Biallelic loss-of-function variants in PLD1 cause congenital right-sided cardiac valve defects and neonatal cardiomyopathy

Najim Lahrouchi; Alex V. Postma; Christian M. Salazar; Daniel M. de Laughter; Fleur Tjong; Lenka Piherová; Forrest Z. Bowling; Dominic Zimmerman; Elisabeth M. Lodder; Asaf Ta-Shma; Zeev Perles; Leander Beekman; Aho Ilgun; Quinn Gunst; Mariam Hababa; Doris Škorić-Milosavljević; Viktor Stránecký; Viktor Tomek; Peter de Knijff; Rick de Leeuw; Jamille Y. Robinson; Sabrina C. Burn; Hiba Mustafa; Matthew Ambrose; Timothy Moss; Jennifer Jacober; Dmitriy M. Niyazov; Barry Wolf; Katherine H. Kim; Sara Cherny; Andreas Rousounides; Aphrodite Aristidou-Kallika; George Tanteles; Bruel Ange-Line; Anne-Sophie Denommé-Pichon; Christine Francannet; Damara Ortiz; Monique C. Haak; Arend D. J. ten Harkel; Gwendolyn T. R. Manten; Annemiek C. Dutman; Katelijne Bouman; Monia Magliozzi; Francesca Clementina Radio; Gijs W. E. Santen; Johanna C. Herkert; H. Alex Brown; Orly Elpeleg; Maurice J. B. van den Hoff; Barbara Mulder; Michael V. Airola; Stanislav Kmoch; Joey V. Barnett; Sally-Ann Clur; Michael A. Frohman; Connie R. Bezzina

doi:10.1172/JCI142148

Biallelic loss-of-function variants in PLD1 cause congenital right-sided cardiac valve defects and neonatal cardiomyopathy

Najim Lahrouchi^*
, Alex V. Postma
, Christian M. Salazar
, Daniel M. de Laughter
, Fleur Tjong
, Lenka Piherová
, Forrest Z. Bowling
, Dominic Zimmerman
, Elisabeth M. Lodder
, Asaf Ta-Shma
, Zeev Perles
, Leander Beekman
, Aho Ilgun
, Quinn Gunst
, Mariam Hababa
, Doris Škorić-Milosavljević
, Viktor Stránecký
, Viktor Tomek
, Peter de Knijff
, Rick de Leeuw

Jamille Y. Robinson, Sabrina C. Burn, Hiba Mustafa, Matthew Ambrose, Timothy Moss, Jennifer Jacober, Dmitriy M. Niyazov, Barry Wolf, Katherine H. Kim, Sara Cherny, Andreas Rousounides, Aphrodite Aristidou-Kallika, George Tanteles, Bruel Ange-Line, Anne-Sophie Denommé-Pichon, Christine Francannet, Damara Ortiz, Monique C. Haak, Arend D. J. ten Harkel, Gwendolyn T. R. Manten, Annemiek C. Dutman, Katelijne Bouman, Monia Magliozzi, Francesca Clementina Radio, Gijs W. E. Santen, Johanna C. Herkert, H. Alex Brown, Orly Elpeleg, Maurice J. B. van den Hoff, Barbara Mulder, Michael V. Airola, Stanislav Kmoch, Joey V. Barnett, Sally-Ann Clur, Michael A. Frohman^*, Connie R. Bezzina^*

^*Corresponding author for this work

Stony Brook University
Vanderbilt University
Charles University
Hebrew University of Jerusalem
University of Amsterdam
Leiden University Medical Center
University of Minnesota Twin Cities
Tulane University
Children's Memorial Hospital
Northwestern University
Makarios Medical Centre, Nicosia, Cyprus.
Ultrasound and Fetal Medicine Diagnostic Centre, Nicosia, Cyprus.
Cyprus School of Molecular Medicine, Nicosia, Cyprus.
Cyprus Institute of Neurology and Genetics
Inserm UMR 1231 GAD, Genetics of Developmental disorders, Université de Bourgogne-Franche Comté, FHU TRANSLAD, Dijon, France
Université de Bourgogne
CHU de Clermont-Ferrand
University of Pittsburgh
Department of Obstetrics and sala Women and Children's Hospital, Zwolle, Netherlands.
Department of Pathology, Isala Women and Children's Hospital, Zwolle, Netherlands.
University of Groningen, University Medical Center Groningen
IRCCS Ospedale pediatrico Bambino Gesù - Roma

