Sage Journals: Discover world-class research

Abstract

Robust diagnostics for many human genetic disorders are much needed in the pursuit of global personalized medicine. Next-generation sequencing now offers new promise for biomarker and diagnostic discovery, in developed as well as resource-limited countries. In this broader global health context, X-linked intellectual disability (XLID) is an inherited genetic disorder that is associated with a range of phenotypes impacting societies in both developed and developing countries. Although intellectual disability arises due to diverse causes, a substantial proportion is caused by genomic alterations. Studies have identified causal XLID genomic alterations in more than 100 protein-coding genes located on the X-chromosome. However, the causes for a substantial number of intellectual disability and associated phenotypes still remain unknown. Identification of causative genes and novel mutations will help in early diagnosis as well as genetic counseling of families. Advent of next-generation sequencing methods has accelerated the discovery of new genes involved in mental health disorders. In this study, we analyzed the exomes of three families from India with nonsyndromic XLID comprising seven affected individuals. The affected individuals had varying degrees of intellectual disability, microcephaly, and delayed motor and language milestones. We identified potential causal variants in three XLID genes, including PAK3 (V294M), CASK (complex structural variant), and MECP2 (P354T). Our findings reported in this study extend the spectrum of mutations and phenotypes associated with XLID, and calls for further studies of intellectual disability and mental health disorders with use of next-generation sequencing technologies.

Get full access to this article

View all access options for this article.

References

1000 Genomes Project Consortium; Abecasis

, Auton

, et al. (2012). An integrated map of genetic variation from 1,092 human genomes. Nature, 491, 56–65.

Adzhubei

, Schmidt

, Peshkin

, et al. (2010). A method and server for predicting damaging missense mutations. Nat Methods, 7, 248–249.

Arias-Romero

, and Chernoff

. (2008). A tale of two Paks. European Cell Biol Org, 100, 97–108.

Bartenhagen

, and Dugas

. (2016). Robust and exact structural variation detection with paired-end and soft-clipped alignments: SoftSV compared with eight algorithms. Brief Bioinform, 17, 51–62.

Belichenko

, Wright

, Belichenko

, et al. (2009). Widespread changes in dendritic and axonal morphology in Mecp2-mutant mouse models of Rett syndrome: Evidence for disruption of neuronal networks. J Comp Neurol, 514, 240–258.

Black

, and Wang

. (2015). Ischemic Stroke: From Next Generation Sequencing and GWAS to Community Genomics?. OMICS, 19, 451–460.

Boda

, Alberi

, Nikonenko

, et al. (2004). The mental retardation protein PAK3 contributes to synapse formation and plasticity in hippocampus. J Neuroscience, 24, 10816–10825.

Chao

, Hong

, Huang

, Lin

, and Hsueh

. (2008). SUMOylation of the MAGUK protein CASK regulates dendritic spinogenesis. J Cell Biol, 182, 141–155.

Cingolani

, Platts

, Wang le

, et al. (2012). A program for annotating and predicting the effects of single nucleotide polymorphisms, SnpEff: SNPs in the genome of Drosophila melanogaster strain w1118; iso-2; iso-3. Fly (Austin), 6, 80–92.

10.

DePristo

, Banks

, Poplin

, et al. (2011). A framework for variation discovery and genotyping using next-generation DNA sequencing data. Nat Genet, 43, 491–498.

11.

Dimitratos

, Woods

, and Bryant

. (1997). Camguk, Lin-2, and CASK: Novel membrane-associated guanylate kinase homologs that also contain CaM kinase domains. Mech Dev, 63, 127–130.

12.

Dunn

, and Ferguson

. (2015). PDZ Protein Regulation of G Protein-Coupled Receptor Trafficking and Signaling Pathways. Mol Pharmacol, 88, 624–639.

13.

Grozeva

, Carss

, Spasic-Boskovic

, et al. (2015). Targeted next-generation sequencing analysis of 1,000 individuals with intellectual disability. Hum Mutation, 36, 1197–1204.

14.

Hekim

, Batyraliev

, Trujillano

, et al. (2016). Whole exome sequencing in a rare disease: A patient with anomalous left coronary artery from the pulmonary artery (Bland-White-Garland Syndrome). OMICS, 20, 325–327.

15.

Holderness Parker

, Donninger

, Birrer

, and Leaner

(2013). p21-activated kinase 3 (PAK3) is an AP-1 regulated gene contributing to actin organisation and migration of transformed fibroblasts. PLoS One, 8, e66892.

16.

Hsueh

, Wang

, Yang

, and Sheng

. (2000). Nuclear translocation and transcription regulation by the membrane-associated guanylate kinase CASK/LIN-2. Nature, 404, 298–302.

17.

Hsueh

, Yang

, Kharazia

, et al. (1998). Direct interaction of CASK/LIN-2 and syndecan heparan sulfate proteoglycan and their overlapping distribution in neuronal synapses. J Cell Biol, 142, 139–151.

18.

, Haas

, Chelly

, et al. (2016). X-exome sequencing of 405 unresolved families identifies seven novel intellectual disability genes. Mol Psychiatry, 21, 133–148.

19.

, and Hsueh

. (2014). Calcium influx and postsynaptic proteins coordinate the dendritic filopodium-spine transition. Dev Neurobiol, 74, 1011–1029.

20.

Imessaoudene

, Bonnefont

, Royer

, et al. (2001). MECP2 mutation in non-fatal, non-progressive encephalopathy in a male. J Med Genet, 38, 171–174.

21.

Jaffer

, and Chernoff

. (2002). p21-activated kinases: Three more join the Pak. Int J Biochem Cell Biol, 34, 713–717.

22.

