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Auteur S. L. LEE |
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Identification of mutations in the PI3K-AKT-mTOR signalling pathway in patients with macrocephaly and developmental delay and/or autism / K. S. YEUNG in Molecular Autism, 8 (2017)
[article]
Titre : Identification of mutations in the PI3K-AKT-mTOR signalling pathway in patients with macrocephaly and developmental delay and/or autism Type de document : Texte imprimé et/ou numérique Auteurs : K. S. YEUNG, Auteur ; W. W. Y. TSO, Auteur ; J. J. K. IP, Auteur ; C. C. Y. MAK, Auteur ; G. K. C. LEUNG, Auteur ; M. H. Y. TSANG, Auteur ; D. YING, Auteur ; S. L. C. PEI, Auteur ; S. L. LEE, Auteur ; W. YANG, Auteur ; B. H. CHUNG, Auteur Article en page(s) : 66p. Langues : Anglais (eng) Mots-clés : Autism spectrum disorder Developmental delay Mtor Macrocephaly Megalencephaly Pik3ca Ppp2r5d Pten Somatic mosaicism Hong Kong/Hospital Authority Hong Kong West Cluster (UW 12-211), and written consent was obtained from the patients' parents.Written informed consent was obtained from the patients' parents for publication of their children's details and accompanying images in this manuscript. The consent form is held by the authors and is available for review by the Editor-in-Chief.The authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Index. décimale : PER Périodiques Résumé : Background: Macrocephaly, which is defined as a head circumference greater than or equal to + 2 standard deviations, is a feature commonly observed in children with developmental delay and/or autism spectrum disorder. Although PTEN is a well-known gene identified in patients with this syndromic presentation, other genes in the PI3K-AKT-mTOR signalling pathway have also recently been suggested to have important roles. The aim of this study is to characterise the mutation spectrum of this group of patients. Methods: We performed whole-exome sequencing of 21 patients with macrocephaly and developmental delay/autism spectrum disorder. Sources of genomic DNA included blood, buccal mucosa and saliva. Germline mutations were validated by Sanger sequencing, whereas somatic mutations were validated by droplet digital PCR. Results: We identified ten pathogenic/likely pathogenic mutations in PTEN (n = 4), PIK3CA (n = 3), MTOR (n = 1) and PPP2R5D (n = 2) in ten patients. An additional PTEN mutation, which was classified as variant of unknown significance, was identified in a patient with a pathogenic PTEN mutation, making him harbour bi-allelic germline PTEN mutations. Two patients harboured somatic PIK3CA mutations, and the level of somatic mosaicism in blood DNA was low. Patients who tested positive for mutations in the PI3K-AKT-mTOR pathway had a lower developmental quotient than the rest of the cohort (DQ = 62.8 vs. 76.1, p = 0.021). Their dysmorphic features were non-specific, except for macrocephaly. Among the ten patients with identified mutations, brain magnetic resonance imaging was performed in nine, all of whom showed megalencephaly. Conclusion: We identified mutations in the PI3K-AKT-mTOR signalling pathway in nearly half of our patients with macrocephaly and developmental delay/autism spectrum disorder. These patients have subtle dysmorphic features and mild developmental issues. Clinically, patients with germline mutations are difficult to distinguish from patients with somatic mutations, and therefore, sequencing of buccal or saliva DNA is important to identify somatic mosaicism. Given the high diagnostic yield and the management implications, we suggest implementing comprehensive genetic testing in the PI3K-AKT-mTOR pathway in the clinical evaluation of patients with macrocephaly and developmental delay and/or autism spectrum disorder. En ligne : http://dx.doi.org/10.1186/s13229-017-0182-4 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=331
in Molecular Autism > 8 (2017) . - 66p.[article] Identification of mutations in the PI3K-AKT-mTOR signalling pathway in patients with macrocephaly and developmental delay and/or autism [Texte imprimé et/ou numérique] / K. S. YEUNG, Auteur ; W. W. Y. TSO, Auteur ; J. J. K. IP, Auteur ; C. C. Y. MAK, Auteur ; G. K. C. LEUNG, Auteur ; M. H. Y. TSANG, Auteur ; D. YING, Auteur ; S. L. C. PEI, Auteur ; S. L. LEE, Auteur ; W. YANG, Auteur ; B. H. CHUNG, Auteur . - 66p.
