ClinGen Dosage Sensitivity Curation Page


Curation Status: Complete

Gene Information

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Evidence for Loss Phenotypes

Evidence for loss of function phenotype
PubMed ID Description
23383720 Bainbridge et al (2013) identified de novo truncating mutations of ASXL3 in four unrelated individuals with Bohring-Opitz syndrome-like clinical features. All four de novo mutations (two nonsense; one 4 bp deletion; and one 1 bp insertion) detected by whole exome / whole genome sequencing were predicted to result in nonsense-mediated decay or truncated protein. No deleterious ASXL3 mutation was detected in a small cohort of patients with Bohring-Opitz syndrome without causative ASXL1 mutation, consistent with ASXL3 mutations caused a different clinical entity, Bainbridge-Ropers syndrome. However, the authors identified four additional truncating mutations in ASXL3 in reportedly phenotypically normal individuals from large-scale datasets (Thousand Genomes, dbSNP, ESP5400, and Cohorts for Heart and Aging Research in Genomic Epidemiology). These potentially benign variants are located 5? and 3? of the disease-causing mutation hotspot within the first half of the penultimate exon11 (Figure 2). Functional studies were not performed in this study. However, authors stated that truncating ASXL3 mutations are uncommon, and their de novo nature makes it even less likely that they identified these individuals by chance.
26647312 Srivastava et al (2016) identified three novel de novo heterozygous truncating variants in unrelated individuals with Bainbridge-Ropers syndrome using clinical exome sequencing. These mutations (two nonsense and 1 bp insertion) were distributed across ASXL3, outside the original mutation hotspot previously described in exon 11 and instead localize to the 5? end of exon 12 (Figure 1E). The authors showed that the mutated allele mRNA transcripts obtained from primary skin fibroblasts from the mutated allele of a patient were prone to nonsense-mediated decay, and expression of ASXL3 was reduced consistent with loss-of-function mutations. Authors stated that previously described ASXL3 nonsense variants detected in normal individuals may represent mutations arising post-zygotically or during later embryogenesis and thus may be explained by the timing of these de novo mutational events and mosaicism.
27901041 Kuechler et al (2017) described six unrelated individuals with Bainbridge-Ropers syndrome with novel heterozygous de novo loss-of-function variants (3 nonsense; one 1 bp deletion; and two 2 bp deletions) in ASXL3 using whole exome sequencing. All mutations are located in exons 11 and 12 that represent 84% of the entire ASXL3 protein-coding region (Figure 2). Functional studies were not performed in this study

Evidence for Triplosenstive Phenotype

NOTE:The loss of function score should be used to evaluate deletions, and the triplosensitivity score should be used to evaluated duplications. CNVs encompassing more than one gene must be evaluated in their totality (e.g. overall size, gain vs. loss, presence of other genes, etc). The rating of a single gene within the CNV should not necessarily be the only criteria by which one defines a clinical interpretation. Individual interpretations must take into account the phenotype described for the patient as well as issues of penetrance and expressivity of the disorder. ACMG has published guidelines for the characterization of postnatal CNVs, and these recommendations should be utilized (Genet Med (2011)13: 680-685). Exceptions to these interpretive correlations will occur, and clinical judgment should always be exercised.