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

Dorota Monies, Mohamed Abouelhoda, Moeenaldeen AlSayed, Zuhair Alhassnan, Maha Alotaibi, Husam Kayyali, Mohammed Al-Owain, Ayaz Shah, Zuhair Rahbeeni, Mohammad A. Al-Muhaizea, Hamad I. Alzaidan, Edward Cupler, Saeed Bohlega, Eissa Faqeih, Maha Faden, Banan Alyounes, Dyala Jaroudi, Ewa Goljan, Hadeel Elbardisy, Asma Akilan & 87 others Renad Albar, Hesham Aldhalaan, Shamshad Gulab, Aziza Chedrawi, Bandar K. Al Saud, Wesam Kurdi, Nawal Makhseed, Tahani Alqasim, Heba Y. El Khashab, Hamoud Al-Mousa, Amal Alhashem, Imaduddin Kanaan, Talal Algoufi, Khalid Alsaleem, Talal A. Basha, Fathiya Al-Murshedi, Sameena Khan, Adila Al-Kindy, Maha Alnemer, Sami Al-Hajjar, Suad Alyamani, Hasan Aldhekri, Ali Al-Mehaidib, Rand Arnaout, Omar Dabbagh, Mohammad Shagrani, Dieter Broering, Maha Tulbah, Amal Alqassmi, Maisoon Almugbel, Mohammed AlQuaiz, Abdulaziz Alsaman, Khalid Al-Thihli, Raashda A. Sulaiman, Wajeeh Al-Dekhail, Abeer Alsaegh, Fahad A. Bashiri, Alya Qari, Suzan Alhomadi, Hisham Alkuraya, Mohammed Alsebayel, Muddathir H. Hamad, Laszlo Szonyi, Faisal Abaalkhail, Sulaiman M. Al-Mayouf, Hamad Almojalli, Khalid S. Alqadi, Hussien Elsiesy, Taghreed M. Shuaib, Mohammed Zain Seidahmed, Ibraheem Abosoudah, Hana Akleh, Abdulaziz AlGhonaium, Turki M. Alkharfy, Fuad Al Mutairi, Wafa Eyaid, Abdullah Alshanbary, Farrukh R. Sheikh, Fahad I. Alsohaibani, Abdullah Alsonbul, Saeed Al Tala, Soher Balkhy, Randa Bassiouni, Ahmed S. Alenizi, Maged H. Hussein, Saeed Hassan, Mohamed Khalil, Brahim Tabarki, Saad Alshahwan, Amira Oshi, Yasser Sabr, Saad Alsaadoun, Mustafa A. Salih, Sarar Mohamed, Habiba Sultana, Abdullah Tamim, Moayad El-Haj, Saif Alshahrani, Dalal K. Bubshait, Majid Alfadhel, Tariq Faquih, Mohamed El-Kalioby, Shazia Subhani, Zeeshan Shah, Nabil Moghrabi, Brian F. Meyer, Fowzan S. Alkuraya

Research output: Contribution to journalArticle

57 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)921-939
Number of pages19
JournalHuman Genetics
Volume136
Issue number8
DOIs
Publication statusPublished - Aug 1 2017

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Exome
Inborn Genetic Diseases
Saudi Arabia
Mutation
Phenotype
Genes
Vesicle-Associated Membrane Protein 1
Dual (Psychiatry) Diagnosis
Intellectual Disability
Dementia
Publications
Population

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Monies, D., Abouelhoda, M., AlSayed, M., Alhassnan, Z., Alotaibi, M., Kayyali, H., ... Alkuraya, F. S. (2017). The landscape of genetic diseases in Saudi Arabia based on the first 1000 diagnostic panels and exomes. Human Genetics, 136(8), 921-939. https://doi.org/10.1007/s00439-017-1821-8

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

In: Human Genetics, Vol. 136, No. 8, 01.08.2017, p. 921-939.

