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
25342064 Hunt et al. 2014 report four unrelated individuals with de novo variants in PURA identified via trio-based whole exome sequencing (WES). The authors note that phenotype amongst the 4 individuals was "variable, but moderate to severe neurodevelopmental delay and learning disability [were] common to all. Neonatal hypotonia, early feeding difficulties and seizures, or ?seizure-like? movements, were also common." The authors report that no other "significant" variations were detected on WES or on cytogenomic microarray for these individuals. Two of the variants were frameshifts, one was a missense, and one was an in-frame deletion. The authors note that, since PURA only has a single exon, the gene products of the frameshift variants would not be expected to undergo nonsense-mediated decay. They recognize that these variants could have " dominant negative or gain-of-function effects or, alternatively, result in functional haploinsufficiency." The authors postulate that, since the other two variants are within highly conserved regions of sequence, they are likely to have functional consequences. No functional studies were performed. Additional information is needed to clarify the mechanism by which variants in PURA may contribute to this phenotype. The authors do note that PURA is within the previously reported 5q31.3 microdeletion phenotype region. The phenotype reported for individuals with deletions in this region does overlap with the features reported in these patients (hypotonia, feeding difficulty and developmental delay), though these findings are relatively nonspecific. The authors suggest that PURA contributes to but is not the sole cause of the 5q31.3 microdeletion phenotype.
25439098 Lalani et al. (2014) describe 11 individuals with clinical features of 5q31.3 microdeletion syndrome (including significant hypotonia, respiratory insufficiency, feeding difficulties, and significant developmental delay) and de novo mutations in PURA amongst 2908 consecutive subjects referred for clinical exome sequencing through Baylor's Whole Genome Laboratory from October 2011 - April 2014. The authors report that "Of the identified PURA mutations, four were truncating (three nonsense and one frameshift), five were missense, and two were in-frame deletions...None of these mutations were detected in 1000 Genomes (release 20110521), dbSNP134, the NHLBI Exome Sequencing Project Exome Variant Server, or the database of Atherosclerosis Risk in Communities (exome data of ~6,000 subjects). No additional contributing mutations in other genes were identified in the 11 individuals with de novo PURA variants." The authors also note that "the crystal structure of the protein reveals that the functionality of Pur-a relies on the three conserved PUR motifs...Interestingly, given that this is a single-exon gene and thus not likely subject to nonsense-mediated decay, all truncating mutations found in our series will result in loss or partial loss of PUR motif(s)."
27148565 Tanaka et al. (2014) identified 6 unrelated children with de novo variants in the PURA gene by whole exome sequencing. The common phenotype among all six patients are hypotonia and developmental delay. None of the variants were seen in dbSNP, 1000 Genomes, Exome Aggregation consortium or Exome Variant Server. All six mutations (2 truncating mutations both frame shift mutations , 2 missense, and 2 in-frame deletion mutations) were seen in highly conserved regions and all, except for Patient 3, were predicted to be deleterious by SIFT, CADD, and Mutation Taster (patient 3 predicted to be deleterious only by CADD and Mutation Taster). This report expands the number and location of mutations in PURA and the associated phenotype.

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.