Abstract
Background
Intellectual disability (ID) is a heterogeneous disorder affecting 1–3% of the population. Elucidation of monogenic variants for ID is a current challenge. These variants can be better demonstrated in consanguineous affected families.
Objective
The study was designed to find the genetic variants of ID in consanguineous families.
Methods
We analyzed five unrelated consanguineous Pakistani families affected with ID using whole exome sequencing (WES). Data was analyzed using different bioinformatics tools and software.
Results
We mapped four variants including three novels in four different ID known genes. Each variant is found in a different family, co-segregating with a recessive pattern of inheritance. The novel variants found are; c. 2_4del (p.?) mapped in ROS1 and c. 718G>A (p.Gly240Arg) in GRM1. Another novel causative variant, c.2673del (p.Gly892Aspfs*17) identified in COL18A1 in a recessive form, a gene reported for Knobloch syndrome that manifests ID along with typical retinal abnormalities, and this phenotype was confirmed on reverse phenotyping. A mutation c.2134C>T (p.Arg712*) in TRAPPC9 has been found first time in the homozygous recessive form in our enrolled three affected siblings while it was previously reported in compound heterozygous form in a Caucasian descent. While fifth family remained unsolved.
Conclusion
These mutations in four different genes with a recessive inheritance would be a contribution to the disease variant database of this devastating disorder.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Data availability
All the data related to this project is available with the corresponding author and will be provided upon request.
References
Basel VL, Attia R, Yahav M, Ferland RJ, Anteki L, Walsh CA, Olender T, Straussberg R, Magal N, Taub E et al (2006) The CC2D1A, a member of a new gene family with C2 domains, is involved in autosomal recessive nonsyndromic mental retardation. J Med Genet 43:203–210
Birchmeier C, O’Neill K, Riggs M, Wigler M (1990) Characterization of ROS1 cDNA from a human glioblastoma cell line. PNAS 87:4799–4803
Caglayan AO, Baranoski JF, Aktar F, Han W, Tuysuz B, Guzel A, Guclu B, Kaymakcalan H, Aktekin B, Akgumus GT et al (2014) Brain malformations associated with Knobloch syndrome—review of literature, expanding clinical spectrum, and identification of novel mutations. Pediatr Neurol 51:806–813
Curry CJ, Stevenson RE, Aughton D, Byrne J, Carey JC, Cassidy S, Cunniff C, Graham JM Jr, Jones MC, Kaback MM et al (1997) Evaluation of mental retardation: recommendations of a consensus conference. Am J Hum Genet 72:468–477
DePristo M, Banks E, Poplin R, Garimella K, Maguire J, Hartl C, Philippakis A, del Angel G, Rivas MA, Hanna M et al (2011) A framework for variation discovery and genotyping using next-generation DNA sequencing data. Nat Genet 43:491–498
Garber KB, Visootsak J, Warren ST (2008) Fragile X syndrome. Eur J Hum Genet 16(6):666–672
Garshasbi M, Hadavi V, Habibi H, Kahrizi K, Kariminejad R, Behjati F, Tzschach A, Najmabadi H, Ropers HH, Kuss AW (2008) A defect in the TUSC3 gene is associated with autosomal recessive mental retardation. Am J Hum Genet 82(5):1158–1164
Guergueltcheva V, Azmanov DN, Angelicheva D, Smith KR, Chamova T, Florez L, Bynevelt M, Nguyen T, Cherninkova S, Bojinova V et al (2012) Autosomal-recessive congenital cerebellar ataxia is caused by mutations in metabotropic glutamate receptor 1. Am J Hum Genet 91:553–564
Higgins JJ, Pucilowska J, Lombardi RQ, Rooney JP (2004) A mutation in a novel ATP-dependent Lon protease gene in a kindred with mild mental retardation. Neurology 63(10):1927–1931
