Monoallelic heterozygous variants might reduce expression and contribute in a multi-causal manner to the susceptibility to heart defects, especially in combination with chromosomal aberrations such as Down syndrome.25 Based on our data, a truncating variant with antimorphic activity combined with a missense variant affecting one of the functional domains of CRELD1 is able to cause severe multisystem disease as in our patient, including muscle weakness, arthrogryposis, developmental delay and epilepsy. This evidence concerns the gene CRELD1 and Down syndrome.