Beyond genomic studies of congenital heart defects through systematic modelling and phenotyping

Deborah Henderson; Ahlam Alqahtani; Bill Chaudhry; andrew cook; Lorraine Eley; Lucile Houyel; marina Hughes; Bernard Keavney; Jose Luis de la Pompa; John Sled; nadine spielmann; Lydia Teboul; Stephane Zaffran; Pleasantine Mill; Karen Liu

Beyond genomic studies of congenital heart defects through systematic modelling and phenotyping

Deborah Henderson^*, Ahlam Alqahtani, Bill Chaudhry, andrew cook, Lorraine Eley, Lucile Houyel, marina Hughes, Bernard Keavney, Jose Luis de la Pompa, John Sled, nadine spielmann, Lydia Teboul, Stephane Zaffran, Pleasantine Mill, Karen Liu

^*Corresponding author for this work

Centre for Craniofacial & Regenerative Biology

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

1 Citation (Scopus)

Abstract

Congenital heart defects (CHDs), the most common congenital anomalies, are considered to have a significant genetic component. However, despite considerable efforts to identify pathogenic genes in patients with CHDs, few gene variants have been proven as causal. The complexity of the genetic architecture underlying human CHDs likely contributes to this poor genetic discovery rate. However, several other factors are likely to contribute. For example, the level of patient phenotyping required for clinical care may be insufficient for research studies focused on mechanistic discovery. Although several hundred mouse gene knockouts have been described with CHDs, these are generally not phenotyped and described in the same way as CHDs in patients, and thus are not readily comparable. Moreover, most patients with CHDs carry variants of uncertain significance of crucial cardiac genes, further complicating comparisons between humans and mouse mutants. In spite of major advances in cardiac developmental biology over the past 25 years, these advances have not been well communicated to geneticists and cardiologists. As a consequence, the latest data from developmental biology are not always used in the design and interpretation of studies aimed at discovering the genetic causes of CHDs. In this Special Article, while considering other in vitro and in vivo models, we create a coherent framework for accurately modelling and phenotyping human CHDs in mice, thereby enhancing the translation of genetic and genomic studies into the causes of CHDs in patients.

Original language	English
Journal	Disease Models & Mechanisms
Volume	17
Issue number	11
Publication status	Published - 24 Nov 2024

Keywords

congenital heart defect
genetics
gene variant
human patient
mouse model
genomics
disease modelling
cardiac phenotyping
developmental biology
structural anomalies

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https://doi.org/10.1242/dmm.050913Licence: CC BY

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title = "Beyond genomic studies of congenital heart defects through systematic modelling and phenotyping",

abstract = "Congenital heart defects (CHDs), the most common congenital anomalies, are considered to have a significant genetic component. However, despite considerable efforts to identify pathogenic genes in patients with CHDs, few gene variants have been proven as causal. The complexity of the genetic architecture underlying human CHDs likely contributes to this poor genetic discovery rate. However, several other factors are likely to contribute. For example, the level of patient phenotyping required for clinical care may be insufficient for research studies focused on mechanistic discovery. Although several hundred mouse gene knockouts have been described with CHDs, these are generally not phenotyped and described in the same way as CHDs in patients, and thus are not readily comparable. Moreover, most patients with CHDs carry variants of uncertain significance of crucial cardiac genes, further complicating comparisons between humans and mouse mutants. In spite of major advances in cardiac developmental biology over the past 25 years, these advances have not been well communicated to geneticists and cardiologists. As a consequence, the latest data from developmental biology are not always used in the design and interpretation of studies aimed at discovering the genetic causes of CHDs. In this Special Article, while considering other in vitro and in vivo models, we create a coherent framework for accurately modelling and phenotyping human CHDs in mice, thereby enhancing the translation of genetic and genomic studies into the causes of CHDs in patients.",

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author = "Deborah Henderson and Ahlam Alqahtani and Bill Chaudhry and andrew cook and Lorraine Eley and Lucile Houyel and marina Hughes and Bernard Keavney and {de la Pompa}, {Jose Luis} and John Sled and nadine spielmann and Lydia Teboul and Stephane Zaffran and Pleasantine Mill and Karen Liu",

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AU - Henderson, Deborah

AU - Alqahtani, Ahlam

AU - Chaudhry, Bill

AU - cook, andrew

AU - Eley, Lorraine

AU - Houyel, Lucile

AU - Hughes, marina

AU - Keavney, Bernard

AU - de la Pompa, Jose Luis

AU - Sled, John

AU - spielmann, nadine

AU - Teboul, Lydia

AU - Zaffran, Stephane

AU - Mill, Pleasantine

AU - Liu, Karen

PY - 2024/11/24

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N2 - Congenital heart defects (CHDs), the most common congenital anomalies, are considered to have a significant genetic component. However, despite considerable efforts to identify pathogenic genes in patients with CHDs, few gene variants have been proven as causal. The complexity of the genetic architecture underlying human CHDs likely contributes to this poor genetic discovery rate. However, several other factors are likely to contribute. For example, the level of patient phenotyping required for clinical care may be insufficient for research studies focused on mechanistic discovery. Although several hundred mouse gene knockouts have been described with CHDs, these are generally not phenotyped and described in the same way as CHDs in patients, and thus are not readily comparable. Moreover, most patients with CHDs carry variants of uncertain significance of crucial cardiac genes, further complicating comparisons between humans and mouse mutants. In spite of major advances in cardiac developmental biology over the past 25 years, these advances have not been well communicated to geneticists and cardiologists. As a consequence, the latest data from developmental biology are not always used in the design and interpretation of studies aimed at discovering the genetic causes of CHDs. In this Special Article, while considering other in vitro and in vivo models, we create a coherent framework for accurately modelling and phenotyping human CHDs in mice, thereby enhancing the translation of genetic and genomic studies into the causes of CHDs in patients.

AB - Congenital heart defects (CHDs), the most common congenital anomalies, are considered to have a significant genetic component. However, despite considerable efforts to identify pathogenic genes in patients with CHDs, few gene variants have been proven as causal. The complexity of the genetic architecture underlying human CHDs likely contributes to this poor genetic discovery rate. However, several other factors are likely to contribute. For example, the level of patient phenotyping required for clinical care may be insufficient for research studies focused on mechanistic discovery. Although several hundred mouse gene knockouts have been described with CHDs, these are generally not phenotyped and described in the same way as CHDs in patients, and thus are not readily comparable. Moreover, most patients with CHDs carry variants of uncertain significance of crucial cardiac genes, further complicating comparisons between humans and mouse mutants. In spite of major advances in cardiac developmental biology over the past 25 years, these advances have not been well communicated to geneticists and cardiologists. As a consequence, the latest data from developmental biology are not always used in the design and interpretation of studies aimed at discovering the genetic causes of CHDs. In this Special Article, while considering other in vitro and in vivo models, we create a coherent framework for accurately modelling and phenotyping human CHDs in mice, thereby enhancing the translation of genetic and genomic studies into the causes of CHDs in patients.

KW - congenital heart defect

KW - genetics

KW - gene variant

KW - human patient

KW - mouse model

KW - genomics

KW - disease modelling

KW - cardiac phenotyping

KW - developmental biology

KW - structural anomalies

M3 - Article

SN - 1754-8403

VL - 17

JO - Disease Models & Mechanisms

JF - Disease Models & Mechanisms

IS - 11

ER -

Beyond genomic studies of congenital heart defects through systematic modelling and phenotyping

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Keywords

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