Mutations in the FBRSL1 gene cause a previously undescribed syndrome associated with malformations and intellectual disability. A study led by scientists of the Institute of Human Genetics at the University Medical Center Göttingen identified de novo truncating mutations in FBRSL1 in three children of unrelated families. They presented an overlapping phenotype of respiratory problems, postnatal growth retardation, microcephaly, global developmental delay and additional malformations.

FBRSL1 and its paralog AUTS2 are components of the same polycomb subcomplexes. They are thus members of the large family of polycomb group proteins, which assemble to form two large molecular complexes. Acting via histone modifications, these complexes have essential roles in regulating cell type-specific gene expression and controlling cellular development, differentiation and proliferation. Mutations in proteins of the PRC1 and PRC2 polycomb complexes have been reported to cause different syndromic disorders, but until now FBRSL1 has not been linked to a disease and its function has remained largely unknown.

Further experiments have now revealed new insights into different FBRSL1 transcripts and the subcellular localization of protein isoforms. The researchers also perfomed experiments in Xenopus frog embryos to investigate the protein function and they showed that knockdown of the gene resulted in craniofacial anomalies and disturbed neurite outgrowth. From their findings, the authors of the study conclude that disruption of the N-terminal isoforms at critical points during embryogenesis lead to a previously undescribed neurodevelopmental syndrome.

The results of the study have been published in Human Genetics.