Research output: Contribution to journalArticle

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 2017, 'The landscape of genetic diseases in Saudi Arabia based on the first 1000 diagnostic panels and exomes', Human Genetics, vol. 136, no. 8, pp. 921-939. https://doi.org/10.1007/s00439-017-1821-8
Monies D, Abouelhoda M, AlSayed M, Alhassnan Z, Alotaibi M, Kayyali H et al. The landscape of genetic diseases in Saudi Arabia based on the first 1000 diagnostic panels and exomes. Human Genetics. 2017 Aug 1;136(8):921-939. https://doi.org/10.1007/s00439-017-1821-8
Monies, Dorota ; Abouelhoda, Mohamed ; AlSayed, Moeenaldeen ; Alhassnan, Zuhair ; Alotaibi, Maha ; Kayyali, Husam ; Al-Owain, Mohammed ; Shah, Ayaz ; Rahbeeni, Zuhair ; Al-Muhaizea, Mohammad A. ; Alzaidan, Hamad I. ; Cupler, Edward ; Bohlega, Saeed ; Faqeih, Eissa ; Faden, Maha ; Alyounes, Banan ; Jaroudi, Dyala ; Goljan, Ewa ; Elbardisy, Hadeel ; Akilan, Asma ; Albar, Renad ; Aldhalaan, Hesham ; Gulab, Shamshad ; Chedrawi, Aziza ; Al Saud, Bandar K. ; Kurdi, Wesam ; Makhseed, Nawal ; Alqasim, Tahani ; El Khashab, Heba Y. ; Al-Mousa, Hamoud ; Alhashem, Amal ; Kanaan, Imaduddin ; Algoufi, Talal ; Alsaleem, Khalid ; Basha, Talal A. ; Al-Murshedi, Fathiya ; Khan, Sameena ; Al-Kindy, Adila ; Alnemer, Maha ; Al-Hajjar, Sami ; Alyamani, Suad ; Aldhekri, Hasan ; Al-Mehaidib, Ali ; Arnaout, Rand ; Dabbagh, Omar ; Shagrani, Mohammad ; Broering, Dieter ; Tulbah, Maha ; Alqassmi, Amal ; Almugbel, Maisoon ; AlQuaiz, Mohammed ; Alsaman, Abdulaziz ; Al-Thihli, Khalid ; Sulaiman, Raashda A. ; Al-Dekhail, Wajeeh ; Alsaegh, Abeer ; Bashiri, Fahad A. ; Qari, Alya ; Alhomadi, Suzan ; Alkuraya, Hisham ; Alsebayel, Mohammed ; Hamad, Muddathir H. ; Szonyi, Laszlo ; Abaalkhail, Faisal ; Al-Mayouf, Sulaiman M. ; Almojalli, Hamad ; Alqadi, Khalid S. ; Elsiesy, Hussien ; Shuaib, Taghreed M. ; Seidahmed, Mohammed Zain ; Abosoudah, Ibraheem ; Akleh, Hana ; AlGhonaium, Abdulaziz ; Alkharfy, Turki M. ; Al Mutairi, Fuad ; Eyaid, Wafa ; Alshanbary, Abdullah ; Sheikh, Farrukh R. ; Alsohaibani, Fahad I. ; Alsonbul, Abdullah ; Al Tala, Saeed ; Balkhy, Soher ; Bassiouni, Randa ; Alenizi, Ahmed S. ; Hussein, Maged H. ; Hassan, Saeed ; Khalil, Mohamed ; Tabarki, Brahim ; Alshahwan, Saad ; Oshi, Amira ; Sabr, Yasser ; Alsaadoun, Saad ; Salih, Mustafa A. ; Mohamed, Sarar ; Sultana, Habiba ; Tamim, Abdullah ; El-Haj, Moayad ; Alshahrani, Saif ; Bubshait, Dalal K. ; Alfadhel, Majid ; Faquih, Tariq ; El-Kalioby, Mohamed ; Subhani, Shazia ; Shah, Zeeshan ; Moghrabi, Nabil ; Meyer, Brian F. ; Alkuraya, Fowzan S. / The landscape of genetic diseases in Saudi Arabia based on the first 1000 diagnostic panels and exomes. In: Human Genetics. 2017 ; Vol. 136, No. 8. pp. 921-939.
