Henderson, Deborah JAlqahtani, AhlamChaudhry, BillCook, AndrewEley, LorraineHouyel, LucileHughes, MarinaKeavney, Bernardde la Pompa, José LuisSled, JohnSpielmann, NadineTeboul, LydiaZaffran, StephaneMill, PleasantineLiu, Karen J2024-11-292024-11-292024-11-01Dis Model Mech. 2024 Nov 1;17(11):dmm050913.https://hdl.handle.net/20.500.12105/25818The National Mouse Genetics Network is funded by Medical Research Council (MRC) MC_PC_21044. B.K. is supported by a British Heart Foundation (BHF) Programme Personal Chair CH/13/2/30154 and BHF Programme Grant RG/F/21/ 110050. D.J.H., B.C., A.A. and L.E. are supported by BHF Programme Grant RG/19/ 2/34256. J.L.d.l.P. is funded by PID2022-104776RB-100 and CB16/11/00399 from Ministerio de Ciencia, Innovación y Universidades (MCIU)/Agencia Estatal de Investigación (AEI), La Caixa Research Health Foundation (HR23-00084) and the European Regional Development Fund. The Centro Nacional de Investigaciones Cardiovasculares (CNIC) is funded by MICIU, Instituto de Salud Carlos III and the Pro-CNIC Foundation and is designated as a Severo Ochoa Center of Excellence financed by MCIU/AEI (CEX2020001041-S). J.S. is supported by Canadian Institutes of Health Research grant PJT169050. L.T. is supported by MRC grant mc_up_2201/1. S.Z. is supported by Additional Ventures (Single Ventricle Research Fund), Agence Nationale de la Recherche (ANR-22-CE13-0047-02 and ANR-23- CE14-0060-01), AFM-Telethon (MoThARD) and Institut National de la Santéet de la Recherche Médicale (INSERM) Programme Transversal ‘HuDeCA’. P.M. is funded by MRC grant MR/Y015002/1 and the European Research Council under the European Union’s Horizon 2020 research and innovation programme (grant agreement no. 866355).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.engVoRhttp://creativecommons.org/licenses/by/4.0/Cardiac phenotypingCongenital heart defectDevelopmental biologyDisease modellingGene variantGeneticsGenomicsHuman patientMouse modelStructural anomaliesAttribution 4.0 International395755091711dmm050913Disease Models and Mechanismsopen access