Open Access Highly Accessed Research

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

Matthew N Bainbridge12, Hao Hu3, Donna M Muzny1, Luciana Musante3, James R Lupski1245, Brett H Graham25, Wei Chen36, Karen W Gripp7, Kim Jenny7, Thomas F Wienker3, Yaping Yang2, V Reid Sutton25, Richard A Gibbs12* and H Hilger Ropers3*

Author Affiliations

1 Human Genome Sequencing Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA

2 Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA

3 Max-Planck-Institute for Molecular Genetics, Ihnestraße, Berlin 14195, Germany

4 Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA

5 Texas Children's Hospital, 6621 Fannin, Houston, TX 77030, USA

6 Max-Delbrueck-Centrum für Molekulare Medizin, Robert-Rössle-Straße, Berlin, 13092, Germany

7 AI duPont Hospital for Children, 1600 Rockland Rd, Wilmington, DE 19803, USA

For all author emails, please log on.

Genome Medicine 2013, 5:11  doi:10.1186/gm415

Published: 5 February 2013

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.