A systematic, large-scale resequencing screen of X-chromosome coding exons in mental retardation

Tarpey, Patrick; Smith, Raffaella; Pleasance, Erin; Whibley, Annabel; Edkins, Sarah; Hardy, Claire; O’Meara, Sarah; Latimer, Calli; Dicks, Ed; Menzies, Andrew; Stephens, Phil; Blow, Matthew J.; Greenman, Christopher; Xue, Yali; Tyler‐Smith, Chris; Thompson, Deborah J.; Gray, Kristian; Andrews, J. M.; Barthorpe, Syd; Buck, Gemma; Cole, Jennifer; Dunmore, Rebecca; Jones, David R.; Maddison, Mark; Mironenko, Tatiana; Turner, R. Jay; Turrell, Kelly; Varian, Jennifer; West, Sofie; Widaa, Sara; Wray, Paul; Teague, Jon W.; Butler, Adam; Jenkinson, Andy; Jia, Mingming; Richardson, David; Shepherd, Rebecca; Wooster, Richard; Tejada, María-Isabel; Martı́nez, Francisco; Carvill, Gemma L.; Goliath, René; Brouwer, Arjan P.M. de; Bokhoven, Hans van; Esch, Hilde Van; Chelly, Jamel; Raynaud, Martine; Ropers, Hans‐Hilger; Abidi, Fatima; Srivastava, Anand; Cox, James J.; Luo, Ying; Mallya, Uma; Moon, Jennifer A.; Parnau, Josef; Mohammed, Shehla; Tolmie, John; Shoubridge, Cheryl; Corbett, Mark; Gardner, Alison; Haan, Eric; Rujirabanjerd, Sinitdhorn; Shaw, Marie; Vandeleur, Lucianne; Fullston, Tod; Easton, Douglas F.; Boyle, Jackie; Partington, M. W.; Hackett, Anna; Field, Michael; Skinner, Cindy; Stevenson, Roger E.; Bobrow, Martin; Turner, Gillian; Schwartz, Charles E.; Gécz, Jozef; Raymond, F. Lucy; Futreal, P. Andrew; Stratton, Michael R.

doi:10.1038/ng.367

Cited by 540 publications

(554 citation statements)

References 38 publications

(38 reference statements)

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“…The phenotype associated with SYP loss of function appears to be non-syndromic intellectual disability. 16 This variant is not reported in public databases, but two hemizygotes for a different change at the same residue, p.Glu72Lys, are recorded in gnomAD. 15 Furthermore, the composite REVEL score is low (0.232), suggesting that the variant is likely to be non-damaging.…”

Section: Resultsmentioning

confidence: 99%

Loss-of-Function and Gain-of-Function Mutations in KCNQ5 Cause Intellectual Disability or Epileptic Encephalopathy

Lehman

Thouta

Mancini

et al. 2017

The American Journal of Human Genetics

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Section: Resultsmentioning

confidence: 99%

Loss-of-Function and Gain-of-Function Mutations in KCNQ5 Cause Intellectual Disability or Epileptic Encephalopathy

Lehman

Thouta

Mancini

et al. 2017

The American Journal of Human Genetics

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“…It is more common in males (an excess of about 30%) [1] because of the high incidence of mutations in genes located on the X chromosome that together explain 10e12% of MR in males [2]. More than 80 X-linked mental retardation (XLMR) genes have so far been identified [3,4]. XLMR has been classified into syndromic and nonsyndromic forms, depending on whether the MR is associated with other clinical, radiological or metabolic features or not, but this subdivision appears unsatisfactory since many genes are involved in both forms [2,5].…”

Section: Introductionmentioning

confidence: 99%

Deletion of the AP1S2 gene in a child with psychomotor delay and hypotonia

Ballarati

Cereda

Caselli

et al. 2012

European Journal of Medical Genetics

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a b s t r a c tWe identified a 495 Kb interstitial deletion of chromosome Xp22.2, centered on the AP1S2 gene, by means of oligonucleotide array comparative genomic hybridisation (array-CGH) in a child with marked hypotonia in the first months of life, psychomotor retardation, severely delayed walking and speech development, and unspecific dysmorphic facial features. The deletion was inherited from the healthy mother. Point mutations of the AP1S2 gene have been identified in patients with X-linked mental retardation (XLMR). The clinical features of our patient are quite similar to those reported in male patients carrying point mutations, thus suggesting that point mutations and deletions of the AP1S2 gene lead to a recognisable XLMR phenotype in males.

