Review for 10.1186/s12876-016-0424-5 (2016)

Reviewer ’s report  
 
Title: Novel exonic mutation inducing aberrant splicing in the IL 10RA gene and resulting in 
infantile -onset inflammatory bowel disease: a case report  
 
Version: 0 Date: 02 Nov 2015  
 
Reviewer: Abdul  Elkadri  
 
Reviewer's report:  
 
The authors describe a Japanese boy with early onset inflammatory bowel disease presenting 
with an odd presentation of ITP and JMML along with the known phenoty pe of IL10 related 
disorders. This is the first publication in people of Japanese descent of an IL10 related mutation. 
The manuscript describes the phenotype of the patient in some basic detail and describes the 
mutation and it's splicing effects. Function al data is provided in the form of STAT3 
phosphorylation, an accepted basic functional assay in patients with IL10 related mutations.  
The manuscript reads quite well, and basically I only have one editing issue on Page 4 line 59 
which is missing the word "to": "…in order to enable…".  
 
There are some areas where the manuscript can benefit from some minor expansion:  
- The first is that there is only a brief mention of the frequency of the variation (page 11, line 
185: "In our patient, a relatively rare..." . From my searching, this variation is not found 
within at least 3 public databases (1000 Genomes, ExAC, or the NHLBI Variant Exome 
server). As there is no consanguinity, it's a bit odd, though definitely not impossible, that the 
rare variant found itself in this one family. If there is data about how rare or how frequent 
this variant is within the Japanese population through internal databases or data collected 
elsewhere, it would definitely help the manuscript.  
- The second is that there is a great deal of work done on sequencing each of the PCR 
products, and the different PCR product findings are quite interesting. I would have expected 
a more definitive splicing alteration. Here, we see at least three different  PCR products with 
different splicing. From what I read in the manuscript, I don't believe there is an explanation 
as to why this is. I will state that I'm ultimately reassured as there is proper and definitive 
functional evidence in the form of STAT3 phos phorylation. Do the authors have any ideas as 
to why these multiple PCR products are found?  
- The third: Using a database such as dbscSNV, a database which gives prediction scores for 
variants within known splice sites, would give further evidence that t he mutation is predicted 
to cause effect, rather than just mentioning that the variant is at the edge of a exon. (Jian X, 
Boerwinkle E and Liu X. In silico prediction of splice -altering single nucleotide variants in 
the human genome. Nucleic Acids Research  Advance Access published November 21, 
2014.) Using this database, the mutation is predicted to cause a splice site variation with a 
Ada score of 0.999957, a very significant score by this algorithm.  
- Finally: The novelty of this manuscript I believe al so comes from the atypical phenotypic 
findings in this patient (ITP and JMML, two phenotypes not yet seen or at least described in 
IL10 disorder related patients). As targeted sequencing was performed for IL10RA and 
IL10RB only, we can only comment on thes e genes and the other genes tested (PTPN11, 
NRAS, KRAS, and CBL). I understand that it may be beyond the scope of this manuscript at 
this time, but seeing next generation sequencing (Whole Genome or Whole Exome 
Sequencing) would have been more reassuring i n trying to connect the atypical phenotype to 
IL10RA. The method of targeted sequencing due to the phenotypic findings used by the 
authors is proper, but I can't help but wonder if there is actually some relation between the 
parents due to the fact that a rare uncharacterized mutation was found in both. Could there 
have been other mutations in other genes as well which could have caused the other 
phenotypes? Some discussion to this point would help introduce the fact that this phenotype 
may be related to IL 10RA, but that it may also be due to some other uncharacterized 
mutation which requires further analysis. I will say, the authors have stated that these 
mutations MIGHT be involved in hematological disorders during infancy, and I believe the 
conclusion tha t this patient had an IL10RA defect. I think the manuscript will benefit from 
some expansion within the discussion to raise the possibility that there may be another gene 
involved here as the remainder of this child's genes have not been tested.  
Otherwise , I will congratulate the authors on a well written manuscript!  
Are the methods appropriate and well described?  
If not, please specify what  is required in your comments to the authors.  
 
Yes 
 
Does the work include the necessary controls?  
If not, please specify which controls are required in your comments to the authors.  
 
Yes 
 
Are the conclusions drawn adequately supported by the data shown?  
If not,  please explain in your comments to the authors.  
 
Yes 
 
Are you able to assess any statistics in the manuscript or would you recommend an  
additional statistical review?  
If an additional statistical review is recommended, please specify what aspects require fur ther 
assessment in your comments to the editors.  
 
I am able to assess the statistics  
 
Quality of written English  
Please indicate the quality of language in the manuscript:  
 
Acceptable  
 
Declaration of competing interests  
Please complete a declaration of competi ng interests, considering the following questions:  
 
1. Have you in the past five years received reimbursements, fees, funding, or salary from an 
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3. Do you hold or are you currently appl ying for any patents relating to  the content of the 
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4. Have you received reimbursements, fees, funding, or salary from an organization that 
holds or has applied for patents relating to the content of the manuscript?  
 
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