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Phenotypic and molecular insights into CASK-related disorders in males

BACKGROUND: Heterozygous loss-of-function mutations in the X-linked CASK gene cause progressive microcephaly with pontine and cerebellar hypoplasia (MICPCH) and severe intellectual disability (ID) in females. Different CASK mutations have also been reported in males. The associated phenotypes range...

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Autores principales: Moog, Ute, Bierhals, Tatjana, Brand, Kristina, Bautsch, Jan, Biskup, Saskia, Brune, Thomas, Denecke, Jonas, de Die-Smulders, Christine E, Evers, Christina, Hempel, Maja, Henneke, Marco, Yntema, Helger, Menten, Björn, Pietz, Joachim, Pfundt, Rolph, Schmidtke, Jörg, Steinemann, Doris, Stumpel, Constance T, Van Maldergem, Lionel, Kutsche, Kerstin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4449965/
https://www.ncbi.nlm.nih.gov/pubmed/25886057
http://dx.doi.org/10.1186/s13023-015-0256-3
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author Moog, Ute
Bierhals, Tatjana
Brand, Kristina
Bautsch, Jan
Biskup, Saskia
Brune, Thomas
Denecke, Jonas
de Die-Smulders, Christine E
Evers, Christina
Hempel, Maja
Henneke, Marco
Yntema, Helger
Menten, Björn
Pietz, Joachim
Pfundt, Rolph
Schmidtke, Jörg
Steinemann, Doris
Stumpel, Constance T
Van Maldergem, Lionel
Kutsche, Kerstin
author_facet Moog, Ute
Bierhals, Tatjana
Brand, Kristina
Bautsch, Jan
Biskup, Saskia
Brune, Thomas
Denecke, Jonas
de Die-Smulders, Christine E
Evers, Christina
Hempel, Maja
Henneke, Marco
Yntema, Helger
Menten, Björn
Pietz, Joachim
Pfundt, Rolph
Schmidtke, Jörg
Steinemann, Doris
Stumpel, Constance T
Van Maldergem, Lionel
Kutsche, Kerstin
author_sort Moog, Ute
collection PubMed
description BACKGROUND: Heterozygous loss-of-function mutations in the X-linked CASK gene cause progressive microcephaly with pontine and cerebellar hypoplasia (MICPCH) and severe intellectual disability (ID) in females. Different CASK mutations have also been reported in males. The associated phenotypes range from nonsyndromic ID to Ohtahara syndrome with cerebellar hypoplasia. However, the phenotypic spectrum in males has not been systematically evaluated to date. METHODS: We identified a CASK alteration in 8 novel unrelated male patients by targeted Sanger sequencing, copy number analysis (MLPA and/or FISH) and array CGH. CASK transcripts were investigated by RT-PCR followed by sequencing. Immunoblotting was used to detect CASK protein in patient-derived cells. The clinical phenotype and natural history of the 8 patients and 28 CASK-mutation positive males reported previously were reviewed and correlated with available molecular data. RESULTS: CASK alterations include one nonsense mutation, one 5-bp deletion, one mutation of the start codon, and five partial gene deletions and duplications; seven were de novo, including three somatic mosaicisms, and one was familial. In three subjects, specific mRNA junction fragments indicated in tandem duplication of CASK exons disrupting the integrity of the gene. The 5-bp deletion resulted in multiple aberrant CASK mRNAs. In fibroblasts from patients with a CASK loss-of-function mutation, no CASK protein could be detected. Individuals who are mosaic for a severe CASK mutation or carry a hypomorphic mutation still showed detectable amount of protein. CONCLUSIONS: Based on eight novel patients and all CASK-mutation positive males reported previously three phenotypic groups can be distinguished that represent a clinical continuum: (i) MICPCH with severe epileptic encephalopathy caused by hemizygous loss-of-function mutations, (ii) MICPCH associated with inactivating alterations in the mosaic state or a partly penetrant mutation, and (iii) syndromic/nonsyndromic mild to severe ID with or without nystagmus caused by CASK missense and splice mutations that leave the CASK protein intact but likely alter its function or reduce the amount of normal protein. Our findings facilitate focused testing of the CASK gene and interpreting sequence variants identified by next-generation sequencing in cases with a phenotype resembling either of the three groups. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13023-015-0256-3) contains supplementary material, which is available to authorized users.
