Patient-specific genomics and cross-species functional analysis implicate lrp2 in hypoplastic left heart syndrome

Jeanne L. Theis; Georg Vogler; Maria A. Missinato; Xing Li; Tanja Nielsen; Xin Xin I. Zeng; Almudena Martinez-Fernandez; Stanley M. Walls; Anaïs Kervadec; James N. Kezos; Katja Birker; Jared M. Evans; Megan M. O’byrne; Zachary C. Fogarty; André Terzic; Paul Grossfeld; Karen Ocorr; Timothy J. Nelson; Timothy M. Olson; Alexandre R. Colas; Rolf Bodmer

doi:10.7554/eLife.59554

Patient-specific genomics and cross-species functional analysis implicate lrp2 in hypoplastic left heart syndrome

Jeanne L. Theis, Georg Vogler, Maria A. Missinato, Xing Li, Tanja Nielsen, Xin Xin I. Zeng, Almudena Martinez-Fernandez, Stanley M. Walls, Anaïs Kervadec, James N. Kezos, Katja Birker, Jared M. Evans, Megan M. O’byrne, Zachary C. Fogarty, André Terzic, Paul Grossfeld, Karen Ocorr, Timothy J. Nelson, Timothy M. Olson, Alexandre R. ColasRolf Bodmer

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

2 Scopus citations

Abstract

Congenital heart diseases (CHDs), including hypoplastic left heart syndrome (HLHS), are genetically complex and poorly understood. Here, a multidisciplinary platform was established to functionally evaluate novel CHD gene candidates, based on whole-genome and iPSC RNA sequencing of a HLHS family-trio. Filtering for rare variants and altered expression in proband iPSCs prioritized 10 candidates. siRNA/RNAi-mediated knockdown in healthy human iPSC-derived cardiomyocytes (hiPSC-CM) and in developing Drosophila and zebrafish hearts revealed that LDL receptor-related protein LRP2 is required for cardiomyocyte proliferation and differentiation. Consistent with hypoplastic heart defects, compared to patents the proband’s iPSC-CMs exhibited reduced proliferation. Interestingly, rare, predicted-damaging LRP2 variants were enriched in a HLHS cohort; however, understanding their contribution to HLHS requires further investigation. Collectively, we have established a multi-species high-throughput platform to rapidly evaluate candidate genes and their interactions during heart development, which are crucial first steps toward deciphering oligogenic underpinnings of CHDs, including hypoplastic left hearts.

Original language	English (US)
Article number	e59554
Pages (from-to)	1-27
Number of pages	27
Journal	eLife
Volume	9
DOIs	https://doi.org/10.7554/eLife.59554
State	Published - Oct 2020

ASJC Scopus subject areas

General Neuroscience
General Biochemistry, Genetics and Molecular Biology
General Immunology and Microbiology

Access to Document

10.7554/eLife.59554

Cite this

Theis, J. L., Vogler, G., Missinato, M. A., Li, X., Nielsen, T., Zeng, X. X. I., Martinez-Fernandez, A., Walls, S. M., Kervadec, A., Kezos, J. N., Birker, K., Evans, J. M., O’byrne, M. M., Fogarty, Z. C., Terzic, A., Grossfeld, P., Ocorr, K., Nelson, T. J., Olson, T. M., ... Bodmer, R. (2020). Patient-specific genomics and cross-species functional analysis implicate lrp2 in hypoplastic left heart syndrome. eLife, 9, 1-27. Article e59554. https://doi.org/10.7554/eLife.59554

Theis, JL, Vogler, G, Missinato, MA, Li, X, Nielsen, T, Zeng, XXI, Martinez-Fernandez, A, Walls, SM, Kervadec, A, Kezos, JN, Birker, K, Evans, JM, O’byrne, MM, Fogarty, ZC, Terzic, A, Grossfeld, P, Ocorr, K, Nelson, TJ, Olson, TM, Colas, AR & Bodmer, R 2020, 'Patient-specific genomics and cross-species functional analysis implicate lrp2 in hypoplastic left heart syndrome', eLife, vol. 9, e59554, pp. 1-27. https://doi.org/10.7554/eLife.59554

@article{d5136f40e8134703bdac9fd4442e9944,

title = "Patient-specific genomics and cross-species functional analysis implicate lrp2 in hypoplastic left heart syndrome",

abstract = "Congenital heart diseases (CHDs), including hypoplastic left heart syndrome (HLHS), are genetically complex and poorly understood. Here, a multidisciplinary platform was established to functionally evaluate novel CHD gene candidates, based on whole-genome and iPSC RNA sequencing of a HLHS family-trio. Filtering for rare variants and altered expression in proband iPSCs prioritized 10 candidates. siRNA/RNAi-mediated knockdown in healthy human iPSC-derived cardiomyocytes (hiPSC-CM) and in developing Drosophila and zebrafish hearts revealed that LDL receptor-related protein LRP2 is required for cardiomyocyte proliferation and differentiation. Consistent with hypoplastic heart defects, compared to patents the proband{\textquoteright}s iPSC-CMs exhibited reduced proliferation. Interestingly, rare, predicted-damaging LRP2 variants were enriched in a HLHS cohort; however, understanding their contribution to HLHS requires further investigation. Collectively, we have established a multi-species high-throughput platform to rapidly evaluate candidate genes and their interactions during heart development, which are crucial first steps toward deciphering oligogenic underpinnings of CHDs, including hypoplastic left hearts.",

