Homozygous loss of function variant in gene causes major brain malformation and perinatal death.

Lamins play a major role in the mechanical stability of cell nuclei, the organisation of chromatin and the DNA replication, transcription and repair. The expression profiles of A-type and B-type lamins vary depending on developmental stages, cell types and tissues. Lamin B2 is expressed very early in embryogenesis, especially in the central nervous system, where it is essential for neuronal migration and brain development. Pathogenic missense variants in lamin B2 have been linked to conditions such as lipodystrophy, progressive myoclonic epilepsy and primary microcephaly. Here, we report clinical data and molecular findings for two related newborns carrying a homozygous loss-of-function variant in the gene. Both newborns died in the perinatal period and exhibited a similar phenotype at birth, including severe brain development abnormalities, which closely mirror findings observed in several -deficient mouse models. Western blot and immunofluorescence cell labelling performed on the patient's fibroblasts obtained at birth confirmed the complete absence of lamin B2 and revealed an increase in lamin B1, together with alterations in alpha-tubulin and vimentin organisation. This novel clinical form of laminopathy associated with lamin B2 deficiency expands the molecular causes of brain development abnormalities to gene variants.