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title = "The landscape of genetic diseases in Saudi Arabia based on the first 1000 diagnostic panels and exomes",
abstract = "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.",
author = "Dorota Monies and Mohamed Abouelhoda and Moeenaldeen AlSayed and Zuhair Alhassnan and Maha Alotaibi and Husam Kayyali and Mohammed Al-Owain and Ayaz Shah and Zuhair Rahbeeni and Al-Muhaizea, {Mohammad A.} and Alzaidan, {Hamad I.} and Edward Cupler and Saeed Bohlega and Eissa Faqeih and Maha Faden and Banan Alyounes and Dyala Jaroudi and Ewa Goljan and Hadeel Elbardisy and Asma Akilan and Renad Albar and Hesham Aldhalaan and Shamshad Gulab and Aziza Chedrawi and {Al Saud}, {Bandar K.} and Wesam Kurdi and Nawal Makhseed and Tahani Alqasim and {El Khashab}, {Heba Y.} and Hamoud Al-Mousa and Amal Alhashem and Imaduddin Kanaan and Talal Algoufi and Khalid Alsaleem and Basha, {Talal A.} and Fathiya Al-Murshedi and Sameena Khan and Adila Al-Kindy and Maha Alnemer and Sami Al-Hajjar and Suad Alyamani and Hasan Aldhekri and Ali Al-Mehaidib and Rand Arnaout and Omar Dabbagh and Mohammad Shagrani and Dieter Broering and Maha Tulbah and Amal Alqassmi and Maisoon Almugbel and Mohammed AlQuaiz and Abdulaziz Alsaman and Khalid Al-Thihli and Sulaiman, {Raashda A.} and Wajeeh Al-Dekhail and Abeer Alsaegh and Bashiri, {Fahad A.} and Alya Qari and Suzan Alhomadi and Hisham Alkuraya and Mohammed Alsebayel and Hamad, {Muddathir H.} and Laszlo Szonyi and Faisal Abaalkhail and Al-Mayouf, {Sulaiman M.} and Hamad Almojalli and Alqadi, {Khalid S.} and Hussien Elsiesy and Shuaib, {Taghreed M.} and Seidahmed, {Mohammed Zain} and Ibraheem Abosoudah and Hana Akleh and Abdulaziz AlGhonaium and Alkharfy, {Turki M.} and {Al Mutairi}, Fuad and Wafa Eyaid and Abdullah Alshanbary and Sheikh, {Farrukh R.} and Alsohaibani, {Fahad I.} and Abdullah Alsonbul and {Al Tala}, Saeed and Soher Balkhy and Randa Bassiouni and Alenizi, {Ahmed S.} and Hussein, {Maged H.} and Saeed Hassan and Mohamed Khalil and Brahim Tabarki and Saad Alshahwan and Amira Oshi and Yasser Sabr and Saad Alsaadoun and Salih, {Mustafa A.} and Sarar Mohamed and Habiba Sultana and Abdullah Tamim and Moayad El-Haj and Saif Alshahrani and Bubshait, {Dalal K.} and Majid Alfadhel and Tariq Faquih and Mohamed El-Kalioby and Shazia Subhani and Zeeshan Shah and Nabil Moghrabi and Meyer, {Brian F.} and Alkuraya, {Fowzan S.}",
year = "2017",
month = "8",
day = "1",
doi = "10.1007/s00439-017-1821-8",
language = "English",
volume = "136",
pages = "921--939",
journal = "Human Genetics",
issn = "0340-6717",
publisher = "Springer Verlag",
number = "8",

}

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.

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

VL - 136

SP - 921

EP - 939

JO - Human Genetics

JF - Human Genetics

SN - 0340-6717

IS - 8

ER -