author = "Theis, {Jeanne L.} and Georg Vogler and Missinato, {Maria A.} and Xing Li and Tanja Nielsen and Zeng, {Xin Xin I.} and Almudena Martinez-Fernandez and Walls, {Stanley M.} and Ana{\"i}s Kervadec and Kezos, {James N.} and Katja Birker and Evans, {Jared M.} and O{\textquoteright}byrne, {Megan M.} and Fogarty, {Zachary C.} and Andr{\'e} Terzic and Paul Grossfeld and Karen Ocorr and Nelson, {Timothy J.} and Olson, {Timothy M.} and Colas, {Alexandre R.} and Rolf Bodmer",

note = "Publisher Copyright: {\textcopyright} Theis et al.",

year = "2020",

month = oct,

doi = "10.7554/eLife.59554",

language = "English (US)",

volume = "9",

pages = "1--27",

journal = "eLife",

issn = "2050-084X",

publisher = "eLife Sciences Publications",

}

TY - JOUR

T1 - Patient-specific genomics and cross-species functional analysis implicate lrp2 in hypoplastic left heart syndrome

AU - Theis, Jeanne L.

AU - Vogler, Georg

AU - Missinato, Maria A.

AU - Li, Xing

AU - Nielsen, Tanja

AU - Zeng, Xin Xin I.

AU - Martinez-Fernandez, Almudena

AU - Walls, Stanley M.

AU - Kervadec, Anaïs

AU - Kezos, James N.

AU - Birker, Katja

AU - Evans, Jared M.

AU - O’byrne, Megan M.

AU - Fogarty, Zachary C.

AU - Terzic, André

AU - Grossfeld, Paul

AU - Ocorr, Karen

AU - Nelson, Timothy J.

AU - Olson, Timothy M.

AU - Colas, Alexandre R.

AU - Bodmer, Rolf

PY - 2020/10

Y1 - 2020/10

N2 - Congenital heart diseases (CHDs), including hypoplastic left heart syndrome (HLHS), are genetically complex and poorly understood. Here, a multidisciplinary platform was established to functionally evaluate novel CHD gene candidates, based on whole-genome and iPSC RNA sequencing of a HLHS family-trio. Filtering for rare variants and altered expression in proband iPSCs prioritized 10 candidates. siRNA/RNAi-mediated knockdown in healthy human iPSC-derived cardiomyocytes (hiPSC-CM) and in developing Drosophila and zebrafish hearts revealed that LDL receptor-related protein LRP2 is required for cardiomyocyte proliferation and differentiation. Consistent with hypoplastic heart defects, compared to patents the proband’s iPSC-CMs exhibited reduced proliferation. Interestingly, rare, predicted-damaging LRP2 variants were enriched in a HLHS cohort; however, understanding their contribution to HLHS requires further investigation. Collectively, we have established a multi-species high-throughput platform to rapidly evaluate candidate genes and their interactions during heart development, which are crucial first steps toward deciphering oligogenic underpinnings of CHDs, including hypoplastic left hearts.

AB - Congenital heart diseases (CHDs), including hypoplastic left heart syndrome (HLHS), are genetically complex and poorly understood. Here, a multidisciplinary platform was established to functionally evaluate novel CHD gene candidates, based on whole-genome and iPSC RNA sequencing of a HLHS family-trio. Filtering for rare variants and altered expression in proband iPSCs prioritized 10 candidates. siRNA/RNAi-mediated knockdown in healthy human iPSC-derived cardiomyocytes (hiPSC-CM) and in developing Drosophila and zebrafish hearts revealed that LDL receptor-related protein LRP2 is required for cardiomyocyte proliferation and differentiation. Consistent with hypoplastic heart defects, compared to patents the proband’s iPSC-CMs exhibited reduced proliferation. Interestingly, rare, predicted-damaging LRP2 variants were enriched in a HLHS cohort; however, understanding their contribution to HLHS requires further investigation. Collectively, we have established a multi-species high-throughput platform to rapidly evaluate candidate genes and their interactions during heart development, which are crucial first steps toward deciphering oligogenic underpinnings of CHDs, including hypoplastic left hearts.

UR - http://www.scopus.com/inward/record.url?scp=85094219857&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85094219857&partnerID=8YFLogxK

U2 - 10.7554/eLife.59554

DO - 10.7554/eLife.59554

M3 - Article

C2 - 33006316

AN - SCOPUS:85094219857

SN - 2050-084X

VL - 9

SP - 1

EP - 27

JO - eLife

JF - eLife

M1 - e59554

ER -

Patient-specific genomics and cross-species functional analysis implicate lrp2 in hypoplastic left heart syndrome

Abstract

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this