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    Expanding the genetic heterogeneity of intellectual disability

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    Type
    Article
    Authors
    Anazi, Shams
    Maddirevula, Sateesh
    Salpietro, Vincenzo
    Asi, Yasmine T.
    Alsahli, Saud
    Alhashem, Amal
    Shamseldin, Hanan E.
    AlZahrani, Fatema
    Patel, Nisha
    Ibrahim, Niema
    Abdulwahab, Firdous M.
    Hashem, Mais
    Alhashmi, Nadia
    Al Murshedi, Fathiya
    Al Kindy, Adila
    Alshaer, Ahmad
    Rumayyan, Ahmed
    Al Tala, Saeed
    Kurdi, Wesam cc
    Alsaman, Abdulaziz
    Alasmari, Ali
    Banu, Selina
    Sultan, Tipu
    Saleh, Mohammed M.
    Alkuraya, Hisham
    Salih, Mustafa A.
    Aldhalaan, Hesham
    Ben-Omran, Tawfeg
    Al Musafri, Fatima
    Ali, Rehab
    Suleiman, Jehan
    Tabarki, Brahim
    El-Hattab, Ayman W.
    Bupp, Caleb
    Alfadhel, Majid
    Al Tassan, Nada
    Monies, Dorota cc
    Arold, Stefan T. cc
    Abouelhoda, Mohamed
    Lashley, Tammaryn
    Houlden, Henry
    Faqeih, Eissa
    Alkuraya, Fowzan S. cc
    KAUST Department
    Biological and Environmental Sciences and Engineering (BESE) Division
    Bioscience Program
    Computational Bioscience Research Center (CBRC)
    Date
    2017-09-22
    Online Publication Date
    2017-09-22
    Print Publication Date
    2017-11
    Permanent link to this record
    http://hdl.handle.net/10754/625777
    
    Metadata
    Show full item record
    Abstract
    Intellectual disability (ID) is a common morbid condition with a wide range of etiologies. The list of monogenic forms of ID has increased rapidly in recent years thanks to the implementation of genomic sequencing techniques. In this study, we describe the phenotypic and genetic findings of 68 families (105 patients) all with novel ID-related variants. In addition to established ID genes, including ones for which we describe unusual mutational mechanism, some of these variants represent the first confirmatory disease-gene links following previous reports (TRAK1, GTF3C3, SPTBN4 and NKX6-2), some of which were based on single families. Furthermore, we describe novel variants in 14 genes that we propose as novel candidates (ANKHD1, ASTN2, ATP13A1, FMO4, MADD, MFSD11, NCKAP1, NFASC, PCDHGA10, PPP1R21, SLC12A2, SLK, STK32C and ZFAT). We highlight MADD and PCDHGA10 as particularly compelling candidates in which we identified biallelic likely deleterious variants in two independent ID families each. We also highlight NCKAP1 as another compelling candidate in a large family with autosomal dominant mild intellectual disability that fully segregates with a heterozygous truncating variant. The candidacy of NCKAP1 is further supported by its biological function, and our demonstration of relevant expression in human brain. Our study expands the locus and allelic heterogeneity of ID and demonstrates the power of positional mapping to reveal unusual mutational mechanisms.
    Citation
    Anazi S, Maddirevula S, Salpietro V, Asi YT, Alsahli S, et al. (2017) Expanding the genetic heterogeneity of intellectual disability. Human Genetics. Available: http://dx.doi.org/10.1007/s00439-017-1843-2.
    Sponsors
    We thank the study families for their enthusiastic participation. This work was supported in part by King Salman Center for Disability Research (FSA). We acknowledge the support of the Saudi Human Genome Program and the Sequencing and Genotyping Core Facilities at KFSRHC. The research by STA reported in this publication was supported by funding from King Abdullah University of Science and Technology (KAUST).
    Publisher
    Springer Nature
    Journal
    Human Genetics
    DOI
    10.1007/s00439-017-1843-2
    PubMed ID
    28940097
    Additional Links
    https://link.springer.com/article/10.1007%2Fs00439-017-1843-2
    ae974a485f413a2113503eed53cd6c53
    10.1007/s00439-017-1843-2
    Scopus Count
    Collections
    Articles; Biological and Environmental Science and Engineering (BESE) Division; Bioscience Program; Computational Bioscience Research Center (CBRC)

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