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Abstract

Congenital heart disease is the most common type of birth defect, accounting for one-third of all congenital anomalies. Using whole-exome sequencing of 2718 patients with congenital heart disease and a search in GeneMatcher, we identified 30 patients from 21 unrelated families of different ancestries with biallelic phospholipase D1 (PLD1) variants who presented predominantly with congenital cardiac valve defects. We also associated recessive PLD1 variants with isolated neonatal cardiomyopathy. Furthermore, we established that p.I668F is a founder variant among Ashkenazi Jews (allele frequency of ~2%) and describe the phenotypic spectrum of PLD1-associated congenital heart defects. PLD1 missense variants were overrepresented in regions of the protein critical for catalytic activity, and, correspondingly, we observed a strong reduction in enzymatic activity for most of the mutant proteins in an enzymatic assay. Finally, we demonstrate that PLD1 inhibition decreased endothelial-mesenchymal transition, an established pivotal early step in valvulogenesis. In conclusion, our study provides a more detailed understanding of disease mechanisms and phenotypic expression associated with PLD1 loss of function.

Original language	English
Article number	e142148
Journal	Journal of clinical investigation
Volume	131
Issue number	5
DOIs	https://doi.org/10.1172/JCI142148
Publication status	Published - 1 Mar 2021

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Biallelic-loss-of-function-variants-in-pld1-cause-congenital-right-sided-cardiac-valve-defects-and-neonatal-cardiomyopat.pdfFinal published version, 6.21 MBLicence: CC BY

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Lahrouchi, N., Postma, A. V., Salazar, C. M., de Laughter, D. M., Tjong, F., Piherová, L., Bowling, F. Z., Zimmerman, D., Lodder, E. M., Ta-Shma, A., Perles, Z., Beekman, L., Ilgun, A., Gunst, Q., Hababa, M., Škorić-Milosavljević, D., Stránecký, V., Tomek, V., de Knijff, P., ... Bezzina, C. R. (2021). Biallelic loss-of-function variants in PLD1 cause congenital right-sided cardiac valve defects and neonatal cardiomyopathy. Journal of clinical investigation, 131(5), Article e142148. https://doi.org/10.1172/JCI142148

@article{a997554f667b4510bd7fa8a0a646525f,

title = "Biallelic loss-of-function variants in PLD1 cause congenital right-sided cardiac valve defects and neonatal cardiomyopathy",

abstract = "Congenital heart disease is the most common type of birth defect, accounting for one-third of all congenital anomalies. Using whole-exome sequencing of 2718 patients with congenital heart disease and a search in GeneMatcher, we identified 30 patients from 21 unrelated families of different ancestries with biallelic phospholipase D1 (PLD1) variants who presented predominantly with congenital cardiac valve defects. We also associated recessive PLD1 variants with isolated neonatal cardiomyopathy. Furthermore, we established that p.I668F is a founder variant among Ashkenazi Jews (allele frequency of \textasciitilde{}2\%) and describe the phenotypic spectrum of PLD1-associated congenital heart defects. PLD1 missense variants were overrepresented in regions of the protein critical for catalytic activity, and, correspondingly, we observed a strong reduction in enzymatic activity for most of the mutant proteins in an enzymatic assay. Finally, we demonstrate that PLD1 inhibition decreased endothelial-mesenchymal transition, an established pivotal early step in valvulogenesis. In conclusion, our study provides a more detailed understanding of disease mechanisms and phenotypic expression associated with PLD1 loss of function.",

