Abstract

Crisponi/cold-induced sweating syndrome (CS/CISS) is a rare autosomal recessive disorder characterized by a complex phenotype (hyperthermia and feeding difficulties in the neonatal period, followed by scoliosis and paradoxical sweating induced by cold since early childhood) and a high neonatal lethality. CS/CISS is a genetically heterogeneous disorder caused by mutations in CRLF1 (CS/CISS1), CLCF1 (CS/CISS2) and KLHL7 (CS/CISS-like). Here, a whole exome sequencing approach in individuals with CS/CISS-like phenotype with unknown molecular defect revealed unpredicted alternative diagnoses. This approach identified putative pathogenic variations in NALCN, MAGEL2 and SCN2A. They were already found implicated in the pathogenesis of other syndromes, respectively the congenital contractures of the limbs and face, hypotonia, and developmental delay syndrome, the Schaaf-Yang syndrome, and the early infantile epileptic encephalopathy-11 syndrome. These results suggest a high neonatal phenotypic overlap among these disorders and will be very helpful for clinicians. Genetic analysis of these genes should be considered for those cases with a suspected CS/CISS during neonatal period who were tested as mutation negative in the known CS/CISS genes, because an expedited and corrected diagnosis can improve patient management and can provide a specific clinical follow-up.


Authors

Angius, Andrea;  Uva, Paolo;  Oppo, Manuela;  Buers, Insa;  Persico, Ivana;  Onano, Stefano;  Cuccuru, Gianmauro;  Van Allen, Margot I.;  Hulait, Gurdip;  Aubertin, Gudrun;  Muntoni, Francesco;  Fry, Andrew E.;  Anneren, Goeran;  Stattin, Eva-Lena;  Palomares-Bralo, Maria;  Santos-Simarro, Fernando;  Cucca, Francesco;  Crisponi, Giangiorgio;  Rutsch, Frank;  Crisponi, Laura

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  • pre-publication peer review (FINAL ROUND)
    Decision Letter
    2019/03/08

    Dear Dr. Crisponi:

    I am very pleased to inform you that your manuscript entitled 'Exome sequencing in Crisponi/CISS-like individuals reveals unpredicted alternative diagnoses.' (CGE-01053-2018.R1), has been received, accepted, and will be forwarded for publication in Clinical Genetics.

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    Decision letter by
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    Reviewer report
    2019/03/08

    The authors properly answered to all comments/criticisms.

    Reviewed by
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    Author Response
    2019/02/20

    Monserrato, February 15th, 2019

    Dear Editor,

    Please find enclosed our manuscript entitled “Exome sequencing in Crisponi/CISS-like individuals reveals unpredicted alternative diagnoses”, revised accordingly to the reviewers’ comments.

    Reviewer: 1

    Comments to the Author

    The manuscript entitled « Exome sequencing in Crisponi/CISS-like individuals reveals unpredicted alternative diagnoses » by Angius et al. deals with five patients with a clinical diagnosis of Crisponi syndrome who do not have variants in the genes previously associated with the condition. The authors found by WES two variants in NALCN, two in MAGEL2 and one in SCN2A. This work is valuable for clinical geneticists. However, the manuscript could be improved.

    Major points:

    The manuscript should be structured differently. Because short reports do not leave room for long descriptions of patients, they were put, along with part of the Methods, in the supporting information section, which is valuable. Patients and the methods for patients selection are briefly described in a “Case presentation” section which could be “Methods: case presentation” (completed by the Methods in Supporting information). There should be a Results section in the main text for the presentation of variants found in patients and to give support for their pathogenicity. Then, the phenotypes would be logically discussed in the Discussion section.

    Following reviewer’s comment, we modified “Case presentation” section with “Methods: case presentations”. Additionally we added a “Molecular results” section where we moved the part regarding presentation of variants found by WES from the Discussion. We also added a Table 2 providing the ACMG criteria satisfying the pathogenic nature of the identified variants in NALCN, MAGEL2 and SCN2A. Considering the limitation in the Short Report length, we were not able to put these details into the “Molecular results” section.

    In the Discussion section, the authors could discuss more thoroughly the phenotype of patient CS_239 who has a suppression burst pattern of EEG which is typically observed in Ohtahara syndrome.

    Unfortunately the Short Report format could be no more than 2500 words in length, so we were not able to address this point in the Discussion section. We added it in the Table 1 and we introduced the following general sentence in the Discussion: “An accurate revaluation of the clinical phenotype of each case reported so far, based on what found by WES, helped us to reassess it within the previous unpredicted diagnosis.” We left the clinical details of each case in the Supporting information.

    The authors should consider the authors guideline mentioning that “For WES-based studies a table must be provided as supplementary material (for review only) listing the variants found after the most obvious filtering steps (segregation, pathogenicity, frequency, etc)”.

