Review for 10.1186/s12876-018-0835-6 (2018)

Reviewer ’s report  
 
Title:  Spectrum of genomic variations in Indian patients with progressive familial intrahepatic 
cholestasis  
 
Version: 0 Date: 14 Apr 2018 
 
Reviewer:  Jean Louis  Delaunay  
 
Reviewer’s report:  
 
Manuscript  Number B MGE -D-18-00168  
 
Sharma and coworkers performed the first genomic analysis of PFIC Indian patients. The authors 
analyzed by Sanger sequencing the coding exon and surrounding splice site regions of the genes 
involved in PFIC 1,2,3, ABCB4, ABCB11 and ATP8B1 f rom a cohort of 25 PFIC patients. They 
identified 9 variations in patients, 1 novel for ABCB11 and one for ATP8B1. It is really 
necessary to improve the manuscript notably data presentation in the different tables. The study 
is interested in all PFICs 1,2 and 3 but it is not clear in which type of PFIC are classified the 9 
patients genotyped with likely pathogenic or pathogenic variations.  
 
Overall, the manuscript is written in good, intelligible and concise English. There are questions, 
precisions and recom mendation to address.  
 
 
Regarding the manuscript  
 
The authors limit themselves to presenting the three main PFICs, 1,2,3 but to date there are other 
PFICs since a total of 6 genes can be associated: ATP8B1, ABCB11, ABCB4, TJP2, NR1H4 or 
Myo5b. The authors might mention that the study could be completed by sequencing the other 
three genes.  
 
Although the authors argue that it is expected that there will be variations identified in Indian 
PFIC patients that differ from those found in other populations, it shoul d be noted that the 
authors found in their study shared variations with other populations.  
 
 
Page 6, line 135  
 
The authors announce a ranking of patients according to the dosage of GGTs in order to orient 
towards PFIC3 or PFIC1 / 2. Where is the ranking of the different patients according to the type 
of PFIC in the manuscript?  
 
All patients underwent a biopsy, to help characterize the type of PFIC that reaches the patients, it 
would have been interesting to know several parameters in the study as the presence  of ductular 
proliferation on a histology of the liver. Can the authors bring this information to the study?  
page 7 Line 140,  "immunohistochemistry for B ... .were not possible". In order to discriminate 
the different PFICs since this immunohistohemistry  is not possible, is it possible to know the 
concentration of bile acids in the serum?  
 
Do the authors have this information in their possession and in this case add it to the study?  
 
page 7, line 143, the authors mention information about the family as I CP events in mothers as 
well as a three -generation pedigree that are not presented in the manuscript.  
 
 
Page 9 Results  
 
ABCB4 of subject 09 is classified in the variations of some significance, it is quite surprising 
that a mutation leading to the production  of a protein corresponding to 159/1279 AA is not at 
least considered as likely pathogenic. Authors should reconsider its ranking in Table 1  
 
 
Page 10, line 213  
 
Regarding Table 3, the authors do not mention the number of patients carrying these variations 
on the 25 PFICs studied.  
 
 
Page 11, line 228, line 242  
 
As mentioned in page 5, line 112, the variation .Gly197LeufsTer10 was already published ref 16 
and should not be considered as a novel variation in this work. Authors should correct it  the text 
of the manuscript and in the table 1.  
 
 
Although the data is correctly present in the manuscript, the presentation of the different tables 
would benefit from being modified:  
 
Table 2 is typically the type of table to be switched in supplementary materials since it goes into 
detail the various algorithms used to c onclude the deleterious impact of the variation on the 
protein presented in the in silico prediction column of Table 1  
 
Regarding the additional Table 1, the interest of carrying out the study on all patients remains 
limited, the authors also do not commen t on this table. It would have been interesting to compare 
the positive genotyped patients to see if these variations show a signature from a clinical or 
biochemical point of view.  
 
The additional table 2 presenting the clinical features of patients carryi ng pathogenic or likely 
pathogenic variations should absolutely be put as the first figure in the manuscript because it 
clearly presents the clinical picture of the patients carrying a pathogenic variations. Regarding 
the clinical data of the patients, are  there extrahepatic manifestations for the patients that would 
make it possible to characterize patients PFIC1 versus PFIC2?  
 
The authors must be able to answer all the requests of the reviewer for an acceptance  
 
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.  
 
No 
 
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 further 
assessment in your comments to the editors.  
 
Not relevant to this manuscript  
 
Quality of written English  
Please indicate the quality of language in the manuscr ipt: 
 
Acceptable  
 
Declaration of competing interests  
Please complete a declaration of competing interests, considering the following questions:  
 
1. Have you in the past five years received reimbursements, fees, funding, or salary from an 
organisation that may in any way gain or lose financially from the publication of this 
manuscript, either now or in the future?  
 
2. Do you hold any stocks or shares in an organisation that may in any way gain or lose 
financially fro m the publication of this manuscript, either now or in the future?  
 
3. Do you hold or are you currently applying for any patents relating to the content of the 
manuscript?  
 
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?  
 
5. Do you have any other financial competing interests?  
 
6. Do you have any non -financial competing interests in relation to this paper?  
 
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below. If your reply is yes to any, please give details below.  
 
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