Novel GAA Variants and Mosaicism in Pompe Disease Identified by Extended Analyses of Patients with an Incomplete DNA Diagnosis

Stijn L.M. in ’t Groen; Douglas O.S. de Faria; Alessandro Iuliano; Johanna M.P. van den Hout; Hannie Douben; Trijnie Dijkhuizen; David Cassiman; Peter Witters; Miguel Ángel Barba Romero; Annelies de Klein; Galhana M. Somers-Bolman; Jasper J. Saris; Lies H. Hoefsloot; Ans T. van der Ploeg; Atze J. Bergsma; W. W.M.Pim Pijnappel

doi:10.1016/j.omtm.2019.12.016

Novel GAA Variants and Mosaicism in Pompe Disease Identified by Extended Analyses of Patients with an Incomplete DNA Diagnosis

Stijn L.M. in ’t Groen, Douglas O.S. de Faria, Alessandro Iuliano, Johanna M.P. van den Hout, Hannie Douben, Trijnie Dijkhuizen, David Cassiman, Peter Witters, Miguel Ángel Barba Romero, Annelies de Klein, Galhana M. Somers-Bolman, Jasper J. Saris, Lies H. Hoefsloot, Ans T. van der Ploeg, Atze J. Bergsma, W. W.M.Pim Pijnappel^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

Pompe disease is a metabolic disorder caused by a deficiency of the glycogen-hydrolyzing lysosomal enzyme acid α-glucosidase (GAA), which leads to progressive muscle wasting. This autosomal-recessive disorder is the result of disease-associated variants located in the GAA gene. In the present study, we performed extended molecular diagnostic analysis to identify novel disease-associated variants in six suspected Pompe patients from four different families for which conventional diagnostic assays were insufficient. Additional assays, such as a generic-splicing assay, minigene analysis, SNP array analysis, and targeted Sanger sequencing, allowed the identification of an exonic deletion, a promoter deletion, and a novel splicing variant located in the 5′ UTR. Furthermore, we describe the diagnostic process for an infantile patient with an atypical phenotype, consisting of left ventricular hypertrophy but no signs of muscle weakness or motor problems. This led to the identification of a genetic mosaicism for a very severe GAA variant caused by a segmental uniparental isodisomy (UPD). With this study, we aim to emphasize the need for additional analyses to detect new disease-associated GAA variants and non-Mendelian genotypes in Pompe disease where conventional DNA diagnostic assays are insufficient.

Original language	English
Pages (from-to)	337-348
Number of pages	12
Journal	Molecular Therapy - Methods and Clinical Development
Volume	17
DOIs	https://doi.org/10.1016/j.omtm.2019.12.016
Publication status	Published - 12 Jun 2020

Bibliographical note

Funding Information:
We thank the members of the Molecular Stem Cell Biology Group for the critical discussions. This work was funded through Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq; Brazil), the Sophia Foundation for Medical Research (SSWO; project number s17 ‐ 32 ), and Metakids (project number 2016 ‐ 063 ). This project has received funding from the Ministry of Economic Affairs under TKI allowance under the TKI‐Programme Life Sciences & Health. The collaboration project is co-funded by the PPP Allowance made available by Health ∼ Holland, Top Sector Life Sciences & Health , to stimulate public-private partnerships (project numbers LSHM16008 and LSHM19015 ). The collaboration project is co-initiated by the Prinses Beatrix Spierfonds.

Funding Information:
We thank the members of the Molecular Stem Cell Biology Group for the critical discussions. This work was funded through Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq; Brazil), the Sophia Foundation for Medical Research (SSWO; project number s17‐32), and Metakids (project number 2016 ‐ 063). This project has received funding from the Ministry of Economic Affairs under TKI allowance under the TKI‐Programme Life Sciences & Health. The collaboration project is co-funded by the PPP Allowance made available by Health ∼ Holland, Top Sector Life Sciences & Health, to stimulate public-private partnerships (project numbers LSHM16008 and LSHM19015). The collaboration project is co-initiated by the Prinses Beatrix Spierfonds.

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© 2020 The Author(s)

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in ’t Groen, S. L. M., de Faria, D. O. S., Iuliano, A., van den Hout, J. M. P., Douben, H., Dijkhuizen, T., Cassiman, D., Witters, P., Barba Romero, M. Á., de Klein, A., Somers-Bolman, G. M., Saris, J. J., Hoefsloot, L. H., van der Ploeg, A. T., Bergsma, A. J., & Pijnappel, W. W. M. P. (2020). Novel GAA Variants and Mosaicism in Pompe Disease Identified by Extended Analyses of Patients with an Incomplete DNA Diagnosis. Molecular Therapy - Methods and Clinical Development, 17, 337-348. https://doi.org/10.1016/j.omtm.2019.12.016

