TY - JOUR
T1 - The landscape of genetic diseases in Saudi Arabia based on the first 1000 diagnostic panels and exomes
AU - Monies, Dorota
AU - Abouelhoda, Mohamed
AU - AlSayed, Moeenaldeen
AU - Alhassnan, Zuhair
AU - Alotaibi, Maha
AU - Kayyali, Husam
AU - Al-Owain, Mohammed
AU - Shah, Ayaz
AU - Rahbeeni, Zuhair
AU - Al-Muhaizea, Mohammad A.
AU - Alzaidan, Hamad I.
AU - Cupler, Edward
AU - Bohlega, Saeed
AU - Faqeih, Eissa
AU - Faden, Maha
AU - Alyounes, Banan
AU - Jaroudi, Dyala
AU - Goljan, Ewa
AU - Elbardisy, Hadeel
AU - Akilan, Asma
AU - Albar, Renad
AU - Aldhalaan, Hesham
AU - Gulab, Shamshad
AU - Chedrawi, Aziza
AU - Al Saud, Bandar K.
AU - Kurdi, Wesam
AU - Makhseed, Nawal
AU - Alqasim, Tahani
AU - El Khashab, Heba Y.
AU - Al-Mousa, Hamoud
AU - Alhashem, Amal
AU - Kanaan, Imaduddin
AU - Algoufi, Talal
AU - Alsaleem, Khalid
AU - Basha, Talal A.
AU - Al-Murshedi, Fathiya
AU - Khan, Sameena
AU - Al-Kindy, Adila
AU - Alnemer, Maha
AU - Al-Hajjar, Sami
AU - Alyamani, Suad
AU - Aldhekri, Hasan
AU - Al-Mehaidib, Ali
AU - Arnaout, Rand
AU - Dabbagh, Omar
AU - Shagrani, Mohammad
AU - Broering, Dieter
AU - Tulbah, Maha
AU - Alqassmi, Amal
AU - Almugbel, Maisoon
AU - AlQuaiz, Mohammed
AU - Alsaman, Abdulaziz
AU - Al-Thihli, Khalid
AU - Sulaiman, Raashda A.
AU - Al-Dekhail, Wajeeh
AU - Alsaegh, Abeer
AU - Bashiri, Fahad A.
AU - Qari, Alya
AU - Alhomadi, Suzan
AU - Alkuraya, Hisham
AU - Alsebayel, Mohammed
AU - Hamad, Muddathir H.
AU - Szonyi, Laszlo
AU - Abaalkhail, Faisal
AU - Al-Mayouf, Sulaiman M.
AU - Almojalli, Hamad
AU - Alqadi, Khalid S.
AU - Elsiesy, Hussien
AU - Shuaib, Taghreed M.
AU - Seidahmed, Mohammed Zain
AU - Abosoudah, Ibraheem
AU - Akleh, Hana
AU - AlGhonaium, Abdulaziz
AU - Alkharfy, Turki M.
AU - Al Mutairi, Fuad
AU - Eyaid, Wafa
AU - Alshanbary, Abdullah
AU - Sheikh, Farrukh R.
AU - Alsohaibani, Fahad I.
AU - Alsonbul, Abdullah
AU - Al Tala, Saeed
AU - Balkhy, Soher
AU - Bassiouni, Randa
AU - Alenizi, Ahmed S.
AU - Hussein, Maged H.
AU - Hassan, Saeed
AU - Khalil, Mohamed
AU - Tabarki, Brahim
AU - Alshahwan, Saad
AU - Oshi, Amira
AU - Sabr, Yasser
AU - Alsaadoun, Saad
AU - Salih, Mustafa A.
AU - Mohamed, Sarar
AU - Sultana, Habiba
AU - Tamim, Abdullah
AU - El-Haj, Moayad
AU - Alshahrani, Saif
AU - Bubshait, Dalal K.
AU - Alfadhel, Majid
AU - Faquih, Tariq
AU - El-Kalioby, Mohamed
AU - Subhani, Shazia
AU - Shah, Zeeshan
AU - Moghrabi, Nabil
AU - Meyer, Brian F.
AU - Alkuraya, Fowzan S.
N1 - Publisher Copyright:
© 2017, The Author(s).
PY - 2017/8/1
Y1 - 2017/8/1
N2 - 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.
AB - 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.
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U2 - 10.1007/s00439-017-1821-8
DO - 10.1007/s00439-017-1821-8
M3 - Article
C2 - 28600779
AN - SCOPUS:85020623042
SN - 0340-6717
VL - 136
SP - 921
EP - 939
JO - Human Genetics
JF - Human Genetics
IS - 8
ER -
