Dear authors,

The study represents an extremely important area of research as it attempts to explore how recently identified de novo variants (associated with a broad spectrum of neurobehavioral and neurodevelopmental phenotypes) correspond to the neurocognitive phenotypes.

There are a few issues to be solved before any final recommendations on the acceptability of this work can be given.

Major issue

1. What is (could be) the course of cognition across the cognitive profile in White-Sutton syndrome and related POGZ mutations?

Rationale

In the study, you have assed neurocognitive phenotype of patients with POGZ pathogenic variants by collecting clinical and molecular data from 19 patients aged from three to 21 years. The cognitive abilities of the patients have been assessed either with psychometric tests or by means of a developmental scale taking into account the patient’s age and their capabilities during testing. The fact that the neuropsychological evaluations have been done to different age patients makes the interpretation of the results challenging.

A general understanding among psychologists and clinicians assessing patients with ID is that cognitive deficits develop during developmental years at individually varying rate regardless of the etiology. Furthermore, it has been shown that that the course of cognition varies depending on the syndrome (e.g. Sauna-aho et al. Mol Genet Genomic Med 2019). A 20-year follow-up of persons with Williams syndrome has shown that verbal functions both develop and deteriorate earlier than performance/nonverbal functions.

All this means that the developmental delay may be different at different age. Therefore, the final magnitude of the neurocognitive delay may not be possible to estimate in a reliable way until the person has reached an early adulthood, and even then there may be some domains that have not developed fully as eg in before mentioned Williams syndrome.

Taken these age-associated possible variabilities into account, the conclusions of the study “This study reveals that the cognitive phenotype of patients with POGZ pathogenic variants can range from learning disabilities to severe ID” are somewhat questionable.

Other issues

1. It is somewhat difficult to understand how the severity of ID was determined?
   In “Neuropsychological assessment” it is stated that “The five patients with learning difficulties (patient 1,2,3,9 and 19) obtained heterogeneous results that did not allow for the calculation of a TIQ (Total Intellectual Quotient) that could faithfully represent their overall cognitive profile.” However, in general, ID is determined according to IQ; IQ 50-60 represents mild ID, IQ 35-49 represents moderate ID, IQ 20-34 represents severe ID and IQ <19 represents profound ID. Could you clarify this?

2. Five patients out of 15 patients, who underwent brain MRI, were found to have different central nervous system malformations, which was stated to be similar to the proportion found by the others. Could there possibly be some additional or other pathologic variants but the ones related to POGZ behind these findings?

3. Could you specify further what do you mean by stating in the conclusions that “…children with learning disabilities could benefit from next generation sequencing techniques.”?

Dear Authors,

Thank you for your replies and revision of the MS.

It is now easier to understand how the level of ID has been determined. In this particular population, it might have been impossible to obtain estimates that would have been more accurate.

The major conclusion of the study that the cognitive phenotype of patients with 17 POGZ pathogenic variants range from learning disabilities to severe ID is not surprising taken the emerging holistic approach in which living organisms are more that sums of their parts. Instead, it is difficult to see without any obvious phenotype-genotype correlation that what would be the additional benefits of next generation sequencing as suggested in the abstract.