Hnoonual A, Graidist P, Kritsaneepaiboon S, Limprasert P (2019) Novel compound heterozygous mutations in the TRAPPC9 gene in two siblings with autism and intellectual disability. Front Genet 10:61
Hu H, Kahrizi K, Musante L, Fattahi Z, Herwig R, Hosseini M, Oppitz C, Abedini SS, Suckow V, Larti F et al (2019) Genetics of intellectual disability in consanguineous families. Mol Psychiatry 24:1027–1039
Hussain R, Bittles AH (1998) The prevalence and demographic characteristics of consanguineous marriages in Pakistan. J Biosoc Sci 30:261–275
Inlow JK, Restifo LL (2004) Molecular and comparative genetics of mental retardation. Genetics 166:835–881
Itan Y, Shang L, Boisson B, Patin E, Bolze A, Moncada-Vélez M, Scott E, Ciancanelli M, Lafaille F, Markle J et al (2015) The human gene damage index as a gene-level approach to prioritize exome variants. PNAS 112(44):13615–13620
Karaca E, Harel T, Pehlivan D, Jhangiani SN, Gambin T, Akdemir ZC, Jauregui CG, Erdin S, Bayram Y, Campbell IM et al (2015) Genes that affect brain structure and function identified by rare variant analyses of Mendelian neurologic disease. Neuron 88:499–513
Kliemann SE, Waetge RT, Suzuki OT, Passos-Bueno MR, Rosemberg S (2003) Evidence of neuronal migration disorders in Knobloch syndrome: clinical and molecular analysis of two novel families. Am J Med Genet 119A(1):15–19
Kochinke K, Zweier C, Nijhof B, Fenckova M, Cizek P, Honti F, Keerthikumar S, Oortveld MA, Kleefstra T, Kramer JM et al (2016) Systematic phenomics analysis deconvolutes genes mutated in intellectual disability into biologically coherent modules. Am J Hum Genet 98(1):149–164
Leonard H, Wen X (2002) The epidemiology of mental retardation: challenges and opportunities in the new millennium. Ment Retard Dev Disabil Res Rev 8:117–134
Mahajan VB, Olney AH, Garrett P, Chary A, Dragan E, Lerner G, Murray J, Bassuk AG (2011) Collagen XVIII mutation in Knobloch syndrome with acute lymphoblastic leukemia. Am J Med Genet A 152(11):2875–2879
Makoff A, Phillips T, Pilling C, Emson P (1997) Expression of a novel splice variant of human mGluR1 in the cerebellum. Neuro Rep 8:2943–2947
Menzel O, Bekkeheien RC, Reymond A, Fukai N, Boye E, Kosztolanyi G, Aftimos S, Deutsch S, Scott HS, Olsen BR et al (2002) Knobloch syndrome: novel mutations in COL18A1, evidence for genetic heterogeneity, and a functionally impaired polymorphism in endostatin. Hum Mutat 23:77–84
Mir A, Kaufman L, Noor A, Motazacker MM, Jamil T, Azam M, Kahrizi K, Rafiq MA, Weksberg R, Nasr T et al (2009) Identification of mutations in TRAPPC9, which encodes the NIK- and IKK-beta-binding protein, in nonsyndromic autosomal-recessive mental retardation. Am J Hum Genet 85:909–915
Modell B, Darr A (2002) Science and society: genetic counseling and customary consanguineous marriage. Nat Rev Genet 3:225–229
Molinari F, Rio M, Meskenatic V, Encha RF, Auge V, Bocq D, Briault S, Vekemans M, Munnich A, Attie BT et al (2002) Truncating neurotrypsin mutation in autosomal recessive nonsyndromic mental retardation. Science 298:1779–1781
Molinari F, Foulquier F, Tarpey PS, Morelle W, Boissel S, Teague J, Edkins S, Futreal PA, Stratton MR, Turner G et al (2008) Oligosaccharyltransferase-subunit mutations in nonsyndromic mental retardation. Am J Hum Genet 82:1150–1157
Mortreux J, Busa T, Germain DP, Nadeau G, Puechberty J, Coubes C, Gatinois V, Cacciagli P, Duffourd Y, Pinard JM et al (2018) The role of CNVs in the etiology of rare autosomal recessive disorders: the example of TRAPPC9-associated intellectual disability. Eur J Hum Genet 26(1):143–148
Motazacker MM, Rost BR, Hucho T, Garshasbi M, Kahrizi K, Ullmann B, Abedini SS, Nieh SE, Amini SH, Goswami C et al (2007) A defect in the ionotropic glutamate receptor 6 gene (GRIK2) is associated with autosomal recessive mental retardation. Am J Hum Genet 81:792–798
