De novo truncating mutations in ASXL3 are associated with a novel clinical phenotype with similarities to Bohring-Opitz syndrome

Abstract

Background: Molecular diagnostics can resolve locus heterogeneity underlying clinical phenotypes that may otherwise be co-assigned as a specific syndrome based on shared clinical features, and can associate phenotypically diverse diseases to a single locus through allelic affinity. Here we describe an apparently novel syndrome, likely caused by de novo truncating mutations in ASXL3, which shares characteristics with Bohring-Opitz syndrome, a disease associated with de novo truncating mutations in ASXL1.

Methods: We used whole-genome and whole-exome sequencing to interrogate the genomes of four subjects with an undiagnosed syndrome.

Results: Using genome-wide sequencing, we identified heterozygous, de novo truncating mutations in ASXL3, a transcriptional repressor related to ASXL1, in four unrelated probands. We found that these probands shared similar phenotypes, including severe feeding difficulties, failure to thrive, and neurologic abnormalities with significant developmental delay. Further, they showed less phenotypic overlap with patients who had de novo truncating mutations in ASXL1.

Conclusion: We have identified truncating mutations in ASXL3 as the likely cause of a novel syndrome with phenotypic overlap with Bohring-Opitz syndrome.

Figure 1

Clinical presentation of four subjects. (A, B) Subject 2 aged (A) 1 month and (B) 38.5 months. Note the high forehead, low-set ears, thin arched eyebrows and anteverted nares. (C) Subject 3, aged 5 years, Note high and broad forehead, periorbital fullness, and anteverted nares. (D-F) Subject 4, aged 41.5 months, showing prominent tall forehead, arched eyebrows with subtle synophrys and periorbital fullness, prominent columella with hypoplastic alae nasi, thin upper lip, and borderline low-set ears. Note that none of the patients has trigonocephaly or prominent metopic ridge, as seen in Boehring-Opitz syndrome. Images were not available for subject 1.

Figure 2

Known nonsense mutations in ASXL3. Known nonsense mutations are shown (dotted line) across the ASXL3 gene, and are given with the phenotypic effect and DNA source. Amino acid position is listed (top) with exon position (light/dark blue). Regions of high vertebrate conservation are shown (purple) along with Prosite regions (dark blue), and conserved and predicted motifs (nuclear localization in black, ASXL-specific motifs in green, phosphorylation sites in red) amino acid similarity between ASXL3 and ASXL1 (top) and ASXL2 (bottom) (highest similarity to lowest: red, pink, green, blue, brown). Adapted from UCSC Genome browser, ENSEMBL, eukaryotic linear motif server, and NCBI-BLASTP.