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

• DOI: 10.1007/s00439-017-1821-8
• Publication Date: 2017-06-09T12:56:46Z
• Authors: Dorota Monies; Mohamed Abouelhoda; Moeenaldeen AlSayed; Zuhair Alhassnan; Maha Alotaibi; Husam Kayyali; Mohammed Al-Owain; Ayaz Shah; Zuhair Rahbeeni; Mohammad A. Al-Mu...; Hamad I. Alzaidan; Edward Cupler; Saeed Bohlega; Eissa Faqeih; Maha Faden; Banan Alyounes; Dyala Jaroudi; Ewa Goljan; Hadeel Elbardisy; Asma Akilan; 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-Ma...; Hamad Almojalli; Khalid S. Alqadi; Hussien Elsiesy; Taghreed M. Shuaib; Mohammed Zain Sei...; 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
• Keywords: Mendelian inheritance; Exome; Founder effect; Human genetics

In this study, we report the experience of only reference clinical next-generation sequencing lab in Saudi Arabia with first 1000 families who span a wide-range suspected Mendelian phenotypes. A total 1019 tests were performed period March 2016-December 2016 comprising 972 solo (index only), 14 duo (parents or affected siblings and 33 trio parents). Multigene panels accounted for 672 tests, while whole exome (WES) represented remaining 347 tests. Pathogenic likely pathogenic variants that explain indications identified 34% (27% 43% exomes), spanning 279 genes including 165 novel variants. While recessive mutations dominated landscape solved cases (71% mutations, 97% which are homozygous), substantial minority (27%) on basis dominant mutations. The highly consanguineous nature study population also facilitated homozygosity many private (only 32.5% founder), as well instances inheritance previously assumed strictly disorders (involving ITPR1, VAMP1, MCTP2, TBP). Surprisingly, however, dual molecular diagnosis was observed 1.5% cases. Finally, have encountered candidate 75 (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, 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, WHSC1) not linked to human phenotypes these presented accelerate post-publication matchmaking. Two independently mutated more than one family similar phenotypes, substantiates their link disease (AKAP6 intellectual disability UBR4 early dementia). If cohort confirmed, yield WES will increased 83%, suggests most "negative" unsolved due interpretation rather technical limitations.