@article{5d8577d2df3a4c76ac51ac60ee956e97,

title = "Novel GAA Variants and Mosaicism in Pompe Disease Identified by Extended Analyses of Patients with an Incomplete DNA Diagnosis",

abstract = "Pompe disease is a metabolic disorder caused by a deficiency of the glycogen-hydrolyzing lysosomal enzyme acid α-glucosidase (GAA), which leads to progressive muscle wasting. This autosomal-recessive disorder is the result of disease-associated variants located in the GAA gene. In the present study, we performed extended molecular diagnostic analysis to identify novel disease-associated variants in six suspected Pompe patients from four different families for which conventional diagnostic assays were insufficient. Additional assays, such as a generic-splicing assay, minigene analysis, SNP array analysis, and targeted Sanger sequencing, allowed the identification of an exonic deletion, a promoter deletion, and a novel splicing variant located in the 5′ UTR. Furthermore, we describe the diagnostic process for an infantile patient with an atypical phenotype, consisting of left ventricular hypertrophy but no signs of muscle weakness or motor problems. This led to the identification of a genetic mosaicism for a very severe GAA variant caused by a segmental uniparental isodisomy (UPD). With this study, we aim to emphasize the need for additional analyses to detect new disease-associated GAA variants and non-Mendelian genotypes in Pompe disease where conventional DNA diagnostic assays are insufficient.",

author = "{in {\textquoteright}t Groen}, {Stijn L.M.} and {de Faria}, {Douglas O.S.} and Alessandro Iuliano and {van den Hout}, {Johanna M.P.} and Hannie Douben and Trijnie Dijkhuizen and David Cassiman and Peter Witters and {Barba Romero}, {Miguel {\'A}ngel} and {de Klein}, Annelies and Somers-Bolman, {Galhana M.} and Saris, {Jasper J.} and Hoefsloot, {Lies H.} and {van der Ploeg}, {Ans T.} and Bergsma, {Atze J.} and Pijnappel, {W. W.M.Pim}",

note = "Funding Information: We thank the members of the Molecular Stem Cell Biology Group for the critical discussions. This work was funded through Conselho Nacional de Desenvolvimento Cient{\'i}fico e Tecnol{\'o}gico (CNPq; Brazil), the Sophia Foundation for Medical Research (SSWO; project number s17 ‐ 32 ), and Metakids (project number 2016 ‐ 063 ). This project has received funding from the Ministry of Economic Affairs under TKI allowance under the TKI‐Programme Life Sciences & Health. The collaboration project is co-funded by the PPP Allowance made available by Health ∼ Holland, Top Sector Life Sciences & Health , to stimulate public-private partnerships (project numbers LSHM16008 and LSHM19015 ). The collaboration project is co-initiated by the Prinses Beatrix Spierfonds. Funding Information: We thank the members of the Molecular Stem Cell Biology Group for the critical discussions. This work was funded through Conselho Nacional de Desenvolvimento Cient{\'i}fico e Tecnol{\'o}gico (CNPq; Brazil), the Sophia Foundation for Medical Research (SSWO; project number s17‐32), and Metakids (project number 2016 ‐ 063). This project has received funding from the Ministry of Economic Affairs under TKI allowance under the TKI‐Programme Life Sciences & Health. The collaboration project is co-funded by the PPP Allowance made available by Health ∼ Holland, Top Sector Life Sciences & Health, to stimulate public-private partnerships (project numbers LSHM16008 and LSHM19015). The collaboration project is co-initiated by the Prinses Beatrix Spierfonds. Publisher Copyright: {\textcopyright} 2020 The Author(s)",

year = "2020",

month = jun,

day = "12",

doi = "10.1016/j.omtm.2019.12.016",

language = "English",

volume = "17",

pages = "337--348",

journal = "Molecular Therapy - Methods and Clinical Development",

issn = "2329-0501",

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in ’t Groen, SLM, de Faria, DOS, Iuliano, A , van den Hout, JMP , Douben, H, Dijkhuizen, T, Cassiman, D, Witters, P, Barba Romero, MÁ, de Klein, A , Somers-Bolman, GM , Saris, JJ , Hoefsloot, LH , van der Ploeg, AT , Bergsma, AJ & Pijnappel, WWMP 2020, 'Novel GAA Variants and Mosaicism in Pompe Disease Identified by Extended Analyses of Patients with an Incomplete DNA Diagnosis', Molecular Therapy - Methods and Clinical Development, vol. 17, pp. 337-348. https://doi.org/10.1016/j.omtm.2019.12.016

Novel GAA Variants and Mosaicism in Pompe Disease Identified by Extended Analyses of Patients with an Incomplete DNA Diagnosis. / in ’t Groen, Stijn L.M.; de Faria, Douglas O.S.; Iuliano, Alessandro et al.
In: Molecular Therapy - Methods and Clinical Development, Vol. 17, 12.06.2020, p. 337-348.

