Whole-Exome Sequencing of Pakistani Consanguineous Families Identified Pathogenic Variants in Genes of Intellectual Disability

Overview

Journal Genes (Basel)

Publisher MDPI

Date 2023 Jan 21

PMID 36672789

Authors

Maria Asif

Maryam Anayat

Faiza Tariq

Tanzeela Noureen

Ghulam Naseer Ud Din

Christian Becker

Kerstin Becker

Holger Thiele

Ehtisham Ul Haq Makhdoom

Pakeeza Arzoo Shaiq

Shahid M Baig

Peter Nurnberg

Muhammad Sajid Hussain

Ghazala Kaukab Raja

Uzma Abdullah

Affiliations

Soon will be listed here.

Abstract

Intellectual disability (ID) is a condition of significant limitation of cognitive functioning and adaptive behavior, with 50% of etiology attributed to genetic predisposition. We recruited two consanguineous Pakistani families manifesting severe ID and developmental delay. The probands were subjected to whole exome sequencing (WES) and variants were further prioritized based on population frequency, predicted pathogenicity and functional relevance. The WES data analysis identified homozygous pathogenic variants in genes and . The pathogenicity of the variants was supported by co-segregation analysis and in silico tool. The findings of this study expand mutation spectrum and provide additional evidence to the role of MBOAT7 and TRAPPC9 in causation of ID.

Citing Articles

Case Report: Whole exome sequencing identifies compound heterozygous variants in the gene in a child with developmental delay.

Yu B, Chen J, Yang S, Wang H, Xiao Y, Liu S Front Genet. 2024; 15:1415194.

PMID: 39184350 PMC: 11341409. DOI: 10.3389/fgene.2024.1415194.

Liver Involvement in Patients with Rare Variants and Intellectual Disability: A Case Report and Literature Review.

Ronzoni L, Mureddu M, Malvestiti F, Moretti V, Bianco C, Periti G Genes (Basel). 2023; 14(8).

PMID: 37628684 PMC: 10454727. DOI: 10.3390/genes14081633.

Defective neurite elongation and branching in Nibp/Trappc9 deficient zebrafish and mice.

Hu M, Bodnar B, Zhang Y, Xie F, Li F, Li S Int J Biol Sci. 2023; 19(10):3226-3248.

PMID: 37416774 PMC: 10321293. DOI: 10.7150/ijbs.78489.

References

Ke Y, Weng M, Chhetri G, Usman M, Li Y, Yu Q . Trappc9 deficiency in mice impairs learning and memory by causing imbalance of dopamine D1 and D2 neurons. Sci Adv. 2020; 6(47). PMC: 7673810. DOI: 10.1126/sciadv.abb7781. View

Vissers L, de Ligt J, Gilissen C, Janssen I, Steehouwer M, De Vries P . A de novo paradigm for mental retardation. Nat Genet. 2010; 42(12):1109-12. DOI: 10.1038/ng.712. View

Gilissen C, Hehir-Kwa J, Tjwan Thung D, van de Vorst M, van Bon B, Willemsen M . Genome sequencing identifies major causes of severe intellectual disability. Nature. 2014; 511(7509):344-7. DOI: 10.1038/nature13394. View

Leite A, Pinto I, Leijsten N, Ruiterkamp-Versteeg M, Pfundt R, de Leeuw N . Diagnostic yield of patients with undiagnosed intellectual disability, global developmental delay and multiples congenital anomalies using karyotype, microarray analysis, whole exome sequencing from Central Brazil. PLoS One. 2022; 17(4):e0266493. PMC: 8989190. DOI: 10.1371/journal.pone.0266493. View

Radenkovic S, Martinelli D, Zhang Y, Preston G, Maiorana A, Terracciano A . TRAPPC9-CDG: A novel congenital disorder of glycosylation with dysmorphic features and intellectual disability. Genet Med. 2022; 24(4):894-904. DOI: 10.1016/j.gim.2021.12.012. View

Schalock R, Luckasson R . A Systematic Approach to Subgroup Classification in Intellectual Disability. Intellect Dev Disabil. 2015; 53(5):358-66. DOI: 10.1352/1934-9556-53.5.358. View

