Clinical morphology and genetics of congenital heart disease

Rationale and WG aims
Congenital heart disease (CHD) is the most common congenital disease, and its morphological spectrum ranges from relatively simple to extremely complex anatomical malformations. The anatomical substrate is a consequence of sequential distortions during embryological development.
Cardiac development is orchestrated by multiple genetic pathways, during which different cell types will contribute and interact. The complex and variable anatomical substrate of CHD, which in contrast to acquired heart disease already develops in utero, requires that in addition to clinical expertise, thorough knowledge is acquired by treating cardiologists regarding the morphology and development of the specific anomaly and the associated defects.
Due to developments in congenital heart surgery and percutaneous interventions in the past decades, over 90 % of patients with CHD now reach the adult, reproductive age. Cardiologists dealing with adult patients with CHD are increasingly confronted with questions regarding the impact of CHD on pregnancy and offspring, rendering genetic counselling increasingly more relevant to clinical practice. Major developments in the field of clinical genetics have expanded possibilities for genetic screening and its low threshold implementation in patient care pathways. However, this does not always linearly facilitate the clinicians’ knowledge and reasoning, as interpretation of often large and abstract DNA-datasets is challenging, especially in the light of morphological and phenotypic heterogeneity and low penetrance, and requires specific expertise.
Moreover, research projects aimed at determining pivotal genetic pathways involved in the development of human CHD and its outcomes, require adequate morphological phenotyping of congenital malformation for proper study design and correct adjudication of patients to specific phenotypes and morphological substrates. For instance, congenital heart diseases such as (functionally) univentricular hearts, pulmonary atresia, double outlet right ventricle, atrial septal defects a.o. occur in a range of differential phenotypes with overt diverse embryological backgrounds, morphological substrates and outcomes. The aim of this working group is to combine, integrate and apply knowledge and expertise on human cardiac pathomorphology, development and clinical genetics, serving the purpose of supporting and setting up research projects, organising educational activities as well as complementing knowledge to the highly complex and top referral care pathways for patients with congenital heart defects.

Proposed WG Goals:
1. Developing a national expertise center of cardiac pathomorphology of congenital heart disease and clinical genetics, thus providing a supporting platform for clinical discussions, that actively stimulates national collaborations in the field of clinical anatomy, developmental and clinical genetics, in order to better understand the substrate, mechanisms and pathways involved in (late sequalae of) human congenital heart disease.
2. To provide a platform to facilitate and support clinical and basic science using and expanding existing biobanks withs cells, blood and tissues of patients with congenital heart disease
3. Supplementing the Pre-cor, Kincor, and Concor registries, with additional “MorphGenCor” registries, in order to support correlation of genetic variants with the clinical phenotype in congenital heart disease, as well as with the morphological and structural phenotype.
4. Promoting and expanding (inter-)national research networks and submitting joint funding applications focusing on clinical morphological and genetic phenotyping and mechanisms of CHD as related to late outcomes.
5. Contributing to local, national and international education of medical professionals to disseminate knowledge and understanding on human pathomorphological, developmental and genetics of complex congenital heart disease; to develop materials for patient counseling and promote patient education and empowerment.

Proposed activities:
1. Working towards extending the Dutch Hartenbank to include Congenital Heart Disease specimens – apply for funding
2. Develop a online overview of congenital heart disease biobanks (blood, cells and tissues) available in the Netherlands and beyond.
3. Apply and coordinate joint (inter-)national research grant applications focused on human morphology and clinical genetics of CHD.
4. Organize a symposium about clinical morphology and genetics of complex congenital heart disease for medical professional, clinical and translational scientists.

Proposed/potential partners (to be expanded and approached after approval/ prior to start date):

• Hartenbank https://www.hartenbank.nl/
• PreCor
• Concor, https://concor.net/nl/
• KinCor, https://kincor.nl/
• Leiden collection of Congenital Malformations (Biobank of congenital heart disease)
• Nederlandse Anatomen Vereniging (NAV)
• NVVC National working group ACHD
• NVVP Post Mortem working group
• EACVP
• VKGN National working group inhered heart disease