    We added supplementary tables 1-3 providing summary of the WES data output (coverage, depth) and a list of the other functionally/clinically relevant variants compatible with AD, AR, X-linked transmission) for individual trios.

    Minor point:

    p.15 l. 32: “hyperthermia of profuse sweating » ⇒ or Done.

    Reviewer: 2

    Comments to the Author

    Angius, Uva and colleagues report on a genomic scan performed on five pediatric patients (3 m – 8 y) with a condition suggestive of Crisponi syndrome/cold-induced sweating syndrome (CS/CISS) but negative for mutations in the CRLF1 and CLCF1 genes. A trio-based WES analysis was performed on these subjects to identify novel CS/CISS genes, based on the consideration that approximately 40% of cases with clinical diagnosis of CS/CISS do not carry mutations in CRLF1 and CLCF1. Unexpectedly, disease-causing mutations in NALCN, MAGEL2 and SCN2A (underlying CLIFAHDD, SHFYNG and EIEE11 syndromes, respectively) were identified in these subjects. Based on these findings, the authors discuss the clinical overlap among these disorders, particularly during infancy.

    The report has clinical relevance, but requires revision to provide data that can be useful for clinicians managing patients affected by these disorders.

    Major issues:

    (1) A major message of this report concerns the clinical overlap between CS/CISS and CLIFAHDD, SHFYNG and EIEE11 syndromes, in particular during infancy. The authors should revise Table 1 to provide an overview of the features characterizing CS/CISS, and CLIFAHDD, SHFYNG and EIEE11 syndromes in the relevant time frame. This picture will allow to more clearly assess similarities and differences among disorders;

    Following reviewer’s comment we tried to details features characterizing CS/CISS, and CLIFAHDD, SHFYNG and EIEE11 syndromes in order to better assess similarities and differences among disorders. Table 1 has been revised accordingly.

    (2) The authors should include a “Result” section briefly reporting on the results of the WES analysis. They should provide the ACMG criteria satisfying the pathogenic nature of the identified variants in NALCN, MAGEL2 and SCN2A;

    Following reviewer’s comment, we added a “Molecular results” section where we moved the part regarding presentation of variants found by WES from the Discussion. We also added a Table 2 providing the ACMG criteria satisfying the pathogenic nature of the identified variants in NALCN, MAGEL2 and SCN2A. Considering the limitation in the Short Report length, we were not able to put these details into the “Molecular results” section.

    (3) The authors should also provide a summary of the WES data output (coverage, depth, and list of the other functionally/clinically relevant variants compatible with AD, AR, X-linked transmission) for individual trios;

    We added Supplementary table 1 providing summary of the WES data output (coverage, depth, number and type of variants observed) and Supplementary tables 2 and 3 (for review only) containing a list of the other functionally/clinically relevant variants compatible with AD, AR, X-linked transmission) for individual trios.

    (4) Based on their findings, the authors should discuss the usefulness of the current diagnostic criteria used for CS/CISS diagnosis in the neonatal period;

    (5) Emphasize the relevance of the data in terms of counseling;

    To address comments (4) and (5) we added the following sentences to the Conclusions section: “Based on the considerable phenotypic overlap between CS/CISS and other syndromes described in this article, the clinical geneticist should employ the current clinical diagnostic criteria for CS/CISS with caution, especially in the neonatal period. Adequate counseling should only be possible after the diagnosis has been confirmed by molecular genetic testing”.

    (6) To this reviewer it is not clear the utility of reporting on the functional role of MAGEL2 and its ubiquitin ligase complex. The para does not provide any significant insight and should be removed. The authors should focus on the clinical implications of their findings.

    We agree with the reviewer and we eliminated the paragraph regarding such information.

    In the text you can find the amendments made to meet referees' concerns in the form of 'Track Changes'.

    We look forward to hearing about the disposition of the manuscript. Sincerely,

    Dr. Laura Crisponi

    Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Cagliari, Italy

    Prof. Frank Rutsch

    Dept. of General Pediatrics, Münster University Children's Hospital, Münster, Germany



    Cite this author response
  • pre-publication peer review (ROUND 1)
    Decision Letter
    2019/01/26

    Dear Dr. Crisponi:

    Thank you for submitting your manuscript entitled 'Exome sequencing in Crisponi/CISS-like individuals reveals unpredicted alternative diagnoses. '. It has now been carefully reviewed.

    The reviewers are supportive but they have both suggested Major revisions. For details, please see the commentary below.

    In keeping with the policy of rapid publication, revised manuscripts should be re-submitted within 25 days of the date on this letter. Manuscripts received after this date may be treated as new submissions. We cannot guarantee acceptance after re-submission, and your revised manuscript will be subject to further review.

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    Prof. Reiner A. Veitia, Ph.D. Acad. Europaea, French National Acad. Med. