To the Editor — We write to express our concerns that the report ‘The complex genetics of hypoplastic left heart syndrome’ by Liu et al.1 is misleading, and the data presented in the figures and in the Mouse Genome Informatics repository do not convincingly demonstrate hypoplastic left heart syndrome (HLHS).

An international nomenclature committee has specifically defined this particular lesion2. This definition is now contained within the Eleventh Revision of the International Classification of Diseases (ICD-11)3. It is the combination of a small non-apex-forming left ventricle, hypoplasia of the ascending aorta, and a combination of aortic and mitral valve stenosis or atresia. The definition requires the presence of concordant ventriculoarterial connections. Hence, the aorta must arise from the left ventricle, and the pulmonary trunk must arise from the right ventricle. The definition specifically excludes diagnoses such as double-outlet right ventricle (DORV), transposition of the great arteries (TGA), common arterial trunk (CAT), and atrioventricular septal defects (AVSD), all of which on occasion can be associated with a small left ventricle.

Liu et al. refer to the CRISPR–Cas9 mutants as the “double-outlet RV variant of HLHS,” which is a contradiction4. The appearances of these mice are similar to that of a well-recognized but rare form of DORV with a restrictive or closed interventricular communication5. Double outlet from the right ventricle is the normal situation in the early embryo, and a lack of transfer of the aorta into the left ventricle redefines the arrangement as a malformation6,7. In HLHS, because there are concordant ventriculoarterial connections by definition, transfer of the aortic root must have taken place8. TGA, CAT, and AVSD all result from different developmental processes9.

It follows that the suggestion that digenic inheritance is likely to be responsible for HLHS is without foundation, because none of the mice described have HLHS. The human genomic data within the paper do not independently support the conclusion of digenic inheritance. The atypical protocadherin implicated in the patient is not homologous to that described for the mouse model, nor is any clinical information provided.

Our overall tenet is that it is inappropriate to reclassify mutants with DORV as HLHS and that, in doing so, this report may risk misleading clinicians, families affected by HLHS, and researchers seeking to understand specific etiologies underlying HLHS.