Expanding the clinical spectrum of recessive truncating mutations of to a Bohring-Opitz-like phenotype.

Background: Bohring-Opitz syndrome (BOS) is a rare genetic disorder characterised by a recognisable craniofacial appearance and a typical 'BOS' posture. BOS is caused by sporadic mutations of. However, several typical patients with BOS have no molecular diagnosis, suggesting clinical and genetic heterogeneity.

Objectives: To expand the phenotypical spectrum of autosomal recessive variants of , reported as causing Crisponi syndrome/cold-induced sweating syndrome type 1 (CS/CISS1)-like syndrome.

Methods: We performed whole-exome sequencing in two families with a suspected recessive mode of inheritance. We used the Matchmaker Exchange initiative to identify additional patients.

Results: Here, we report six patients with microcephaly, facial dysmorphism, including exophthalmos, nevus flammeus of the glabella and joint contractures with a suspected BOS posture in five out of six patients. We identified autosomal recessive truncating mutations in the gene. encodes a BTB-kelch protein implicated in the cell cycle and in protein degradation by the ubiquitin-proteasome pathway. Recently, biallelic mutations in the gene were reported in four families and associated with CS/CISS1, characterised by clinical features overlapping with our patients.

Conclusion: We have expanded the clinical spectrum of autosomal recessive variants by describing a syndrome with features overlapping CS/CISS1 and BOS.