2. Academic Validation
  3. De novo truncating mutations in ASXL3 are associated with a novel clinical phenotype with similarities to Bohring-Opitz syndrome

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

  • Genome Med. 2013 Feb 5;5(2):11. doi: 10.1186/gm415.
Matthew N Bainbridge 1,  Hao Hu 2,  Donna M Muzny 3,  Luciana Musante 2,  James R Lupski 4,  Brett H Graham 5,  Wei Chen 6,  Karen W Gripp 7,  Kim Jenny 7,  Thomas F Wienker 2,  Yaping Yang 8,  V Reid Sutton 5,  Richard A Gibbs 1,  H Hilger Ropers 2
Affiliations

Affiliations

  • 1 Human Genome Sequencing Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA ; Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
  • 2 Max-Planck-Institute for Molecular Genetics, Ihnestraße, Berlin 14195, Germany.
  • 3 Human Genome Sequencing Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
  • 4 Human Genome Sequencing Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA ; Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA ; Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA ; Texas Children's Hospital, 6621 Fannin, Houston, TX 77030, USA.
  • 5 Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA ; Texas Children's Hospital, 6621 Fannin, Houston, TX 77030, USA.
  • 6 Max-Planck-Institute for Molecular Genetics, Ihnestraße, Berlin 14195, Germany ; 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.
  • 8 Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
PMID: 23383720 DOI: 10.1186/gm415
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.

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