Najmabadi H, Motazacker MM, Garshasbi M, Kahrizi K, Tzschach A, Chen W, Behjati F, Hadavi V, Nieh SE, Abedini SS et al (2007) Homozygosity mapping in consanguineous families reveals extreme heterogeneity of non-syndromic autosomal recessive mental retardation and identifies 8 novel gene loci. Hum Genet 121(1):43–48
Najmabadi H, Hu H, Garshasbi M, Zemojtel T, Abedini SS, Chen W, Hosseini M, Behjati F, Haas S, Jamali P et al (2011) Deep sequencing reveals 50 novel genes for recessive cognitive disorders. Nature 478:57–66
Renieri A, Pescucci C, Longo I, Ariani F, Mari F, Meloni I (2005) Non-syndromic X-linked mental retardation: from a molecular to a clinical point of view. J Cell Physiol 204:8–20
Rentzsch P, Witten D, Cooper GM, Shendure J, Kircher M (2019) CADD: predicting the deleteriousness of variants throughout the human genome. Nucleic Acids Res 47(D1):D886–D894
Ropers HH (2008) Genetics of intellectual disability. Curr Opin Genet Dev 18(3):241–250
Ropers HH, Hamel BC (2005) X-linked mental retardation. Nat Rev Genet 6:46–57
Sertie AL, Sossi V, Camargo AA, Zatz M, Brahe C, Passos-Bueno MR (2000) Collagen XVIII, containing an endogenous inhibitor of angiogenesis and tumor growth, plays a critical role in the maintenance of retinal structure and in neural tube closure (Knobloch syndrome). Hum Mol Genet 9:2051–2058
Stephan D, Bon C, Holzwarth JA, Galvan M, Mpruss R (1996) Human metabotropic glutamate receptor 1: mRNA distribution, chromosome localization and functional expression of two splice variants. Neuropharmacology 35:1649–1660
Tarasov A, Vilella AJ, Cuppen E, Nijman IJ, Prins P (2015) Sambamba: fast processing of NGS alignment formats. Bioinformatics 31(12):2032–2034
Vanagaite BL (2007) Genetics of autosomal recessive non-syndromic mental retardation: recent advances. Clin Genet 72:167–174
Wilton KM, Gunderson LB, Hasadsri L, Wood CP, Schimmenti LA (2020) Profound intellectual disability caused by homozygous TRAPPC9 pathogenic variant in a man from Malta. Mol Genet Genom Med 8(5):e1211
Acknowledgements
The authors would like to thank the families for participating in the study.
Funding
This work is supported by departmental support for PhD research scholar by Institute of Biochemistry and Biotechnology, Faculty of Bio-sciences, University of Veterinary and Animal Sciences, Lahore and short term IRSIP training program by Higher Education Commission of Pakistan.
Author information
Authors and Affiliations
Contributions
IGR performed major lab work as her Ph.D. thesis work; MYZ, IGR and WS: planned and executed the project; MI and MAB: did data collection and families enrollment; FA and HQA: also performed lab work and families’ enrollment; MYZ and IGR: wrote the manuscript; TM and AAA: performed bioinformatics and statistical data analysis.
Corresponding author
Ethics declarations
Conflict of interest
All authors declare that they have no conflict of interest of any sort with anyone.
Ethical approval
This study was approved by the Independent Institutional Ethics Committee (IIEC), the University of Veterinary and Animal Sciences, Lahore Pakistan (Ethical approval letter. DAS/1259).
Informed consent
Informed written consent or guardian consent is also approved by the committee.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Rasool, I.G., Zahoor, M.Y., Iqbal, M. et al. Whole exome sequencing revealed novel variants in consanguineous Pakistani families with intellectual disability. Genes Genom 43, 503–512 (2021). https://doi.org/10.1007/s13258-021-01070-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s13258-021-01070-7