ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000015.9) (NC_000015.10)
  • Haploinsufficiency score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

Haploinsufficiency phenotype comments:

OTUD7A encodes a putative deubiquinating enzyme that localizes to dendritic spines and contributes to synaptic and dendritic signaling in neurons. This gene is contained within the 15q13.3 recurrent (BP4-BP5; CHRNA7 included) microdeletion region and has been recently proposed as a candidate gene for the 15q13.3 deletion syndrome phenotype. As yet, isolated (focal) OTUD7A deletions and loss-of-function mutations have not been described in clinical populations. Whether loss of OTUD7A contributes to the phenotypes associated with these deletions remains unknown. Additional relevant evidence is summarized below. PMID 29395074: Uddin et al (2018) presented a comprehensive human and mouse-model study in support of OTUD7A in neurodevelopmental disorders. Within this study, the authors reported an atypical (presumably non-focal) 15q13.3 deletion, "...that spanned BP4-BP5 including OTUD7A but not CHRNA7 (Fig S3B)." in a 5 year old female, previously unreported, with global developmental delay. Inheritance information was not provided. The authors argue other genes (including OTUD7A) may contribute to the 15q13.3 (BP4-BP5) deletion phenotype. Uddin et al also investigated sequence-level mutations in the 10 genes within the 15q13.3 (BP4-BP5) deletion region, focusing on de novo mutations, identified from whole genome sequencing of 84 ASD quad families and exome sequencing of 5,953 ASD trios. Amongst 8 total de novo mutations identified, three impacted OTUD7A: one exonic 9 bp non-frameshift deletion (N492_K494), one intronic indel 2 bp deletion, and one intronic SNV. The N492_K494 variant was identified in two non-twin brothers with ASD, however the apparent discrepancy for de novo qualification was not addressed. In addition, this deletion is known to be a rare population variant (SNP rs779533771). Furthermore, functional studies of a N492_K494 construct in vitro showed evidence for a dominant-negative effect and no evidence in support of a loss-of-function. Thus, none of these sequence-level variants were counted towards the haploinsufficiency score Uddin et al also studied the Df(h15q13)/+ heterozygous mouse, a model for the 15q13.3 (BP4-BP5) recurrent deletion in humans. Phenotypes included altered neuronal firing in the prefrontal cortex and dendritic spine defects. The authors argue that although CHRNA7 is a main candidate gene for the human phenotype, it is known that the mouse Chrna7 KO mouse is only mildly affected as compared to the Df(h15q13) heterozygous mouse, which includes loss of Otud7a. The authors showed that Otud7a re-introduction could rescue the dendritic defects in heterozygous Df(h15q13) mice. The researchers proposed that in humans, OTUD7A is an important contributor to the human BP4-BP5 deletion phenotype. PMID 8135719; McRae et al., 2017 (DDD): OTUD7A p.(R89*) variant, ExAC freq= .000008. Animal models: In addition to the study by Uddin et al (2018), additional evidence regarding the role of OTUD7A in the 15q13.3 (BP4-BP5) recurrent deletion phenotype from mouse models are summarized below. PMID 27459725: Forsingdal et al (2016) described the behavioral and physiological deficits in the Df(h15q13)-/- mouse, a model for the human 15q13.3 BP4-BP5 deletion syndrome region. Mouse phenotypes were compared between wt, +/- and -/- . Several behavioral phenotypes were noted in the +/- mice that worsened in the -/- mice. Single gene knockout mice Klf13, Trpmi and Chrna7 were comparatively mildly affected, suggesting that none of these genes alone could explain the +/- and -/- phenotypes. PMID 29395075: Yin et al. (2018) studied Otud7a KO mice and found that they exhibited abnormal body weight, delayed development, seizures, decreased dendritic spine production and behavioral abnormalities. Heterozygous KO mice had only a mild phenotype (reduced ultrasonic vocalization and acoustic startle deficit). Furthermore, the KO mice did not display cognitive or social deficits. The authors suggested that genetic background might play a role in this.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity