Expanding the genetic heterogeneity of intellectual disability

Shams Anazi, Sateesh Maddirevula, Vincenzo Salpietro, Yasmine T. Asi, Saud Alsahli, Amal Alhashem, Hanan E. Shamseldin, Fatema AlZahrani, Nisha Patel, Niema Ibrahim, Firdous M. Abdulwahab, Mais Hashem, Nadia Alhashmi, Fathiya Al Murshedi, Adila Al Kindy, Ahmad Alshaer, Ahmed Rumayyan, Saeed Al Tala, Wesam Kurdi, Abdulaziz AlsamanAli Alasmari, Selina Banu, Tipu Sultan, Mohammed M. Saleh, Hisham Alkuraya, Mustafa A. Salih, Hesham Aldhalaan, Tawfeg Ben-Omran, Fatima Al Musafri, Rehab Ali, Jehan Suleiman, Brahim Tabarki, Ayman W. El-Hattab, Caleb Bupp, Majid Alfadhel, Nada Al Tassan, Dorota Monies, Stefan T. Arold, Mohamed Abouelhoda, Tammaryn Lashley, Henry Houlden, Eissa Faqeih, Fowzan S. Alkuraya

Research output: Contribution to journalArticle

37 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1-11
Number of pages11
JournalHuman Genetics
DOIs
Publication statusAccepted/In press - Sep 22 2017

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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    Anazi, S., Maddirevula, S., Salpietro, V., Asi, Y. T., Alsahli, S., Alhashem, A., Shamseldin, H. E., AlZahrani, F., Patel, N., Ibrahim, N., Abdulwahab, F. M., Hashem, M., Alhashmi, N., Al Murshedi, F., Al Kindy, A., Alshaer, A., Rumayyan, A., Al Tala, S., Kurdi, W., ... Alkuraya, F. S. (Accepted/In press). Expanding the genetic heterogeneity of intellectual disability. Human Genetics, 1-11. https://doi.org/10.1007/s00439-017-1843-2