Brain malformations involving the corpus callosum are common in children with developmental disabilities. We identified DCC mutations in four families and five sporadic individuals with isolated agenesis of the corpus callosum (ACC) without intellectual disability. DCC mutations result in variable dominant phenotypes with decreased penetrance, including mirror movements and ACC associated with a favorable developmental prognosis. Possible phenotypic modifiers include the type and location of mutation and the sex of the individual.

Re: A neuropsychological profile for agenesis of the corpus callosum? Cognitive, academic, executive, social and behavioral functioning in school-age children JINS#-17- RR-108Thank you for accepting our manuscript for publication with minor revisions.We would like to thank again the reviewers for their positive and constructive comments.Below we provide responses to each reviewer comment. The associated amendments in the manuscript are highlighted in red (and the amendments related to the previous revisions are highlighted in yellow). Best wishes, Dr Vanessa Siffredi and Dr Megan Spencer-Smith Reviewer 1Comment: The authors have been very responsive to feedback provided by the Reviewers and Action Editor. I have no further suggestions for revision.Response: Thank you. Reviewer 2Comment: You have been very diligent in responding to the questions I raised in my earlier review-thank you! Response: Thank you.Comment: My only lingering concern is whether this report will be really useful, and to whom. The heterogeneity of callosal agenesis both behaviorally and genetically makes it difficult to use the data with reference to particular individuals, although suppose the study can at least indicate the likely range of presentation. You suggest that heterogeneity is a positive feature, although even the heterogeneity is limited given the source of the data. Even so, this study is perhaps a useful contrast with the Quebec studies, where there was relative homogeneity, especially genetically.Response: This report provides crucial information for clinicians (neonatologists, neurologists, and neuropsychologists) Comment: From my perspective, the most useful observation was the even distribution of handedness, ignored in the first version and skipped over here. There is quite a lot of evidence that handedness is random in the absence of any congenital bias, and the data now seem to suggest that it is indeed random among those with agenesis of the corpus callosum. Could this mean that handedness itself depends on normal development of the corpus callosum? To me at least, this is something that does need further comment. (Raymond, Pontier, Dufour, Moller, 1996) 56% (e.g., Lábadi & Beke, 2017;Sauerwein & Lassonde, 1994;Chiarello, 1980) Response: In the general population, the percentage of left-handedness is around 10 to 13%

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The corpus callosum is the largest white matter pathway in the brain connecting the two hemispheres. In the context of developmental absence (agenesis) of the corpus callosum (AgCC), a proposed candidate for neuroplastic response is strengthening of intrahemispheric pathways. To test this hypothesis, we assessed structural and functional connectivity in a uniquely large cohort of children with AgCC (n = 20) compared with typically developing controls (TDC, n = 29), and then examined associations with neurobehavioral outcomes using a multivariate data-driven approach (partial least squares correlation, PLSC). For structural connectivity, children with AgCC showed a significant increase in intrahemispheric connectivity in addition to a significant decrease in interhemispheric connectivity compared with TDC, in line with the aforementioned hypothesis. In contrast, for functional connectivity, children with AgCC and TDC showed a similar pattern of intrahemispheric and interhemispheric connectivity. In conclusion, we observed structural strengthening of intrahemispheric pathways in children born without corpus callosum, which seems to allow for functional connectivity comparable to a typically developing brain, and were relevant to explain neurobehavioral outcomes in this population. This neuroplasticity might be relevant to other disorders of axonal guidance, and developmental disorders in which corpus callosum alteration is observed.

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