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“…In excess of 215 XLMR conditions have been recorded (http://xlmr.interfree.it/home.htm and http://www.ggc.org/xlmr.htm) and 90 XLMR genes have been identified. 3,4 Genes for 87 conditions have been mapped by linkage analysis and/or cytogenetic breakpoints, but for 38 conditions, genes have been neither identified nor mapped to candidate loci. In addition, more than 300 X-linked protein-coding genes are expressed in brain tissue, suggesting that many XLMR genes remain to be unidentified.…”

Section: Introductionmentioning

confidence: 99%

“…In addition, more than 300 X-linked protein-coding genes are expressed in brain tissue, suggesting that many XLMR genes remain to be unidentified. 5 Array-based comparative genomic hybridization (aCGH) has revealed copy-number variations (CNVs) to be the cause of MR. [6][7][8] Although Tarpey et al 4 screened for mutations in the coding regions of 718 genes on the X chromosome in probands from 208 families by means of resequencing, only three XLMR-associated genes have been identified, suggesting structural variations other than point mutations, including CNVs or variants in regulatory regions, to contribute to unidentified XLMR conditions.…”

Section: Introductionmentioning

confidence: 99%

Copy-number variations on the X chromosome in Japanese patients with mental retardation detected by array-based comparative genomic hybridization analysis

et al. 2010

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Mental Retardation Consortium 8X-linked mental retardation (XLMR) is a common, clinically complex and genetically heterogeneous disease arising from many mutations along the X chromosome. Although research during the past decade has identified 490 XLMR genes, many more remain uncharacterized. In this study, copy-number variations (CNVs) were screened in individuals with MR from 144 families by array-based comparative genomic hybridization (aCGH) using a bacterial artificial chromosome-based X-tiling array. Candidate pathogenic CNVs (pCNVs) were detected in 10 families (6.9%). Five of the families had pCNVs involving known XLMR genes, duplication of Xq28 containing MECP2 in three families, duplication of Xp11.22-p11.23 containing FTSJ1 and PQBP1 in one family, and deletion of Xp11.22 bearing SHROOM4 in one family. New candidate pCNVs were detected in five families as follows: identical complex pCNVs involved in dup(X)(p22.2) and dup(X)(p21.3) containing part of REPS2, NHS and IL1RAPL1 in two unrelated families, duplication of Xp22.2 including part of FRMPD4, duplication of Xq21.1 including HDX and deletion of Xq24 noncoding region in one family, respectively. Both parents and only mother samples were available in six and three families, respectively, and pCNVs were inherited from each of their mothers in those families other than a family of the proband with deletion of SHROOM4. This study should help to identify the novel XLMR genes and mechanisms leading to MR and reveal the clinical conditions and genomic background of XLMR.

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A systematic, large-scale resequencing screen of X-chromosome coding exons in mental retardation

Cited by 540 publications

References 38 publications

Loss-of-Function and Gain-of-Function Mutations in KCNQ5 Cause Intellectual Disability or Epileptic Encephalopathy

Loss-of-Function and Gain-of-Function Mutations in KCNQ5 Cause Intellectual Disability or Epileptic Encephalopathy

Deletion of the AP1S2 gene in a child with psychomotor delay and hypotonia

Copy-number variations on the X chromosome in Japanese patients with mental retardation detected by array-based comparative genomic hybridization analysis

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