Maternal and Parent-of-Origin Gene–Environment Effects on the Etiology of Orofacial Clefting
, Mohan R. Rakesh 1, Kelly M. Burkett 3, Debashree Ray 4,5, Peter A. Mossey 6, Borut Peterlin 7, Mohammad Faisal J. Khan 2, Amin Ravaei 2, Luca Autelitano 8, Maria C. Meazzini 8, Julian Little 1 and Marie-Hélène Roy-Gagnon 1,*
Round 1
Reviewer 1 Report
Comments and Suggestions for AuthorsGenetic issues affects an important segment of population around the world with various medical impact such as orofacial clefting and further with mental health impact too. Studies were run to check the effects on various fields such as the speak, the hear, appearance and cognition. Results were obtained suggesting that the maternal genetic and the parent-of-origin genetic have could have influence on OFCs. As already confirmed in decades, the literature has many reports on the benefits of the folic acid during early pregnancy. For mother using supplements with folic acid in pregnancy the risk of nonsyndromic CL/P is lower with 40% and the CPO with 12%. On the other side, the maternal smoking, either active or passive, during the first trimester, produce a positive response on OFC.
The current study is focused on the interaction of two environmental factors: maternal smoking and maternal use of supplements containing folic acid. Cases from the EUROCRAN and ITALCLEFT studies were analyzed (404 case-parent triads and 40 dyads from Europe).
The paper is well organized, easy to read, the materials and methods are described. This study implies invasive action on the subjects (q: "Both studies included collection of peripheral blood specimens or buccal cell samples from children and their parents."). Informed consent were obtained from the parents for their implications on the study and for involving the children in the study too. A mother was accepted in the study if she used supplement containing folic acid of at least 0.4mg/day or for at least one month during the periconceptional period. Other condition to include a mother on the study was represented by the positive smoker of at least one cigaretter a day status. At the end, the analysis included 1292 persons (404 triaes and 40 dyades). The study sample characteristics are presented. Half of triads were from Italy, around 10% from Western Europe and the remaining from Central/Eastern Europe. 39% of the offsping were female. The percentage of mothers that confirmed they smoked in the periconceptional period was of 22.3%. Around half of the mothers confirmed they used supplements containing folic acid during periconceptional period.
The study concluions are supported by the presented results. Interactions were found in/near genes LRRC7 (maternal gene-folate interaction), NCKAP5 (PoO-smoking interaction), IFT43 and GPATCH2L (PoO-folate interaction).
Author Response
Comment: The paper is well organized, easy to read, the materials and methods are described. This study implies invasive action on the subjects (q: "Both studies included collection of peripheral blood specimens or buccal cell samples from children and their parents."). Informed consent were obtained from the parents for their implications on the study and for involving the children in the study too. A mother was accepted in the study if she used supplement containing folic acid of at least 0.4mg/day or for at least one month during the periconceptional period. Other condition to include a mother on the study was represented by the positive smoker of at least one cigarette a day status. At the end, the analysis included 1292 persons (404 triads and 40 dyads). The study sample characteristics are presented. Half of triads were from Italy, around 10% from Western Europe and the remaining from Central/Eastern Europe. 39% of the offspring were female. The percentage of mothers that confirmed they smoked in the periconceptional period was of 22.3%. Around half of the mothers confirmed they used supplements containing folic acid during periconceptional period.
The study conclusions are supported by the presented results. Interactions were found in/near genes LRRC7 (maternal gene-folate interaction), NCKAP5 (PoO-smoking interaction), IFT43 and GPATCH2L (PoO-folate interaction).
Response: We thank the reviewer for this positive review.
Reviewer 2 Report
Comments and Suggestions for AuthorsDear Authors,
Good and interesting manuscript devoted to the 2nd most common anomaly in the world. However, I have some objections regarding the final part of the Discussion:
1) please, separate Conclusions (they are important regarding these 3 genes) and instead of the last paragraph in Discussion part add the future directions.
Also avoid please such sentences as: "... further investigation... will be clarified... " in the Conclusions. (Acutally, for instance, me, who is working in the field of clefts already for more than 25 years, expects more precise conclusions, even if they are not completely proved in comparison to empty well known truth that all has to be proved and proved multiple times!)
2) please, remove these 2 old references, do not fit neither for your group, nor for the manuscript.
Good luck, waiting for your next manuscript!
Author Response
Comment: Good and interesting manuscript devoted to the 2nd most common anomaly in the world. However, I have some objections regarding the final part of the Discussion: 1) please, separate Conclusions (they are important regarding these 3 genes) and instead of the last paragraph in Discussion part add the future directions.
Response: We thank the reviewer for the positive comment and helpful suggestions. As suggested by the Reviewer, we replaced the last paragraph of the Discussion by our conclusions and future directions (lines 313-317).
Comment: Also avoid please such sentences as: "... further investigation... will be clarified... " in the Conclusions. (Acutally, for instance, me, who is working in the field of clefts already for more than 25 years, expects more precise conclusions, even if they are not completely proved in comparison to empty well known truth that all has to be proved and proved multiple times!)
Response: We changed the language in the Conclusions, both in the Abstract (lines 40-43) and the last Discussion paragraph (lines 313-317).
Comment: 2) please, remove these 2 old references, do not fit neither for your group, nor for the manuscript.
Response: Thanks for your suggestions. We have removed the older references 17 and 18 from the manuscript according to your suggestion.