Langues : Anglais (eng)
in Molecular Autism > 8 (2017) . - 66p.
Mots-clés : Autism spectrum disorder Developmental delay Mtor Macrocephaly Megalencephaly Pik3ca Ppp2r5d Pten Somatic mosaicism Hong Kong/Hospital Authority Hong Kong West Cluster (UW 12-211), and written consent was obtained from the patients' parents.Written informed consent was obtained from the patients' parents for publication of their children's details and accompanying images in this manuscript. The consent form is held by the authors and is available for review by the Editor-in-Chief.The authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Index. décimale : PER Périodiques Résumé : Background: Macrocephaly, which is defined as a head circumference greater than or equal to + 2 standard deviations, is a feature commonly observed in children with developmental delay and/or autism spectrum disorder. Although PTEN is a well-known gene identified in patients with this syndromic presentation, other genes in the PI3K-AKT-mTOR signalling pathway have also recently been suggested to have important roles. The aim of this study is to characterise the mutation spectrum of this group of patients. Methods: We performed whole-exome sequencing of 21 patients with macrocephaly and developmental delay/autism spectrum disorder. Sources of genomic DNA included blood, buccal mucosa and saliva. Germline mutations were validated by Sanger sequencing, whereas somatic mutations were validated by droplet digital PCR. Results: We identified ten pathogenic/likely pathogenic mutations in PTEN (n = 4), PIK3CA (n = 3), MTOR (n = 1) and PPP2R5D (n = 2) in ten patients. An additional PTEN mutation, which was classified as variant of unknown significance, was identified in a patient with a pathogenic PTEN mutation, making him harbour bi-allelic germline PTEN mutations. Two patients harboured somatic PIK3CA mutations, and the level of somatic mosaicism in blood DNA was low. Patients who tested positive for mutations in the PI3K-AKT-mTOR pathway had a lower developmental quotient than the rest of the cohort (DQ = 62.8 vs. 76.1, p = 0.021). Their dysmorphic features were non-specific, except for macrocephaly. Among the ten patients with identified mutations, brain magnetic resonance imaging was performed in nine, all of whom showed megalencephaly. Conclusion: We identified mutations in the PI3K-AKT-mTOR signalling pathway in nearly half of our patients with macrocephaly and developmental delay/autism spectrum disorder. These patients have subtle dysmorphic features and mild developmental issues. Clinically, patients with germline mutations are difficult to distinguish from patients with somatic mutations, and therefore, sequencing of buccal or saliva DNA is important to identify somatic mosaicism. Given the high diagnostic yield and the management implications, we suggest implementing comprehensive genetic testing in the PI3K-AKT-mTOR pathway in the clinical evaluation of patients with macrocephaly and developmental delay and/or autism spectrum disorder. En ligne : http://dx.doi.org/10.1186/s13229-017-0182-4 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=331 Use of clinical chromosomal microarray in Chinese patients with autism spectrum disorder-implications of a copy number variation involving DPP10 / A. S. L. MAK in Molecular Autism, 8 (2017)
[article]
Titre : Use of clinical chromosomal microarray in Chinese patients with autism spectrum disorder-implications of a copy number variation involving DPP10 Type de document : Texte imprimé et/ou numérique Auteurs : A. S. L. MAK, Auteur ; A. T. G. CHIU, Auteur ; G. K. C. LEUNG, Auteur ; C. C. Y. MAK, Auteur ; Y. W. Y. CHU, Auteur ; G. T. K. MOK, Auteur ; W. F. TANG, Auteur ; K. Y. K. CHAN, Auteur ; M. H. Y. TANG, Auteur ; E. T. LAU YIM, Auteur ; K. W. SO, Auteur ; V. Q. TAO, Auteur ; C. W. FUNG, Auteur ; Virginia C.N. WONG, Auteur ; M. UDDIN, Auteur ; S. L. LEE, Auteur ; C. R. MARSHALL, Auteur ; Stephen SCHERER, Auteur ; A. S. Y. KAN, Auteur ; B. H. Y. CHUNG, Auteur Article en page(s) : 31p. Langues : Anglais (eng) Mots-clés : Array comparative genomic hybridization (aCGH) Autism spectrum disorder (ASD) Chinese Copy number variations (CNVs) Dpp10 Index. décimale : PER Périodiques Résumé : BACKGROUND: