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Disruption of PHF21A causes syndromic intellectual disability with craniofacial anomalies, epilepsy, hypotonia, and neurobehavioral problems including autism

BACKGROUND: PHF21A has been associated with intellectual disability and craniofacial anomalies based on its deletion in the Potocki-Shaffer syndrome region at 11p11.2 and its disruption in three patients with balanced translocations. In addition, three patients with de novo truncating mutations in P...

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Autores principales: Kim, Hyung-Goo, Rosenfeld, Jill A., Scott, Daryl A., Bénédicte, Gerard, Labonne, Jonathan D., Brown, Jason, McGuire, Marianne, Mahida, Sonal, Naidu, Sakkubai, Gutierrez, Jacqueline, Lesca, Gaetan, des Portes, Vincent, Bruel, Ange-Line, Sorlin, Arthur, Xia, Fan, Capri, Yline, Muller, Eric, McKnight, Dianalee, Torti, Erin, Rüschendorf, Franz, Hummel, Oliver, Islam, Zeyaul, Kolatkar, Prasanna R., Layman, Lawrence C., Ryu, Duchwan, Kong, Il-Keun, Madan-Khetarpal, Suneeta, Kim, Cheol-Hee
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6805429/
https://www.ncbi.nlm.nih.gov/pubmed/31649809
http://dx.doi.org/10.1186/s13229-019-0286-0
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author Kim, Hyung-Goo
Rosenfeld, Jill A.
Scott, Daryl A.
Bénédicte, Gerard
Labonne, Jonathan D.
Brown, Jason
McGuire, Marianne
Mahida, Sonal
Naidu, Sakkubai
Gutierrez, Jacqueline
Lesca, Gaetan
des Portes, Vincent
Bruel, Ange-Line
Sorlin, Arthur
Xia, Fan
Capri, Yline
Muller, Eric
McKnight, Dianalee
Torti, Erin
Rüschendorf, Franz
Hummel, Oliver
Islam, Zeyaul
Kolatkar, Prasanna R.
Layman, Lawrence C.
Ryu, Duchwan
Kong, Il-Keun
Madan-Khetarpal, Suneeta
Kim, Cheol-Hee
author_facet Kim, Hyung-Goo
Rosenfeld, Jill A.
Scott, Daryl A.
Bénédicte, Gerard
Labonne, Jonathan D.
Brown, Jason
McGuire, Marianne
Mahida, Sonal
Naidu, Sakkubai
Gutierrez, Jacqueline
Lesca, Gaetan
des Portes, Vincent
Bruel, Ange-Line
Sorlin, Arthur
Xia, Fan
Capri, Yline
Muller, Eric
McKnight, Dianalee
Torti, Erin
Rüschendorf, Franz
Hummel, Oliver
Islam, Zeyaul
Kolatkar, Prasanna R.
Layman, Lawrence C.
Ryu, Duchwan
Kong, Il-Keun
Madan-Khetarpal, Suneeta
Kim, Cheol-Hee
author_sort Kim, Hyung-Goo
collection PubMed
description BACKGROUND: PHF21A has been associated with intellectual disability and craniofacial anomalies based on its deletion in the Potocki-Shaffer syndrome region at 11p11.2 and its disruption in three patients with balanced translocations. In addition, three patients with de novo truncating mutations in PHF21A were reported recently. Here, we analyze genomic data from seven unrelated individuals with mutations in PHF21A and provide detailed clinical descriptions, further expanding the phenotype associated with PHF21A haploinsufficiency. METHODS: Diagnostic trio whole exome sequencing, Sanger sequencing, use of GeneMatcher, targeted gene panel sequencing, and MiSeq sequencing techniques were used to identify and confirm variants. RT-qPCR was used to measure the normal expression pattern of PHF21A in multiple human tissues including 13 different brain tissues. Protein-DNA modeling was performed to substantiate the pathogenicity of the missense mutation. RESULTS: We have identified seven heterozygous coding mutations, among which six are de novo (not maternal in one). Mutations include four frameshifts, one nonsense mutation in two patients, and one heterozygous missense mutation in the AT Hook domain, predicted to be deleterious and likely to cause loss of PHF21A function. We also found a new C-terminal domain composed of an intrinsically disordered region. This domain is truncated in six patients and thus likely to play an important role in the function of PHF21A, suggesting that haploinsufficiency is the likely underlying mechanism in the phenotype of seven patients. Our results extend the phenotypic spectrum of PHF21A mutations by adding autism spectrum disorder, epilepsy, hypotonia, and neurobehavioral problems. Furthermore, PHF21A is highly expressed in the human fetal brain, which is consistent with the neurodevelopmental phenotype. CONCLUSION: Deleterious nonsense, frameshift, and missense mutations disrupting the AT Hook domain and/or an intrinsically disordered region in PHF21A were found to be associated with autism spectrum disorder, epilepsy, hypotonia, neurobehavioral problems, tapering fingers, clinodactyly, and syndactyly, in addition to intellectual disability and craniofacial anomalies. This suggests that PHF21A is involved in autism spectrum disorder and intellectual disability, and its haploinsufficiency causes a diverse neurological phenotype. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13229-019-0286-0) contains supplementary material, which is available to authorized users.
