De novo variants in LDB1 are linked to distinct neurodevelopmental phenotypes determined by variant location and differing pathomechanisms

LDB1 (de novo variants — N-term vs C-term)

N-term = LOF of the dimerization domain; C-term = dominant-negative effect (hypothesis) — ventriculomegaly associated with C-term variants

Analysis of 16 individuals carrying de novo variants in LDB1, a transcriptional regulator of neurogenesis. N-term variants (11 cases) impair the dimerization domain via LOF, while C-term variants (5 cases) appear to act through a dominant-negative mechanism, with ventriculomegaly specifically associated. Two distinct pathomechanisms depending on variant location.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

Particularly useful genotype–phenotype correlation for interpretation: LDB1 variant location → phenotypic prediction (ventriculomegaly or not). Preprint to watch for final publication.

consolidated new gene +2; de novo +2; original G/P correlation +2; 16 patients +1; preprint −1; interpretation impact +1; mechanism +1