Bolat H, Unsel-Bolat G, Derin H, Sen A, Ceylaner S . Distinct Autism Spectrum Disorder Phenotype and Hand-Flapping Stereotypes: Two Siblings with Novel Homozygous Mutation in Gene and Literature Review. Mol Syndromol. 2022; 13(4):263-269. PMC: 9421696. DOI: 10.1159/000522041. View

Barrowman J, Bhandari D, Reinisch K, Ferro-Novick S . TRAPP complexes in membrane traffic: convergence through a common Rab. Nat Rev Mol Cell Biol. 2010; 11(11):759-63. DOI: 10.1038/nrm2999. View

Perez-Chacon G, Astudillo A, Balgoma D, Balboa M, Balsinde J . Control of free arachidonic acid levels by phospholipases A2 and lysophospholipid acyltransferases. Biochim Biophys Acta. 2009; 1791(12):1103-13. DOI: 10.1016/j.bbalip.2009.08.007. View

10.

Vissers L, Gilissen C, Veltman J . Genetic studies in intellectual disability and related disorders. Nat Rev Genet. 2015; 17(1):9-18. DOI: 10.1038/nrg3999. View

11.

Alvarez-Mora M, Corominas J, Gilissen C, Sanchez A, Madrigal I, Rodriguez-Revenga L . Novel Compound Heterozygous Mutation in Gene: The Relevance of Whole Genome Sequencing. Genes (Basel). 2021; 12(4). PMC: 8068822. DOI: 10.3390/genes12040557. View

12.

Johansen A, Rosti R, Musaev D, Sticca E, Harripaul R, Zaki M . Mutations in MBOAT7, Encoding Lysophosphatidylinositol Acyltransferase I, Lead to Intellectual Disability Accompanied by Epilepsy and Autistic Features. Am J Hum Genet. 2016; 99(4):912-916. PMC: 5065650. DOI: 10.1016/j.ajhg.2016.07.019. View

13.

Usman M, Li Y, Ke Y, Chhetri G, Islam M, Wang Z . Trappc9 Deficiency Impairs the Plasticity of Stem Cells. Int J Mol Sci. 2022; 23(9). PMC: 9101649. DOI: 10.3390/ijms23094900. View

14.

Hussain M, Baig S, Neumann S, Nurnberg G, Farooq M, Ahmad I . A truncating mutation of CEP135 causes primary microcephaly and disturbed centrosomal function. Am J Hum Genet. 2012; 90(5):871-8. PMC: 3376485. DOI: 10.1016/j.ajhg.2012.03.016. View

15.

Leonard H, Wen X . The epidemiology of mental retardation: challenges and opportunities in the new millennium. Ment Retard Dev Disabil Res Rev. 2002; 8(3):117-34. DOI: 10.1002/mrdd.10031. View

16.

Lee J, Shamim A, Park J, Jang J, Kim J, Kwon J . Functional and Structural Changes in the Membrane-Bound O-Acyltransferase Family Member 7 (MBOAT7) Protein: The Pathomechanism of a Novel Variant in Patients With Intellectual Disability. Front Neurol. 2022; 13:836954. PMC: 9058081. DOI: 10.3389/fneur.2022.836954. View

17.

Caddeo A, Jamialahmadi O, Solinas G, Pujia A, Mancina R, Pingitore P . MBOAT7 is anchored to endomembranes by six transmembrane domains. J Struct Biol. 2019; 206(3):349-360. DOI: 10.1016/j.jsb.2019.04.006. View

18.

Genereaux D, van Karnebeek C, Birch P . Costs of caring for children with an intellectual developmental disorder. Disabil Health J. 2015; 8(4):646-51. DOI: 10.1016/j.dhjo.2015.03.011. View

19.

Han J, Lee I . Genetic tests by next-generation sequencing in children with developmental delay and/or intellectual disability. Clin Exp Pediatr. 2020; 63(6):195-202. PMC: 7303420. DOI: 10.3345/kjp.2019.00808. View

20.

Ma D, Wang Z, Merrikh C, Lang K, Lu P, Li X . Crystal structure of a membrane-bound O-acyltransferase. Nature. 2018; 562(7726):286-290. PMC: 6529733. DOI: 10.1038/s41586-018-0568-2. View