Array comparative genomic hybridization (aCGH) is recommended as a first-tier genetic test for children with autism spectrum disorder (ASD). However, interpretation of results can often be challenging partly due to the fact that copy number variants (CNVs) in non-European ASD patients are not well studied. To address this literature gap, we report the CNV findings in a cohort of Chinese children with ASD. METHODS: DNA samples were obtained from 258 Chinese ASD patients recruited from a child assessment center between January 2011 and August 2014. aCGH was performed using NimbleGen-CGX-135k or Agilent-CGX 60k oligonucleotide array. Results were classified based on existing guidelines and literature. RESULTS: Ten pathogenic CNVs and one likely pathogenic CNV were found in nine patients, with an overall diagnostic yield of 3.5%. A 138 kb duplication involving 3' exons of DPP10 (arr[GRCh37] 2q14.1(116534689_116672358)x3), reported to be associated with ASD, was identified in one patient (0.39%). The same CNV was reported as variant of uncertain significance (VUS) in DECIPHER database. Multiple individuals of typical development carrying a similar duplication were identified among our ancestry-matched control with a frequency of 6/653 (0.92%) as well as from literature and genomic databases. CONCLUSIONS: The DPP10 duplication is likely a benign CNV polymorphism enriched in Southern Chinese with a population frequency of ~1%. This highlights the importance of using ancestry-matched controls in interpretation of aCGH findings. En ligne : http://dx.doi.org/10.1186/s13229-017-0136-x Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=330
in Molecular Autism > 8 (2017) . - 31p.[article] Use of clinical chromosomal microarray in Chinese patients with autism spectrum disorder-implications of a copy number variation involving DPP10 [Texte imprimé et/ou numérique] / A. S. L. MAK, Auteur ; A. T. G. CHIU, Auteur ; G. K. C. LEUNG, Auteur ; C. C. Y. MAK, Auteur ; Y. W. Y. CHU, Auteur ; G. T. K. MOK, Auteur ; W. F. TANG, Auteur ; K. Y. K. CHAN, Auteur ; M. H. Y. TANG, Auteur ; E. T. LAU YIM, Auteur ; K. W. SO, Auteur ; V. Q. TAO, Auteur ; C. W. FUNG, Auteur ; Virginia C.N. WONG, Auteur ; M. UDDIN, Auteur ; S. L. LEE, Auteur ; C. R. MARSHALL, Auteur ; Stephen SCHERER, Auteur ; A. S. Y. KAN, Auteur ; B. H. Y. CHUNG, Auteur . - 31p.
Langues : Anglais (eng)
in Molecular Autism > 8 (2017) . - 31p.
Mots-clés : Array comparative genomic hybridization (aCGH) Autism spectrum disorder (ASD) Chinese Copy number variations (CNVs) Dpp10 Index. décimale : PER Périodiques Résumé : BACKGROUND: Array comparative genomic hybridization (aCGH) is recommended as a first-tier genetic test for children with autism spectrum disorder (ASD). However, interpretation of results can often be challenging partly due to the fact that copy number variants (CNVs) in non-European ASD patients are not well studied. To address this literature gap, we report the CNV findings in a cohort of Chinese children with ASD. METHODS: DNA samples were obtained from 258 Chinese ASD patients recruited from a child assessment center between January 2011 and August 2014. aCGH was performed using NimbleGen-CGX-135k or Agilent-CGX 60k oligonucleotide array. Results were classified based on existing guidelines and literature. RESULTS: Ten pathogenic CNVs and one likely pathogenic CNV were found in nine patients, with an overall diagnostic yield of 3.5%. A 138 kb duplication involving 3' exons of DPP10 (arr[GRCh37] 2q14.1(116534689_116672358)x3), reported to be associated with ASD, was identified in one patient (0.39%). The same CNV was reported as variant of uncertain significance (VUS) in DECIPHER database. Multiple individuals of typical development carrying a similar duplication were identified among our ancestry-matched control with a frequency of 6/653 (0.92%) as well as from literature and genomic databases. CONCLUSIONS: The DPP10 duplication is likely a benign CNV polymorphism enriched in Southern Chinese with a population frequency of ~1%. This highlights the importance of using ancestry-matched controls in interpretation of aCGH findings. En ligne : http://dx.doi.org/10.1186/s13229-017-0136-x Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=330