Maternal Uniparental Isodisomy of Chromosome 6: A Novel Case of Teratoma and Autism Spectrum Disorder with a Diagnostic and Management Framework

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Thank you for inviting me to review this manuscript which describes a case of the rare UPD(6)mat of chromosome 6 and then offers a broader review. The maunscript is well written and easy to follow, and will be of interest to the readership of the journal. I have a few minor points for consideration:

1. I draw your attention to the detailed review of Jiang et al, Molecular Cytogenetics 17(1) which you cite in your Table. As this manuscript also reviews UPD(6)mat, you need to be clear as to  what new information yours brings. 

2. I just wanted to make certain that consent has been given for the use of the identifying photos?

 

3. Given that sacrococcygeal teratoma is rare, and is not so far identified as associated with any genetic abnormality, does it not seem likely that this is an incidental finding independent of the patient's UPD(6)mat? The argument for it being a phenotypic feature of this genetic disorder needs to be stronger. 

 

4. I also note that the ASD and other cognitive impairments that are described may be non-specific manifestations of intellectual disability. Has this patient had an IQ test? If so this should be included in the report, or at least mentioned. 

 

Author Response

We sincerely thank Reviewer 1 for taking the time to review our manuscript and for providing thoughtful and constructive feedback. We have carefully considered each point and revised the manuscript accordingly, as detailed below.

Comment 1:
I draw your attention to the detailed review of Jiang et al., Molecular Cytogenetics 17(1), which you cite in your Table. As this manuscript also reviews UPD(6)mat, you need to be clear as to what new information yours brings.

Response 1:
Thank you very much for this valuable comment. We have clarified that our report presents one additional molecularly confirmed case (the 24th to date), and is the first to describe a sacrococcygeal teratoma in this context. Furthermore, we introduce a structured diagnostic and management framework, suggest key clinical assessments, and discuss potential pathogenic mechanisms including imprinting errors, autosomal recessive variants, and mosaicism.

Comment 2:
I just wanted to make certain that consent has been given for the use of the identifying photos?

Response 2:
We confirm that written informed consent was obtained from the proband’s parents for study participation and for publication of clinical details, including identifying photographs. Inserted sentence (Materials and Methods, p. 3): “Informed consent was obtained from the proband’s parents for their participation in this study, including permission to publish clinical data and identifying photographs.”

Comment 3:
Given that sacrococcygeal teratoma is rare, and is not so far identified as associated with any genetic abnormality, does it not seem likely that this is an incidental finding independent of the patient's UPD(6)mat?

Response 3:
Thank you for highlighting this. We have revised the relevant section in the Discussion to state that the teratoma is most likely a sporadic finding. However, we also note that most cases of UPD(6)mat have been reported after 2006 and involve young patients with limited follow-up, which could lead to underreporting of late-onset features. We therefore briefly address the need for clinical vigilance. Updated text (Discussion, Section 4.3): “It remains unclear whether the teratoma observed in our patient is related to UPD(6)mat or represents a sporadic finding. The vast majority of sacrococcygeal teratomas are sporadic, with a marked female predominance (4:1), and a family history of twin gestation reported in approximately 10% of cases.”

Comment 4:
ASD and cognitive impairments may be non-specific. Has this patient had an IQ test?

Response 4:
We appreciate this important point. The patient underwent an in-depth neuropsychological evaluation by a licensed clinical psychologist. While a formal IQ score was not obtained, the assessment confirmed global developmental delay, particularly affecting communication and motor domains.

Reviewer 2 Report

Comments and Suggestions for Authors

Authors missed major parts of available UPD(6) cases - maternal and paternal derived ones - they need to check on https://cs-tl.de/DB/CA/UPD/0-Start.html and will find 195 cases with UPD(6)

 

Also there are more cases with UPD and tumor development in the literature - it is not recomended to try to provide a copmplete review here. Also, UPD in tumors is not driven by imprinting,  but tumor supressorgenes. 

Besides, imprinting seems to play no role in chr. 6. 

in https://pmc.ncbi.nlm.nih.gov/articles/PMC6848996/ there are almost 10 cases of normal population describe which have UPD(6).