Research output: Contribution to journal › Article › Academic › peer-review

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T1 - Novel GAA Variants and Mosaicism in Pompe Disease Identified by Extended Analyses of Patients with an Incomplete DNA Diagnosis

AU - in ’t Groen, Stijn L.M.

AU - de Faria, Douglas O.S.

AU - Iuliano, Alessandro

AU - van den Hout, Johanna M.P.

AU - Douben, Hannie

AU - Dijkhuizen, Trijnie

AU - Cassiman, David

AU - Witters, Peter

AU - Barba Romero, Miguel Ángel

AU - de Klein, Annelies

AU - Somers-Bolman, Galhana M.

AU - Saris, Jasper J.

AU - Hoefsloot, Lies H.

AU - van der Ploeg, Ans T.

AU - Bergsma, Atze J.

AU - Pijnappel, W. W.M.Pim

N1 - Funding Information: We thank the members of the Molecular Stem Cell Biology Group for the critical discussions. This work was funded through Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq; Brazil), the Sophia Foundation for Medical Research (SSWO; project number s17 ‐ 32 ), and Metakids (project number 2016 ‐ 063 ). This project has received funding from the Ministry of Economic Affairs under TKI allowance under the TKI‐Programme Life Sciences & Health. The collaboration project is co-funded by the PPP Allowance made available by Health ∼ Holland, Top Sector Life Sciences & Health , to stimulate public-private partnerships (project numbers LSHM16008 and LSHM19015 ). The collaboration project is co-initiated by the Prinses Beatrix Spierfonds. Funding Information: We thank the members of the Molecular Stem Cell Biology Group for the critical discussions. This work was funded through Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq; Brazil), the Sophia Foundation for Medical Research (SSWO; project number s17‐32), and Metakids (project number 2016 ‐ 063). This project has received funding from the Ministry of Economic Affairs under TKI allowance under the TKI‐Programme Life Sciences & Health. The collaboration project is co-funded by the PPP Allowance made available by Health ∼ Holland, Top Sector Life Sciences & Health, to stimulate public-private partnerships (project numbers LSHM16008 and LSHM19015). The collaboration project is co-initiated by the Prinses Beatrix Spierfonds. Publisher Copyright: © 2020 The Author(s)

PY - 2020/6/12

Y1 - 2020/6/12

N2 - Pompe disease is a metabolic disorder caused by a deficiency of the glycogen-hydrolyzing lysosomal enzyme acid α-glucosidase (GAA), which leads to progressive muscle wasting. This autosomal-recessive disorder is the result of disease-associated variants located in the GAA gene. In the present study, we performed extended molecular diagnostic analysis to identify novel disease-associated variants in six suspected Pompe patients from four different families for which conventional diagnostic assays were insufficient. Additional assays, such as a generic-splicing assay, minigene analysis, SNP array analysis, and targeted Sanger sequencing, allowed the identification of an exonic deletion, a promoter deletion, and a novel splicing variant located in the 5′ UTR. Furthermore, we describe the diagnostic process for an infantile patient with an atypical phenotype, consisting of left ventricular hypertrophy but no signs of muscle weakness or motor problems. This led to the identification of a genetic mosaicism for a very severe GAA variant caused by a segmental uniparental isodisomy (UPD). With this study, we aim to emphasize the need for additional analyses to detect new disease-associated GAA variants and non-Mendelian genotypes in Pompe disease where conventional DNA diagnostic assays are insufficient.

AB - Pompe disease is a metabolic disorder caused by a deficiency of the glycogen-hydrolyzing lysosomal enzyme acid α-glucosidase (GAA), which leads to progressive muscle wasting. This autosomal-recessive disorder is the result of disease-associated variants located in the GAA gene. In the present study, we performed extended molecular diagnostic analysis to identify novel disease-associated variants in six suspected Pompe patients from four different families for which conventional diagnostic assays were insufficient. Additional assays, such as a generic-splicing assay, minigene analysis, SNP array analysis, and targeted Sanger sequencing, allowed the identification of an exonic deletion, a promoter deletion, and a novel splicing variant located in the 5′ UTR. Furthermore, we describe the diagnostic process for an infantile patient with an atypical phenotype, consisting of left ventricular hypertrophy but no signs of muscle weakness or motor problems. This led to the identification of a genetic mosaicism for a very severe GAA variant caused by a segmental uniparental isodisomy (UPD). With this study, we aim to emphasize the need for additional analyses to detect new disease-associated GAA variants and non-Mendelian genotypes in Pompe disease where conventional DNA diagnostic assays are insufficient.

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U2 - 10.1016/j.omtm.2019.12.016

DO - 10.1016/j.omtm.2019.12.016

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EP - 348

JO - Molecular Therapy - Methods and Clinical Development

JF - Molecular Therapy - Methods and Clinical Development

ER -

Novel GAA Variants and Mosaicism in Pompe Disease Identified by Extended Analyses of Patients with an Incomplete DNA Diagnosis

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