De novo nonsense mutations in ASXL1 cause Bohring-Opitz syndrome

Abstract

Bohring-Opitz syndrome is characterized by severe intellectual disability, distinctive facial features and multiple congenital malformations. We sequenced the exomes of three individuals with Bohring-Opitz syndrome and in each identified heterozygous de novo nonsense mutations in ASXL1, which is required for maintenance of both activation and silencing of Hox genes. In total, 7 out of 13 subjects with a Bohring-Opitz phenotype had de novo ASXL1 mutations, suggesting that the syndrome is genetically heterogeneous.

Disease gene identification strategies for exome sequencing

“…33 Recently, we showed that combining data from three individuals was sufficient to identify the gene for Bohring-Opitz syndrome. 34 Although in the individual patients we found between 130 and 222 novel non-synonymous variants, the overlap for any two patients yielded 26 candidate genes whereas the overlap from three patients pointed only to a single gene.…”

“…After this, typically between 150 and 500 private non-synonymous or splicesite variants are prioritized as potential pathogenic variants (see Figures 1 and 2). 4,[28][29][30][31][32][33][34] It is important to emphasize that prioritization may discard the pathogenic variant. A variant that is present at low frequency in a heterozygous state in the normal population may be removed even though it causes disease if present in a homozygous state.…”

Bainbridge–Ropers syndrome caused by loss-of-function variants in ASXL3: a recognizable condition

“…[3][4][5] In 2011, germline mutations in ASXL1 (MIM *612990) were shown to be causative for Bohring-Opitz syndrome. 6 ASXL3 and ASXL1 belong to the same gene family. Together with ASXL2 (MIM *612991), they constitute the ASXL family of additional sex combs like genes, human homologs of the Asx gene in Drosophila, 7 which serve as epigenetic scaffolding proteins.…”

The ASXL1 mutation p.Gly646Trpfs*12 found in a Turkish boy with Bohring‐Opitz Syndrome

“…Heterozygous ASXL1 truncating mutations have been identified as the main cause of BOS 1, 2. A recent publication 3 called the attention to the fact that mutations associated with BOS are also present in the ExAC (Exome Aggregation Consortium) database 4.…”