Kishi

, and Macklis

. (2004). MECP2 is progressively expressed in post-migratory neurons and is involved in neuronal maturation rather than cell fate decisions. Mol Cell Neurosci, 27, 306–321.

23.

Kochinke

, Zweier

, Nijhof

, et al. (2016). Systematic phenomics analysis deconvolutes genes mutated in intellectual disability into biologically coherent modules. Am J Hum Genet, 98, 149–164.

24.

Kreis

, Thevenot

, Rousseau

, Boda

, Muller

, and Barnier

. (2007). The p21-activated kinase 3 implicated in mental retardation regulates spine morphogenesis through a Cdc42-dependent pathway. J Biol Chem, 282, 21497–21506.

25.

Kumar

, Henikoff

, and Ng

. (2009). Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat Protocols, 4, 1073–1081.

26.

Kumar

, Goswami

, Sharma

, et al. (2015). Harnessing next generation sequencing in climate change: RNA-Seq analysis of heat stress-responsive genes in wheat (Triticum aestivum L.). OMICS, 19, 632–647.

27.

Lam

, Yeung

, Ko

, et al. (2000). Spectrum of mutations in the MECP2 gene in patients with infantile autism and Rett syndrome. J Med Genet, 37, E41.

28.

Leonard

, and Wen

. (2002). The epidemiology of mental retardation: Challenges and opportunities in the new millennium. Ment Retard Dev Disabil Res Rev, 8, 117–134.

29.

, and Durbin

. (2010). Fast and accurate long-read alignment with Burrows-Wheeler transform. Bioinformatics, 26, 589–595.

30.

Lubs

, Stevenson

, and Schwartz

. (2012). Fragile X and X-linked intellectual disability: Four decades of discovery. Am J Hum Genet, 90, 579–590.

31.

Magini

, Pippucci

, Tsai

, et al. (2014). A mutation in PAK3 with a dual molecular effect deregulates the RAS/MAPK pathway and drives an X-linked syndromic phenotype. Hum Mol Genet, 23, 3607–3617.

32.

Manichaikul

, Mychaleckyj

, Rich

, Daly

, Sale

, and Chen

. (2010). Robust relationship inference in genome-wide association studies. Bioinformatics, 26, 2867–2873.

33.

McLaren

, and Bryson

. (1987). Review of recent epidemiological studies of mental retardation: Prevalence, associated disorders, and etiology. Am J Ment Retard, 92, 243–254.

34.

Meng

, Meng

, Hanna

, Janus

, and Jia

. (2005). Abnormal long-lasting synaptic plasticity and cognition in mice lacking the mental retardation gene Pak3. J Neurosci, 25, 6641–6650.

35.

Moog

, Van Roozendaal

, Smeets

, et al. (2006). MECP2 mutations are an infrequent cause of mental retardation associated with neurological problems in male patients. Brain Dev, 28, 305–310.

36.

Moore

, Siopes

, Steele

, and Underwood

. (2002). Pineal melatonin secretion, but not ocular melatonin secretion, is sufficient to maintain normal immune responses in Japanese quail (Coturnix coturnix japonica). Gen Comparative Endocrinol, 126, 352–358.

37.

Node-Langlois

, Muller

, and Boda

. (2006). Sequential implication of the mental retardation proteins ARHGEF6 and PAK3 in spine morphogenesis. J Cell Science, 119, 4986–4993.

38.

Richards

, Aziz

, Bale

, et al. (2015). Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med, 17, 405–424.

39.

Robinson

, Thorvaldsdottir

, Winckler

, et al. (2011). Integrative genomics viewer. Nature Biotech, 29, 24–26.

40.

Roeleveld

, Zielhuis

, and Gabreels

. (1997). The prevalence of mental retardation: A critical review of recent literature. Dev Med Child Neurol, 39, 125–132.

41.

Seabright

. (1971). A rapid banding technique for human chromosomes. Lancet, 2, 971–972.

42.

Smrt

, Eaves-Egenes

, Barkho

, et al. (2007). Mecp2 deficiency leads to delayed maturation and altered gene expression in hippocampal neurons. Neurobiol Dis, 27, 77–89.

43.

Thevenot

, Moreau

, Rousseau

, et al. (2011). p21-Activated kinase 3 (PAK3) protein regulates synaptic transmission through its interaction with the Nck2/Grb4 protein adaptor. J Biol Chem, 286, 40044–40059.

44.

Van der Auwera

, Carneiro

, Hartl

, et al. (2013). From FastQ data to high confidence variant calls: The Genome Analysis Toolkit best practices pipeline. Curr Protocols Bioinformatics, 11, 1110–1133.

45.

World Health Organization (WHO). The ICD-10 classification of mental and behavioural disorders: Clinical descriptions and diagnostic guidelines. Geneva, 1992. http://www.who.int/classifications/icd/en/bluebook.pdf. Accessed March 16, 2017.

46.

, Chahrour

, Coulter

, et al. (2013). Using whole-exome sequencing to identify inherited causes of autism. Neuron, 77, 259–273.

47.

Zhao

, DA D, Lim

, et al. (2009). The N-Myc-DLL3 cascade is suppressed by the ubiquitin ligase Huwe1 to inhibit proliferation and promote neurogenesis in the developing brain. Dev Cell, 17, 210–221.

48.

Zhao

, Heng

, Guardavaccaro

, et al. (2008). The HECT-domain ubiquitin ligase Huwe1 controls neural differentiation and proliferation by destabilizing the N-Myc oncoprotein. Nat Cell Biol, 10, 643–653.

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

0.00 MB

0.10 MB

0.19 MB

0.37 MB

0.15 MB

0.13 MB

0.03 MB

0.02 MB

Next-Generation Sequencing Reveals Novel Mutations in X-linked Intellectual Disability

Abstract

Abstract

Get full access to this article

References

Supplementary Material