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. 2017 Nov;136(11-12):1419-1429.
doi: 10.1007/s00439-017-1843-2. Epub 2017 Sep 22.

Expanding the genetic heterogeneity of intellectual disability

Shams Anazi  1 , Sateesh Maddirevula  1 , Vincenzo Salpietro  2 , Yasmine T Asi  3 , Saud Alsahli  1 , Amal Alhashem  4 , Hanan E Shamseldin  1 , Fatema AlZahrani  1 , Nisha Patel  1 , Niema Ibrahim  1 , Firdous M Abdulwahab  1 , Mais Hashem  1 , Nadia Alhashmi  5 , Fathiya Al Murshedi  5 , Adila Al Kindy  5 , Ahmad Alshaer  6 , Ahmed Rumayyan  7   8 , Saeed Al Tala  9 , Wesam Kurdi  10 , Abdulaziz Alsaman  11 , Ali Alasmari  11 , Selina Banu  12 , Tipu Sultan  13 , Mohammed M Saleh  11 , Hisham Alkuraya  14 , Mustafa A Salih  15 , Hesham Aldhalaan  6 , Tawfeg Ben-Omran  16 , Fatima Al Musafri  16 , Rehab Ali  16 , Jehan Suleiman  17 , Brahim Tabarki  4 , Ayman W El-Hattab  18 , Caleb Bupp  19 , Majid Alfadhel  20 , Nada Al Tassan  1   21 , Dorota Monies  1   21 , Stefan T Arold  22 , Mohamed Abouelhoda  1   21 , Tammaryn Lashley  3 , Henry Houlden  2 , Eissa Faqeih  11 , Fowzan S Alkuraya  23   24   25   26   27
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Free article

Expanding the genetic heterogeneity of intellectual disability

Shams Anazi et al. Hum Genet. 2017 Nov.
Free article

Erratum in

  • Correction to: Expanding the genetic heterogeneity of intellectual disability.
    Anazi S, Maddirevula S, Salpietro V, Asi YT, Alsahli S, Alhashem A, Shamseldin HE, AlZahrani F, Patel N, Ibrahim N, Abdulwahab FM, Hashem M, Alhashmi N, Al Murshedi F, Al Kindy A, Alshaer A, Rumayyan A, Al Tala S, Kurdi W, Alsaman A, Alasmari A, Banu S, Sultan T, Saleh MM, Alkuraya H, Salih MA, Aldhalaan H, Ben-Omran T, Al Musafri F, Ali R, Suleiman J, Tabarki B, El-Hattab AW, Bupp C, Alfadhel M, Al Tassan N, Monies D, Arold ST, Abouelhoda M, Lashley T, Houlden H, Faqeih E, Alkuraya FS. Anazi S, et al. Hum Genet. 2018 Jan;137(1):105-109. doi: 10.1007/s00439-017-1859-7. Hum Genet. 2018. PMID: 29288388

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.

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