Asi, Yasmine T.
Shamseldin, Hanan E.
Abdulwahab, Firdous M.
Al Murshedi, Fathiya
Al Kindy, Adila
Al Tala, Saeed
Saleh, Mohammed M.
Salih, Mustafa A.
Al Musafri, Fatima
El-Hattab, Ayman W.
Al Tassan, Nada
Arold, Stefan T.
Alkuraya, Fowzan S.
KAUST DepartmentBiological and Environmental Sciences and Engineering (BESE) Division
Computational Bioscience Research Center (CBRC)
Online Publication Date2017-09-22
Print Publication Date2017-11
Permanent link to this recordhttp://hdl.handle.net/10754/625777
MetadataShow full item record
AbstractIntellectual 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.
CitationAnazi 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.
SponsorsWe 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).
- Novel candidate genes and variants underlying autosomal recessive neurodevelopmental disorders with intellectual disability.
- Authors: Santos-Cortez RLP, Khan V, Khan FS, Mughal ZU, Chakchouk I, Lee K, Rasheed M, Hamza R, Acharya A, Ullah E, Saqib MAN, Abbe I, Ali G, Hassan MJ, Khan S, Azeem Z, Ullah I, Bamshad MJ, Nickerson DA, Schrauwen I, Ahmad W, Ansar M, Leal SM
- Issue date: 2018 Sep
- Next Generation Sequencing and Genome-Wide Genotyping Identify the Genetic Causes of Intellectual Disability in Ten Consanguineous Families from Jordan.
- Authors: Froukh TJ
- Issue date: 2017 Dec
- Exome sequencing revealed a novel homozygous METTL23 gene mutation leading to familial mild intellectual disability with dysmorphic features.
- Authors: Smaili W, Elalaoui SC, Zrhidri A, Raymond L, Egéa G, Taoudi M, Mouatassim SEL, Sefiani A, Lyahyai J
- Issue date: 2020 Jul
- A null mutation in TNIK defines a novel locus for intellectual disability.
- Authors: Anazi S, Shamseldin HE, AlNaqeb D, Abouelhoda M, Monies D, Salih MA, Al-Rubeaan K, Alkuraya FS
- Issue date: 2016 Jul
- Exome sequencing reveals predominantly de novo variants in disorders with intellectual disability (ID) in the founder population of Finland.
- Authors: Järvelä I, Määttä T, Acharya A, Leppälä J, Jhangiani SN, Arvio M, Siren A, Kankuri-Tammilehto M, Kokkonen H, Palomäki M, Varilo T, Fang M, Hadley TD, Jolly A, Linnankivi T, Paetau R, Saarela A, Kälviäinen R, Olme J, Nouel-Saied LM, Cornejo-Sanchez DM, Llaci L, Lupski JR, Posey JE, Leal SM, Schrauwen I
- Issue date: 2021 Jul