 

In the reported case the clinical signs are most likely due to a monosomy 6 mosaic in placenta and most likly a similar non-detectable mosaic in  body tissue of the patient. Search for a activated causative recessive gene failed here and there are many UPD cases in which a causative gene was never found. All must be attrbited to cryptic monsomy and/or trisomy mosaics here. 

 

 

Comments on the Quality of English Language

Already the title has a wrong expression: "with a primer on"

native speaker help is needed here 

Author Response

We sincerely thank Reviewer 2 for taking the time to review our manuscript and for providing thoughtful and constructive feedback. We have carefully considered each point and revised the manuscript accordingly, as outlined below.

Comment 1:
Authors missed major parts of available UPD(6) cases – maternal and paternal derived ones – they need to check on https://cs-tl.de/DB/CA/UPD/0-Start.html and will find 195 cases with UPD(6).

Response 1:
Thank you for this helpful comment. While 195 cases of UPD(6) are listed in the database, we chose to focus specifically on maternal UPD(6), which is significantly rarer. Including our case, we identified 24 confirmed UPD(6)mat cases with sufficient clinical and genetic data. We revised our literature review accordingly and described the methodology in the updated Methods section. Update (Section 4.1 – Literature Review): “A structured literature search was performed on March 23, 2025, in PubMed, Embase, and Scopus… After removing duplicates, 70 unique articles remained, and 19 met inclusion criteria: confirmed UPD(6)mat and available clinical data. We excluded studies on UPD(6)pat, unconfirmed cases, animal studies, and reviews lacking patient-level detail.”

Comment 2:
There are more cases with UPD and tumor development in the literature. It is not recommended to try to provide a complete review here. Also, UPD in tumors is not driven by imprinting, but by tumor suppressor genes.

Response 2:
We agree and have removed the extended tumor table. Instead, we now provide a brief and balanced discussion, emphasizing that UPD in tumors is typically somatic and driven by loss of heterozygosity involving tumor suppressor genes, not imprinting. Update (Section 4.3 – Neoplasms in Uniparental Disomy): “It remains unclear whether the teratoma observed in our patient is related to UPD(6)mat or represents a sporadic finding. The vast majority of sacrococcygeal teratomas are sporadic, with a marked female predominance (4:1), and a family history of twin gestation reported in approximately 10% of cases.”

Comment 3:
Besides, imprinting seems to play no role in chr. 6.

Response 3:
We acknowledge that imprinting on chromosome 6 remains debated. In the revised discussion, we outline both imprinting disturbances and cryptic trisomy mosaicism as plausible mechanisms.

Comment 4:
In https://pmc.ncbi.nlm.nih.gov/articles/PMC6848996/ there are almost 10 cases of normal population described which have UPD(6).

Response 4:
We reviewed this study and now acknowledge the presence of UPD(6) in asymptomatic individuals from large-scale datasets. Notably, the same study found that UPD(6) was associated with lower birth weight and shorter stature—findings consistent with our observations.

Comment 5:
In the reported case, the clinical signs are most likely due to a monosomy 6 mosaic in placenta and most likely a similar non-detectable mosaic in body tissue. Search for a causative gene failed. This is likely due to cryptic monosomy and/or trisomy mosaics.

Response 5:
We agree and have added this explanation to the discussion. We highlight that chromosomal rescue and cryptic mosaicism remain strong candidate mechanisms in the absence of detectable pathogenic variants. Update (Conclusions): “The most plausible explanations include disturbances in genomic imprinting, as seen in UPD(6)pat, and cryptic trisomy mosaicism, particularly in heterodisomic cases where tri- somy rescue may have occurred.”

Comment 6:
Already the title has a wrong expression: “with a primer on”

Response 6:
Thank you for this remark. We revised the title for clarity and precision. Updated title: “Maternal Uniparental Isodisomy of Chromosome 6: A Novel Case with Teratoma and Autism Spectrum Disorder and a Framework for Diagnosis and Management.”

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

authors worked in paper and comments

 

all fine from my side now

Comments on the Quality of English Language

ok