PF19: Genetics Question 3

For complex pancreatic disease GENETIC VARIANT DESCRIPTIONS, what descriptive information shall be included in the initial publication and subsequent reports?

Chairs: Lu Chen PhD,Pramod Garg MD and TBA

Delegates: Brandon Blobner PhD, Jia-Min Chen, John Neoptolemos MD, Eszter Hegyi MD PhD, Balázs Németh MD PhD and TBA (email request to Dr. Whitcomb or Dr. Sahin-Toth)

Considerations: This should likely include accurate MAF information for the relevant comparison populations, detailed contextual information of the comparison groups, effect prediction methods, other? Initial publication should contain replication cohort. Need consensus what other genes should be always looked at to provide genetic context. New problem: how to utilize and report exome or genome Seq data?

11 Replies to “PF19: Genetics Question 3”

  1. Regarding the information included in the descriptions of pancreatic disease variants, I think that the descriptions of the variants should include chromosome and position, the reference genome build, the rs number, predictive measures of deleteriousness (SIFT and PolyPhen), the MAF and the ancestry of the population in which the variant was detected as well as MAF in other ancestry groups if possible, and any prior associations that may exist for each variant.

  2. Regarding the variants description, I think it is also important that :
    1. The names of the variants are reported according to HGVS (Human Genome Variation Society) recommendations ( and in this respect the used version of HGVS recommendation should be given (e.g. HGVS 2.00 or 15.11). The variants should be named on c.DNA and protein level. The chromosomal position should be rather given for NGS variants.

    2. The crucial point is to provide the reference sequence used (according to which the variants was named. Of note is that only public files from NCBI or EBI are accepted as reference sequence files.

    3. MAF should be provided for selected variants of interests as found in local databases (with samples of the same ethnical origin, if available), and genomic databases such as dbSNP, ExaC or gnomAD, taking into account ancestry of the population.

    3. Since CP may be associated with complex genotypes , the genetic status of major CP genes (PRSS1, CPA1, SPINK1, CTRC, CFTR) in investigated cohort should be provided.
    Regarding the NGS data
    4. Of note is that detection of PRSS1 mutations by NGS is not recommended since the gene has high homology to other genes/pseudogenes from trypsinogen family and NGS analysis may lead to false positive results.

    5. The NGS data should be supplied with the BED file where the chromosomal input regions are specified by chromosome number, start position and end position. This is very important in the whole exome and retargeted sequencing methods since there is a number of different kits to prepare the DNA library and the actual chromosomal input regions may differ between them.

    1. Re: What other genes should be always looked at to provide genetic context – we should define not only the genes but the method as well (e.g. sequencing of all exons in all major CP genes as also recommended in the pediatric guideline PMID: 29398347).

  3. Our groups suggested the following:

    Reporting: RSID, gene:location, Reference build number, MAF in affected vs population, number of subjects with GT call, zygosity.

  4. I have a couple of comments.

    It may be obvious but genetic testing for clinical management must only be undertaken in an accredited genetics lab (or I missed this).

    Also again this seems obvious but do we need to know the family history, and where possible the genetic findings in affected adult members?

    This applies in some way or another to all of the other questions but I have not seen this expressly stated (or I missed it).

    1. Pramod, your comment on replication is a little confusing. Do you mean to say that any report of genetic variants associated with pancreatitis should include replication from an additional independent cohort? This, of course, is now standard in the reporting of genetic associations via publication. However, the replication cohort does not have to be from a publicly available database.

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