res Ctr, Dept Med, Riyadh, Saudi Arabia

[16] Alfaisal Univ, Coll Med, Riyadh, Saudi Arabia

[17] Sultan Qaboos Univ Hosp, Dept Genet, Muscat, Oman

[18] Prince Sultan Mil Med City, Dept Pediat, Riyadh, Saudi Arabia

[19] King Faisal Specialist Hosp & Res Ctr, Dept Liver Transplantat, Riyadh, Saudi Arabia

[20] Med Diagnost Lab, Riyadh, Saudi Arabia

[21] Dr Suliman Al Habib Med Grp, Dept Pediat, Riyadh, Saudi Arabia

[22] Saudi German Hosp, Aseer, Saudi Arabia

[23] Univ Dammam, Dept Pediat, King Fahd Hosp Univ, Coll Med, Dammam, Saudi Arabia

[24] Childrens Hosp, Dept Pediat Subspecialties, King Fahad Med City, Riyadh, Saudi Arabia

[25] Al Hammadi Hosp, Neonatol, Riyadh, Saudi Arabia

[26] King Faisal Specialist Hosp & Res Ctr, Dept Pediat, Jeddah, Saudi Arabia

[27] Natl Neurosci Inst, Pediat Neurol Dept, King Fahad Med City, Riyadh, Saudi Arabia

[28] King Abdulaziz Univ, Dept Pediat, Jeddah, Saudi Arabia

[29] Specialized Med Ctr Hosp, Global Eye Care, Riyadh, Saudi Arabia

[30] King Abdulaziz City Sci & Technol, Saudi Human Genome Program, Riyadh, Saudi Arabia

[31] Matern & Childrens Hosp, Mecca, Saudi Arabia

[32] King Faisal Specialist Hosp & Res Ctr, Dept Oncol, Jeddah, Saudi Arabia

[33] King Saud Univ, Dept Obstet & Gynaecol, Coll Med, Riyadh, Saudi Arabia

来源：

HUMAN GENETICS | 2017年 / 136卷 / 08期

关键词：

KABUKI SYNDROMES; CHARGE;

D O I：

10.1007/s00439-017-1821-8

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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.

引用

页码：921 / 939

页数：19

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