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spelling pubmed-44499652015-06-01 Phenotypic and molecular insights into CASK-related disorders in males Moog, Ute Bierhals, Tatjana Brand, Kristina Bautsch, Jan Biskup, Saskia Brune, Thomas Denecke, Jonas de Die-Smulders, Christine E Evers, Christina Hempel, Maja Henneke, Marco Yntema, Helger Menten, Björn Pietz, Joachim Pfundt, Rolph Schmidtke, Jörg Steinemann, Doris Stumpel, Constance T Van Maldergem, Lionel Kutsche, Kerstin Orphanet J Rare Dis Research BACKGROUND: Heterozygous loss-of-function mutations in the X-linked CASK gene cause progressive microcephaly with pontine and cerebellar hypoplasia (MICPCH) and severe intellectual disability (ID) in females. Different CASK mutations have also been reported in males. The associated phenotypes range from nonsyndromic ID to Ohtahara syndrome with cerebellar hypoplasia. However, the phenotypic spectrum in males has not been systematically evaluated to date. METHODS: We identified a CASK alteration in 8 novel unrelated male patients by targeted Sanger sequencing, copy number analysis (MLPA and/or FISH) and array CGH. CASK transcripts were investigated by RT-PCR followed by sequencing. Immunoblotting was used to detect CASK protein in patient-derived cells. The clinical phenotype and natural history of the 8 patients and 28 CASK-mutation positive males reported previously were reviewed and correlated with available molecular data. RESULTS: CASK alterations include one nonsense mutation, one 5-bp deletion, one mutation of the start codon, and five partial gene deletions and duplications; seven were de novo, including three somatic mosaicisms, and one was familial. In three subjects, specific mRNA junction fragments indicated in tandem duplication of CASK exons disrupting the integrity of the gene. The 5-bp deletion resulted in multiple aberrant CASK mRNAs. In fibroblasts from patients with a CASK loss-of-function mutation, no CASK protein could be detected. Individuals who are mosaic for a severe CASK mutation or carry a hypomorphic mutation still showed detectable amount of protein. CONCLUSIONS: Based on eight novel patients and all CASK-mutation positive males reported previously three phenotypic groups can be distinguished that represent a clinical continuum: (i) MICPCH with severe epileptic encephalopathy caused by hemizygous loss-of-function mutations, (ii) MICPCH associated with inactivating alterations in the mosaic state or a partly penetrant mutation, and (iii) syndromic/nonsyndromic mild to severe ID with or without nystagmus caused by CASK missense and splice mutations that leave the CASK protein intact but likely alter its function or reduce the amount of normal protein. Our findings facilitate focused testing of the CASK gene and interpreting sequence variants identified by next-generation sequencing in cases with a phenotype resembling either of the three groups. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13023-015-0256-3) contains supplementary material, which is available to authorized users. BioMed Central 2015-04-12 /pmc/articles/PMC4449965/ /pubmed/25886057 http://dx.doi.org/10.1186/s13023-015-0256-3 Text en © Moog et al.; licensee BioMed Central. 2015 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. 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
Moog, Ute
Bierhals, Tatjana
Brand, Kristina
Bautsch, Jan
Biskup, Saskia
Brune, Thomas
Denecke, Jonas
de Die-Smulders, Christine E
Evers, Christina
Hempel, Maja
Henneke, Marco
Yntema, Helger
Menten, Björn
Pietz, Joachim
Pfundt, Rolph
Schmidtke, Jörg
Steinemann, Doris
Stumpel, Constance T
Van Maldergem, Lionel
Kutsche, Kerstin
Phenotypic and molecular insights into CASK-related disorders in males
title Phenotypic and molecular insights into CASK-related disorders in males
title_full Phenotypic and molecular insights into CASK-related disorders in males
title_fullStr Phenotypic and molecular insights into CASK-related disorders in males
title_full_unstemmed Phenotypic and molecular insights into CASK-related disorders in males
title_short Phenotypic and molecular insights into CASK-related disorders in males
title_sort phenotypic and molecular insights into cask-related disorders in males
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4449965/
https://www.ncbi.nlm.nih.gov/pubmed/25886057
http://dx.doi.org/10.1186/s13023-015-0256-3
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