Diagnostic Tools for Autism Spectrum Disorders by Gender: Analysis of Current Status and Future Lines

Round 1

Reviewer 1 Report

• Please, introduce a reference to the difference between genetic forms of autism due to specific mutation of a gene and undefined forms of autism: is there a sex/gender bias difference?
• In the introduction you should mention that some forms of autism are related to X-linked genes like FMR1, MECP2, ARX, PCDH19. However, these mutations represent a small fraction of ASD cases, since more than 70 genes have been identified as involved in genetic autism. These data suggest that other locus on the X chromosome may play a role in the development of ASD. Add in the introduction a sentence relative to this problem.
• You should cite the fact that autism has a specific co-morbidity with other pathologies such as epilepsy in 40% of cases, psychiatric disorders, intellectual disabilities. Are these secondary aspects more prominent in females respects to males? If there is a major percentage of females in this case, it depends on the fact that male embryos with certain mutations die before birth or soon after this. Please, add and comment in your manuscript this issue.

• Paragraph 3 (from line 306) could be divided in four sub-paragraph, each titled with the relative theoretical approach (a) the approach of brain differentiation; (b) the theory of the extreme male brain; (c) the theory of sexual differentiation Empathy-Systematization, and (d) the approach based on the use of complementary evaluation questionnaires. In this way, this section would be easier to be read, according to me.

• Figure 1 is small and difficult to be read. You should simplify/render more immediate for a general reader interested in autism this scheme. The first rectangle contains a sentence difficult to be understood. It could be eliminated. Start directly from the bias in ASD diagnosis in males vs females (with an approximative percentage), then you have question 1: are tools to render diagnosis biased or are clinicians biased?.....the new perspective: admit that females can show ASD signs, even if most times not so explicit.

Question 2: non-biological factors determining ASD insurgence..In this case, four approaches are possible: the approach of brain differentiation; (b) the theory of the extreme male brain; (c) the theory of sexual differentiation Empathy-Systematization, and (d) the approach based on the use of complementary evaluation questionnaires.

Author Response

Thank you for your comments. We have made an exhaustive revision of the article introducing changes in the English expressions in order to improve the comprehension of the article.
Regarding the comment on the introduction we have introduced a reference to the differences between the different genetic forms of autism (syndromic autism) in males and females and their relationship with X chromosome.
Paragraph 3 (from line 306) the recommendation made by you has been introduced and the figure on the same line has also been modified.

Reviewer 2 Report

It is a well structured and organized review article covering major aspects of diagnostics tool and assessment of ASD. It is a crucial area of research requiring further attention and advancement.

Author Response

Thank you for your appreciation

Reviewer 3 Report

The present submission forms an interesting an well-informed  review of the topic.

The only aspect I would urge the authors to include in their discussion of future perspectives is the potential role for digital/technological tools. Electronic diagnostic tools that rely (in part) on trends in behavioural markers could be useful as they could address gender bias by explicit blinding.

Author Response

Thank you for your appreciation, we have incorporated a paragraph with the possibility that the development of electronic diagnostic tools with machine learning  may help in the future.

Reviewer 4 Report

I congratulate with the Authors of this work is promising a nice development about the topic of Autism Disorders.

Kind Regards.

Author Response

Thank you for your appreciation