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spelling pubmed-68054292019-10-24 Disruption of PHF21A causes syndromic intellectual disability with craniofacial anomalies, epilepsy, hypotonia, and neurobehavioral problems including autism Kim, Hyung-Goo Rosenfeld, Jill A. Scott, Daryl A. Bénédicte, Gerard Labonne, Jonathan D. Brown, Jason McGuire, Marianne Mahida, Sonal Naidu, Sakkubai Gutierrez, Jacqueline Lesca, Gaetan des Portes, Vincent Bruel, Ange-Line Sorlin, Arthur Xia, Fan Capri, Yline Muller, Eric McKnight, Dianalee Torti, Erin Rüschendorf, Franz Hummel, Oliver Islam, Zeyaul Kolatkar, Prasanna R. Layman, Lawrence C. Ryu, Duchwan Kong, Il-Keun Madan-Khetarpal, Suneeta Kim, Cheol-Hee Mol Autism Research BACKGROUND: PHF21A has been associated with intellectual disability and craniofacial anomalies based on its deletion in the Potocki-Shaffer syndrome region at 11p11.2 and its disruption in three patients with balanced translocations. In addition, three patients with de novo truncating mutations in PHF21A were reported recently. Here, we analyze genomic data from seven unrelated individuals with mutations in PHF21A and provide detailed clinical descriptions, further expanding the phenotype associated with PHF21A haploinsufficiency. METHODS: Diagnostic trio whole exome sequencing, Sanger sequencing, use of GeneMatcher, targeted gene panel sequencing, and MiSeq sequencing techniques were used to identify and confirm variants. RT-qPCR was used to measure the normal expression pattern of PHF21A in multiple human tissues including 13 different brain tissues. Protein-DNA modeling was performed to substantiate the pathogenicity of the missense mutation. RESULTS: We have identified seven heterozygous coding mutations, among which six are de novo (not maternal in one). Mutations include four frameshifts, one nonsense mutation in two patients, and one heterozygous missense mutation in the AT Hook domain, predicted to be deleterious and likely to cause loss of PHF21A function. We also found a new C-terminal domain composed of an intrinsically disordered region. This domain is truncated in six patients and thus likely to play an important role in the function of PHF21A, suggesting that haploinsufficiency is the likely underlying mechanism in the phenotype of seven patients. Our results extend the phenotypic spectrum of PHF21A mutations by adding autism spectrum disorder, epilepsy, hypotonia, and neurobehavioral problems. Furthermore, PHF21A is highly expressed in the human fetal brain, which is consistent with the neurodevelopmental phenotype. CONCLUSION: Deleterious nonsense, frameshift, and missense mutations disrupting the AT Hook domain and/or an intrinsically disordered region in PHF21A were found to be associated with autism spectrum disorder, epilepsy, hypotonia, neurobehavioral problems, tapering fingers, clinodactyly, and syndactyly, in addition to intellectual disability and craniofacial anomalies. This suggests that PHF21A is involved in autism spectrum disorder and intellectual disability, and its haploinsufficiency causes a diverse neurological phenotype. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13229-019-0286-0) contains supplementary material, which is available to authorized users. BioMed Central 2019-10-22 /pmc/articles/PMC6805429/ /pubmed/31649809 http://dx.doi.org/10.1186/s13229-019-0286-0 Text en © The Author(s). 2019 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Kim, Hyung-Goo
Rosenfeld, Jill A.
Scott, Daryl A.
Bénédicte, Gerard
Labonne, Jonathan D.
Brown, Jason
McGuire, Marianne
Mahida, Sonal
Naidu, Sakkubai
Gutierrez, Jacqueline
Lesca, Gaetan
des Portes, Vincent
Bruel, Ange-Line
Sorlin, Arthur
Xia, Fan
Capri, Yline
Muller, Eric
McKnight, Dianalee
Torti, Erin
Rüschendorf, Franz
Hummel, Oliver
Islam, Zeyaul
Kolatkar, Prasanna R.
Layman, Lawrence C.
Ryu, Duchwan
Kong, Il-Keun
Madan-Khetarpal, Suneeta
Kim, Cheol-Hee
Disruption of PHF21A causes syndromic intellectual disability with craniofacial anomalies, epilepsy, hypotonia, and neurobehavioral problems including autism
title Disruption of PHF21A causes syndromic intellectual disability with craniofacial anomalies, epilepsy, hypotonia, and neurobehavioral problems including autism
title_full Disruption of PHF21A causes syndromic intellectual disability with craniofacial anomalies, epilepsy, hypotonia, and neurobehavioral problems including autism
title_fullStr Disruption of PHF21A causes syndromic intellectual disability with craniofacial anomalies, epilepsy, hypotonia, and neurobehavioral problems including autism
title_full_unstemmed Disruption of PHF21A causes syndromic intellectual disability with craniofacial anomalies, epilepsy, hypotonia, and neurobehavioral problems including autism
title_short Disruption of PHF21A causes syndromic intellectual disability with craniofacial anomalies, epilepsy, hypotonia, and neurobehavioral problems including autism
title_sort disruption of phf21a causes syndromic intellectual disability with craniofacial anomalies, epilepsy, hypotonia, and neurobehavioral problems including autism
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6805429/
https://www.ncbi.nlm.nih.gov/pubmed/31649809
http://dx.doi.org/10.1186/s13229-019-0286-0
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