title: Accelerating novel candidate gene discovery in neurogenetic disorders via whole-exome sequencing of prescreened multiplex consanguineous families.
abstract: Our knowledge of disease genes in neurological disorders is incomplete. With the aim of closing this gap, we performed whole-exome sequencing on 143 multiplex consanguineous families in whom known disease genes had been excluded by autozygosity mapping and candidate gene analysis. This prescreening step led to the identification of 69 recessive genes not previously associated with disease, of which 33 are here described (SPDL1, TUBA3E, INO80, NID1, TSEN15, DMBX1, CLHC1, C12orf4, WDR93, ST7, MATN4, SEC24D, PCDHB4, PTPN23, TAF6, TBCK, FAM177A1, KIAA1109, MTSS1L, XIRP1, KCTD3, CHAF1B, ARV1, ISCA2, PTRH2, GEMIN4, MYOCD, PDPR, DPH1, NUP107, TMEM92, EPB41L4A, and FAM120AOS). We also encountered instances in which the phenotype departed significantly from the established clinical presentation of a known disease gene. Overall, a likely causal mutation was identified in >73% of our cases. This study contributes to the global effort toward a full compendium of disease genes affecting brain function.
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.
authors.forename: Anas M
authors.initials: AM
authors.lastname: Alazami
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.
authors.forename: Nisha
authors.initials: N
authors.lastname: Patel
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.
authors.forename: Hanan E
authors.initials: HE
authors.lastname: Shamseldin
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.
authors.forename: Shamsa
authors.initials: S
authors.lastname: Anazi
authors.affiliation: Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia.
authors.forename: Mohammed S
authors.initials: MS
authors.lastname: Al-Dosari
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.
authors.forename: Fatema
authors.initials: F
authors.lastname: Alzahrani
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.
authors.forename: Hadia
authors.initials: H
authors.lastname: Hijazi
authors.affiliation: Department of Pediatrics, King Khalid University Hospital and College of Medicine, King Saud University, Riyadh 11451, Saudi Arabia.
authors.forename: Muneera
authors.initials: M
authors.lastname: Alshammari
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.
authors.forename: Mohammed A
authors.initials: MA
authors.lastname: Aldahmesh
authors.affiliation: Department of Pediatrics, King Khalid University Hospital and College of Medicine, King Saud University, Riyadh 11451, Saudi Arabia.
authors.forename: Mustafa A
authors.initials: MA
authors.lastname: Salih
authors.affiliation: Department of Pediatrics, King Fahad Medical City, Riyadh 11525, Saudi Arabia.
authors.forename: Eissa
authors.initials: E
authors.lastname: Faqeih
authors.affiliation: Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia; Department of Pediatrics, Prince Sultan Military Medical City, Riyadh 11159, Saudi Arabia.
authors.forename: Amal
authors.initials: A
authors.lastname: Alhashem
authors.affiliation: Department of Pediatrics, King Khalid University Hospital and College of Medicine, King Saud University, Riyadh 11451, Saudi Arabia.
authors.forename: Fahad A
authors.initials: FA
authors.lastname: Bashiri
authors.affiliation: Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia; Department of Medical Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Al-Owain
authors.affiliation: Department of Pediatrics, King Khalid University Hospital and College of Medicine, King Saud University, Riyadh 11451, Saudi Arabia.
authors.forename: Amal Y
authors.initials: AY
authors.lastname: Kentab
authors.affiliation: Department of Pediatrics, King Fahad General Hospital, Jeddah 23325, Saudi Arabia.
authors.forename: Sameera
authors.initials: S
authors.lastname: Sogaty
authors.affiliation: Department of Pediatrics, Armed Forces Hospital, Khamis Mushayt 62413, Saudi Arabia.
authors.forename: Saeed
authors.initials: S
authors.lastname: Al Tala
authors.affiliation: Department of Pediatrics, King Khalid University Hospital and College of Medicine, King Saud University, Riyadh 11451, Saudi Arabia.
authors.forename: Mohamad-Hani
authors.initials: MH
authors.lastname: Temsah
authors.affiliation: Department of Obstetrics & Gynecology, King Faisal Specialist Hospital, Riyadh 11211, Saudi Arabia.
authors.forename: Maha
authors.initials: M
authors.lastname: Tulbah
authors.affiliation: Center of Excellence for Genomics, King Abdulaziz City for Science and Technology, Riyadh 11442, Saudi Arabia.
authors.forename: Rasha F
authors.initials: RF
authors.lastname: Aljelaify
authors.affiliation: Department of Pediatrics, Prince Sultan Military Medical City, Riyadh 11159, Saudi Arabia.
authors.forename: Saad A
authors.initials: SA
authors.lastname: Alshahwan
authors.affiliation: Department of Pediatrics, Security Forces Hospital, Riyadh 12625, Saudi Arabia.
authors.forename: Mohammed Zain
authors.initials: MZ
authors.lastname: Seidahmed
authors.affiliation: Department of Pediatrics, King Khalid University Hospital and College of Medicine, King Saud University, Riyadh 11451, Saudi Arabia.
authors.forename: Adnan A
authors.initials: AA
authors.lastname: Alhadid
authors.affiliation: Department of Neurosciences, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.
