Biallelic Variants in LRRC45 Impair Ciliogenesis and Cause a Severe Neurological Disorder.

Leucine - rich repeat containing 45 protein (LRRC45) protein localizes at the proximal end of centrioles and forms a component of the proteinaceous linker between them, with an important role in centrosome cohesion. In addition, a pool of it localizes at the distal appendages of the modified parent centriole that forms the primary cilium and it has essential functions in the establishment of the transition zone and axonemal extension during early ciliogenesis. Here, we describe three individuals from two unrelated families with severe central nervous system anomalies. Exome sequencing identified biallelic variants in LRRC45 in the affected individuals: P1: c.1402-2A>G; P2 and P3: c.1262G>C (p.Arg421Thr). Investigation of the variant c.1402-2A>G in patient-derived skin fibroblasts revealed that it triggers aberrant splicing, leading to an abnormal LRRC45 transcript that lacks exon 14. Consistent with this the mRNA and protein levels of LRRC45 were drastically reduced in P1-derived fibroblast cells compared to the controls. P1 fibroblasts showed a significant reduction of primary cilia frequency and length. In silico modeling of the missense variant in P2/P3 suggested a destabilizing effect on LRRC45. Given these findings, we propose that the pathogenic loss-of-function variants in LRRC45 are associated with a novel spectrum of neurological ciliopathy phenotypes.