author = "Najim Lahrouchi and Postma, \{Alex V.\} and Salazar, \{Christian M.\} and \{de Laughter\}, \{Daniel M.\} and Fleur Tjong and Lenka Piherov{\'a} and Bowling, \{Forrest Z.\} and Dominic Zimmerman and Lodder, \{Elisabeth M.\} and Asaf Ta-Shma and Zeev Perles and Leander Beekman and Aho Ilgun and Quinn Gunst and Mariam Hababa and Doris {\v S}kori{\'c}-Milosavljevi{\'c} and Viktor Str{\'a}neck{\'y} and Viktor Tomek and \{de Knijff\}, Peter and \{de Leeuw\}, Rick and Robinson, \{Jamille Y.\} and Burn, \{Sabrina C.\} and Hiba Mustafa and Matthew Ambrose and Timothy Moss and Jennifer Jacober and Niyazov, \{Dmitriy M.\} and Barry Wolf and Kim, \{Katherine H.\} and Sara Cherny and Andreas Rousounides and Aphrodite Aristidou-Kallika and George Tanteles and Bruel Ange-Line and Anne-Sophie Denomm{\'e}-Pichon and Christine Francannet and Damara Ortiz and Haak, \{Monique C.\} and \{ten Harkel\}, \{Arend D. J.\} and Manten, \{Gwendolyn T. R.\} and Dutman, \{Annemiek C.\} and Katelijne Bouman and Monia Magliozzi and Radio, \{Francesca Clementina\} and Santen, \{Gijs W. E.\} and Herkert, \{Johanna C.\} and \{Alex Brown\}, H. and Orly Elpeleg and \{van den Hoff\}, \{Maurice J. B.\} and Barbara Mulder and Airola, \{Michael V.\} and Stanislav Kmoch and Barnett, \{Joey V.\} and Sally-Ann Clur and Frohman, \{Michael A.\} and Bezzina, \{Connie R.\}",

note = "Funding Information: We thank the families for their participation and collaboration. CRB, AVP and NL acknowledge the support from the Dutch Heart Foundation (CVON 2018-30 PREDICT2 and CVON2014-18 CONCOR-GENES to CRB), the Netherlands Organization for Scientific Research (VICI fellowship, 016.150.610, to CRB), the Children{\textquoteright}s Heart Foundation (to CRB), and the PROCEED project funded under the ERA PerMed Joint Translational Call Initiative (to CRB). NL acknowledges support from the CONCOR-GENES Young Talent Program. This work was supported by NIH grants R35GM128666 (to MVA), T32GM092714 (to FZB), R01GM084251 (to MAF), and U54092551 (to DMD, JYR, and JVB) and National Science Foundation (NSF) grant 1612689 (to CMS). SK, VS, and LP were supported by the Ministry of Health of the Czech Republic (NV19-07-00136) and by institutional programs of the Charles University in Prague (UNCE/MED/007, SVV2016/260148 and PROGRES-Q26/LF1). We thank The National Center for Medical Genomics (LM2018132) for instrumental and technical support with the sequencing analysis (to SK, VS, and LP). The authors thank Daoud Sie (Amsterdam UMC, Amsterdam, the Netherlands) for advice on analyses of PCGC WES data. A subset of the WES data was generated by the PCGC under the auspices of the NHLBI{\textquoteright}s Bench to Bassinet Program (https://benchtobassinet.com) (dbGaP study accession number phs001194.v2.p2). The PCGC program is funded by the National Heart, Lung, and Blood Institute (NHLBI), NIH, US Department of Health and Human Services, through grants UM1HL128711, UM1HL098162, UM1HL098147, UM1HL098123, UM1HL128761, and U01HL131003. This manuscript was not prepared in collaboration with investigators of the PCGC, has not been reviewed or approved by the PCGC, and does not necessarily reflect the opinions of the PCGC investigators or the NHLBI. Publisher Copyright: {\textcopyright} 2021, American Society for Clinical Investigation.",

year = "2021",

month = mar,

day = "1",

doi = "10.1172/JCI142148",

language = "English",

volume = "131",

journal = "Journal of clinical investigation",

issn = "0021-9738",

publisher = "The American Society for Clinical Investigation",

number = "5",

}

Lahrouchi, N , Postma, AV, Salazar, CM, de Laughter, DM, Tjong, F, Piherová, L, Bowling, FZ, Zimmerman, D , Lodder, EM, Ta-Shma, A, Perles, Z, Beekman, L , Ilgun, A , Gunst, Q, Hababa, M, Škorić-Milosavljević, D, Stránecký, V, Tomek, V, de Knijff, P, de Leeuw, R, Robinson, JY, Burn, SC, Mustafa, H, Ambrose, M, Moss, T, Jacober, J, Niyazov, DM, Wolf, B, Kim, KH, Cherny, S, Rousounides, A, Aristidou-Kallika, A, Tanteles, G, Ange-Line, B, Denommé-Pichon, A-S, Francannet, C, Ortiz, D, Haak, MC, ten Harkel, ADJ, Manten, GTR, Dutman, AC, Bouman, K, Magliozzi, M, Radio, FC, Santen, GWE, Herkert, JC, Alex Brown, H, Elpeleg, O, van den Hoff, MJB , Mulder, B, Airola, MV, Kmoch, S, Barnett, JV, Clur, S-A, Frohman, MA & Bezzina, CR 2021, 'Biallelic loss-of-function variants in PLD1 cause congenital right-sided cardiac valve defects and neonatal cardiomyopathy', Journal of clinical investigation, vol. 131, no. 5, e142148. https://doi.org/10.1172/JCI142148

TY - JOUR

T1 - Biallelic loss-of-function variants in PLD1 cause congenital right-sided cardiac valve defects and neonatal cardiomyopathy

AU - Lahrouchi, Najim

AU - Postma, Alex V.

AU - Salazar, Christian M.

AU - de Laughter, Daniel M.

AU - Tjong, Fleur

AU - Piherová, Lenka

AU - Bowling, Forrest Z.

AU - Zimmerman, Dominic

AU - Lodder, Elisabeth M.

AU - Ta-Shma, Asaf

AU - Perles, Zeev

AU - Beekman, Leander

AU - Ilgun, Aho

AU - Gunst, Quinn

AU - Hababa, Mariam

AU - Škorić-Milosavljević, Doris

AU - Stránecký, Viktor

AU - Tomek, Viktor

AU - de Knijff, Peter

AU - de Leeuw, Rick

AU - Robinson, Jamille Y.

AU - Burn, Sabrina C.

AU - Mustafa, Hiba

AU - Ambrose, Matthew

AU - Moss, Timothy

AU - Jacober, Jennifer

AU - Niyazov, Dmitriy M.

AU - Wolf, Barry

AU - Kim, Katherine H.

AU - Cherny, Sara

AU - Rousounides, Andreas

AU - Aristidou-Kallika, Aphrodite

AU - Tanteles, George

AU - Ange-Line, Bruel

AU - Denommé-Pichon, Anne-Sophie

AU - Francannet, Christine

AU - Ortiz, Damara

AU - Haak, Monique C.

AU - ten Harkel, Arend D. J.

AU - Manten, Gwendolyn T. R.

AU - Dutman, Annemiek C.

AU - Bouman, Katelijne

AU - Magliozzi, Monia

AU - Radio, Francesca Clementina

AU - Santen, Gijs W. E.

AU - Herkert, Johanna C.

AU - Alex Brown, H.

AU - Elpeleg, Orly

AU - van den Hoff, Maurice J. B.

AU - Mulder, Barbara

AU - Airola, Michael V.

AU - Kmoch, Stanislav

AU - Barnett, Joey V.

AU - Clur, Sally-Ann

AU - Frohman, Michael A.

AU - Bezzina, Connie R.

N1 - Funding Information: We thank the families for their participation and collaboration. CRB, AVP and NL acknowledge the support from the Dutch Heart Foundation (CVON 2018-30 PREDICT2 and CVON2014-18 CONCOR-GENES to CRB), the Netherlands Organization for Scientific Research (VICI fellowship, 016.150.610, to CRB), the Children’s Heart Foundation (to CRB), and the PROCEED project funded under the ERA PerMed Joint Translational Call Initiative (to CRB). NL acknowledges support from the CONCOR-GENES Young Talent Program. This work was supported by NIH grants R35GM128666 (to MVA), T32GM092714 (to FZB), R01GM084251 (to MAF), and U54092551 (to DMD, JYR, and JVB) and National Science Foundation (NSF) grant 1612689 (to CMS). SK, VS, and LP were supported by the Ministry of Health of the Czech Republic (NV19-07-00136) and by institutional programs of the Charles University in Prague (UNCE/MED/007, SVV2016/260148 and PROGRES-Q26/LF1). We thank The National Center for Medical Genomics (LM2018132) for instrumental and technical support with the sequencing analysis (to SK, VS, and LP). The authors thank Daoud Sie (Amsterdam UMC, Amsterdam, the Netherlands) for advice on analyses of PCGC WES data. A subset of the WES data was generated by the PCGC under the auspices of the NHLBI’s Bench to Bassinet Program (https://benchtobassinet.com) (dbGaP study accession number phs001194.v2.p2). The PCGC program is funded by the National Heart, Lung, and Blood Institute (NHLBI), NIH, US Department of Health and Human Services, through grants UM1HL128711, UM1HL098162, UM1HL098147, UM1HL098123, UM1HL128761, and U01HL131003. This manuscript was not prepared in collaboration with investigators of the PCGC, has not been reviewed or approved by the PCGC, and does not necessarily reflect the opinions of the PCGC investigators or the NHLBI. Publisher Copyright: © 2021, American Society for Clinical Investigation.

PY - 2021/3/1

Y1 - 2021/3/1

N2 - Congenital heart disease is the most common type of birth defect, accounting for one-third of all congenital anomalies. Using whole-exome sequencing of 2718 patients with congenital heart disease and a search in GeneMatcher, we identified 30 patients from 21 unrelated families of different ancestries with biallelic phospholipase D1 (PLD1) variants who presented predominantly with congenital cardiac valve defects. We also associated recessive PLD1 variants with isolated neonatal cardiomyopathy. Furthermore, we established that p.I668F is a founder variant among Ashkenazi Jews (allele frequency of ~2%) and describe the phenotypic spectrum of PLD1-associated congenital heart defects. PLD1 missense variants were overrepresented in regions of the protein critical for catalytic activity, and, correspondingly, we observed a strong reduction in enzymatic activity for most of the mutant proteins in an enzymatic assay. Finally, we demonstrate that PLD1 inhibition decreased endothelial-mesenchymal transition, an established pivotal early step in valvulogenesis. In conclusion, our study provides a more detailed understanding of disease mechanisms and phenotypic expression associated with PLD1 loss of function.

AB - Congenital heart disease is the most common type of birth defect, accounting for one-third of all congenital anomalies. Using whole-exome sequencing of 2718 patients with congenital heart disease and a search in GeneMatcher, we identified 30 patients from 21 unrelated families of different ancestries with biallelic phospholipase D1 (PLD1) variants who presented predominantly with congenital cardiac valve defects. We also associated recessive PLD1 variants with isolated neonatal cardiomyopathy. Furthermore, we established that p.I668F is a founder variant among Ashkenazi Jews (allele frequency of ~2%) and describe the phenotypic spectrum of PLD1-associated congenital heart defects. PLD1 missense variants were overrepresented in regions of the protein critical for catalytic activity, and, correspondingly, we observed a strong reduction in enzymatic activity for most of the mutant proteins in an enzymatic assay. Finally, we demonstrate that PLD1 inhibition decreased endothelial-mesenchymal transition, an established pivotal early step in valvulogenesis. In conclusion, our study provides a more detailed understanding of disease mechanisms and phenotypic expression associated with PLD1 loss of function.

UR - https://www.scopus.com/pages/publications/85099642591

U2 - 10.1172/JCI142148

DO - 10.1172/JCI142148

M3 - Article

C2 - 33645542

SN - 0021-9738

VL - 131

JO - Journal of clinical investigation

JF - Journal of clinical investigation

IS - 5

M1 - e142148

ER -

Biallelic loss-of-function variants in PLD1 cause congenital right-sided cardiac valve defects and neonatal cardiomyopathy

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