authors.forename: Hesham
authors.initials: H
authors.lastname: Aldhalaan
authors.affiliation: Department of Neurosciences, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.
authors.forename: Fatema
authors.initials: F
authors.lastname: AlQallaf
authors.affiliation: Department of Obstetrics & Gynecology, King Faisal Specialist Hospital, Riyadh 11211, Saudi Arabia.
authors.forename: Wesam
authors.initials: W
authors.lastname: Kurdi
authors.affiliation: Division of Genetics, Department of Pediatrics, King Saud bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City, Riyadh 14611, Saudi Arabia.
authors.forename: Majid
authors.initials: M
authors.lastname: Alfadhel
authors.affiliation: Department of Obstetrics and Gynecology, College of Medicine, King Saud University, Riyadh 11451, Saudi Arabia.
authors.forename: Zainab
authors.initials: Z
authors.lastname: Babay
authors.affiliation: Department of Psychiatry, College of Medicine, King Saud University, Riyadh 11451, Saudi Arabia.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Alsogheer
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.
authors.forename: Namik
authors.initials: N
authors.lastname: Kaya
authors.affiliation: Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia; Department of Medical Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.
authors.forename: Zuhair N
authors.initials: ZN
authors.lastname: Al-Hassnan
authors.affiliation: Department of Clinical Genetics, Human Genetics and Genome Research Division, National Research Centre, Cairo 12345, Egypt.
authors.forename: Ghada M H
authors.initials: GM
authors.lastname: Abdel-Salam
authors.affiliation: Department of Pediatrics, Johns Hopkins Aramco Healthcare, Dhahran 34465, Saudi Arabia.
authors.forename: Nouriya
authors.initials: N
authors.lastname: Al-Sannaa
authors.affiliation: Division of Genetics, Department of Pediatrics, King Saud bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City, Riyadh 14611, Saudi Arabia.
authors.forename: Fuad
authors.initials: F
authors.lastname: Al Mutairi
authors.affiliation: Department of Pediatrics, King Khalid University Hospital and College of Medicine, King Saud University, Riyadh 11451, Saudi Arabia; Department of Pediatrics, Children's Hospital, Ain Shams University, Cairo 01234, Egypt.
authors.forename: Heba Y
authors.initials: HY
authors.lastname: El Khashab
authors.affiliation: Department of Neurosciences, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.
authors.forename: Saeed
authors.initials: S
authors.lastname: Bohlega
authors.affiliation: Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520, USA.
authors.forename: Xiaofei
authors.initials: X
authors.lastname: Jia
authors.affiliation: Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520, USA.
authors.forename: Henry C
authors.initials: HC
authors.lastname: Nguyen
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.
authors.forename: Rakad
authors.initials: R
authors.lastname: Hammami
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.
authors.forename: Nouran
authors.initials: N
authors.lastname: Adly
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.
authors.forename: Jawahir Y
authors.initials: JY
authors.lastname: Mohamed
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.
authors.forename: Firdous
authors.initials: F
authors.lastname: Abdulwahab
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.
authors.forename: Niema
authors.initials: N
authors.lastname: Ibrahim
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia; Saudi Human Genome Program, King Abdulaziz City for Science and Technology, Riyadh 11442, Saudi Arabia.
authors.forename: Ewa A
authors.initials: EA
authors.lastname: Naim
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia; Saudi Human Genome Program, King Abdulaziz City for Science and Technology, Riyadh 11442, Saudi Arabia.
authors.forename: Banan
authors.initials: B
authors.lastname: Al-Younes
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia; Saudi Human Genome Program, King Abdulaziz City for Science and Technology, Riyadh 11442, Saudi Arabia.
authors.forename: Brian F
authors.initials: BF
authors.lastname: Meyer
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.
authors.forename: Mais
authors.initials: M
authors.lastname: Hashem
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.
authors.forename: Ranad
authors.initials: R
authors.lastname: Shaheen
authors.affiliation: Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520, USA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Xiong
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia; Saudi Human Genome Program, King Abdulaziz City for Science and Technology, Riyadh 11442, Saudi Arabia.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Abouelhoda
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia; Department of Internal Medicine, College of Medicine, King Saud University, Riyadh 11451, Saudi Arabia.
authors.forename: Abdulrahman A
authors.initials: AA
authors.lastname: Aldeeri
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia; Saudi Human Genome Program, King Abdulaziz City for Science and Technology, Riyadh 11442, Saudi Arabia.
authors.forename: Dorota M
authors.initials: DM
authors.lastname: Monies
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia; Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia; Saudi Human Genome Program, King Abdulaziz City for Science and Technology, Riyadh 11442, Saudi Arabia. Electronic address: falkuraya@kfshrc.edu.sa.
authors.forename: Fowzan S
authors.initials: FS
authors.lastname: Alkuraya
mesh_terms: D002493:Central Nervous System Diseases / Q000235:genetics* / Q000473:pathology; D002874:Chromosome Mapping; D005260:Female; D056726:Genetic Association Studies; D059014:High-Throughput Nucleotide Sequencing; D006720:Homozygote; D006801:Humans; D008297:Male; D010375:Pedigree; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA