Expanding the genetic heterogeneity of intellectual disability

Handle URI:
http://hdl.handle.net/10754/625777
Title:
Expanding the genetic heterogeneity of intellectual disability
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; 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; Arold, Stefan T. ( 0000-0001-5278-0668 ) ; Abouelhoda, Mohamed; Lashley, Tammaryn; Houlden, Henry; Faqeih, Eissa; Alkuraya, Fowzan S. ( 0000-0003-4158-341X )
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.
KAUST Department:
Biological and Environmental Sciences and Engineering (BESE) Division; Computational Bioscience Research Center (CBRC)
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.
Publisher:
Springer Nature
Journal:
Human Genetics
Issue Date:
22-Sep-2017
DOI:
10.1007/s00439-017-1843-2
Type:
Article
ISSN:
0340-6717; 1432-1203
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).
Additional Links:
https://link.springer.com/article/10.1007%2Fs00439-017-1843-2
Appears in Collections:
Articles; Computational Bioscience Research Center (CBRC); Biological and Environmental Sciences and Engineering (BESE) Division

Full metadata record

DC FieldValue Language
dc.contributor.authorAnazi, Shamsen
dc.contributor.authorMaddirevula, Sateeshen
dc.contributor.authorSalpietro, Vincenzoen
dc.contributor.authorAsi, Yasmine T.en
dc.contributor.authorAlsahli, Sauden
dc.contributor.authorAlhashem, Amalen
dc.contributor.authorShamseldin, Hanan E.en
dc.contributor.authorAlZahrani, Fatemaen
dc.contributor.authorPatel, Nishaen
dc.contributor.authorIbrahim, Niemaen
dc.contributor.authorAbdulwahab, Firdous M.en
dc.contributor.authorHashem, Maisen
dc.contributor.authorAlhashmi, Nadiaen
dc.contributor.authorAl Murshedi, Fathiyaen
dc.contributor.authorAl Kindy, Adilaen
dc.contributor.authorAlshaer, Ahmaden
dc.contributor.authorRumayyan, Ahmeden
dc.contributor.authorAl Tala, Saeeden
dc.contributor.authorKurdi, Wesamen
dc.contributor.authorAlsaman, Abdulazizen
dc.contributor.authorAlasmari, Alien
dc.contributor.authorBanu, Selinaen
dc.contributor.authorSultan, Tipuen
dc.contributor.authorSaleh, Mohammed M.en
dc.contributor.authorAlkuraya, Hishamen
dc.contributor.authorSalih, Mustafa A.en
dc.contributor.authorAldhalaan, Heshamen
dc.contributor.authorBen-Omran, Tawfegen
dc.contributor.authorAl Musafri, Fatimaen
dc.contributor.authorAli, Rehaben
dc.contributor.authorSuleiman, Jehanen
dc.contributor.authorTabarki, Brahimen
dc.contributor.authorEl-Hattab, Ayman W.en
dc.contributor.authorBupp, Caleben
dc.contributor.authorAlfadhel, Majiden
dc.contributor.authorAl Tassan, Nadaen
dc.contributor.authorMonies, Dorotaen
dc.contributor.authorArold, Stefan T.en
dc.contributor.authorAbouelhoda, Mohameden
dc.contributor.authorLashley, Tammarynen
dc.contributor.authorHoulden, Henryen
dc.contributor.authorFaqeih, Eissaen
dc.contributor.authorAlkuraya, Fowzan S.en
dc.date.accessioned2017-10-03T12:49:39Z-
dc.date.available2017-10-03T12:49:39Z-
dc.date.issued2017-09-22en
dc.identifier.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.en
dc.identifier.issn0340-6717en
dc.identifier.issn1432-1203en
dc.identifier.doi10.1007/s00439-017-1843-2en
dc.identifier.urihttp://hdl.handle.net/10754/625777-
dc.description.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.en
dc.description.sponsorshipWe 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).en
dc.publisherSpringer Natureen
dc.relation.urlhttps://link.springer.com/article/10.1007%2Fs00439-017-1843-2en
dc.titleExpanding the genetic heterogeneity of intellectual disabilityen
dc.typeArticleen
dc.contributor.departmentBiological and Environmental Sciences and Engineering (BESE) Divisionen
dc.contributor.departmentComputational Bioscience Research Center (CBRC)en
dc.identifier.journalHuman Geneticsen
dc.contributor.institutionDepartment of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.en
dc.contributor.institutionDepartment of Molecular Neuroscience, UCL Institute of Neurology, London, UK.en
dc.contributor.institutionQueen Square Brain Bank for Neurological Disorders, Department of Molecular Neuroscience, UCL Institute of Neurology, University College London, London, UK.en
dc.contributor.institutionDepartment of Pediatrics, Prince Sultan Military Medical City, Riyadh, Saudi Arabia.en
dc.contributor.institutionDepartment of Genetics, College of Medicine, Sultan Qaboos University, Muscat, Sultanate of Oman.en
dc.contributor.institutionPediatric Neurology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.en
dc.contributor.institutionNeurology Division, Department of Pediatrics, King Abdulaziz Medical City, Riyadh, Saudi Arabia.en
dc.contributor.institutionDepartment of Pediatrics and Genetic Unit, Armed Forces Hospital, Khamis Mushayt, Saudi Arabia.en
dc.contributor.institutionDepartment of Obstetrics and Gynecology, King Faisal Specialist Hospital, Riyadh, Saudi Arabia.en
dc.contributor.institutionDepartment of Pediatric Subspecialties, Children's Hospital, King Fahad Medical City, Riyadh, Saudi Arabia.en
dc.contributor.institutionDepartment of Pediatric Neurology, ICH and SSF Hospital Mirpur, Dhaka, 1216, Bangladesh.en
dc.contributor.institutionDepartment of Pediatric Neurology, Institute of Child Health and The Children's Hospital Lahore, 381-D/2, Lahore, Pakistan.en
dc.contributor.institutionDepartment of Ophthalmology, Specialized Medical Center Hospital, Riyadh, Saudi Arabia.en
dc.contributor.institutionDivision of Pediatric Neurology, Department of Pediatrics, King Khalid University Hospital and College of Medicine, King Saud University, Riyadh, Saudi Arabia.en
dc.contributor.institutionClinical and Metabolic Genetics, Department of Pediatrics, Hamad Medical Corporation, Doha, Qatar.en
dc.contributor.institutionDivision of Neurology, Department of Pediatrics, Tawam Hospital, Al Ain, United Arab Emirates.en
dc.contributor.institutionDivision of Clinical Genetics and Metabolic Disorders, Department of Pediatrics, Tawam Hospital, Al-Ain, United Arab Emirates.en
dc.contributor.institutionSpectrum Health Genetics, Grand Rapids, MI, USA.en
dc.contributor.institutionGenetics Division, Department of Pediatrics, King Abdullah International Medical Research Centre, King Saud bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City, Riyadh, Saudi Arabia.en
dc.contributor.institutionSaudi Human Genome Program, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia.en
kaust.authorArold, Stefan T.en
kaust.authorAlkuraya, Fowzan S.en
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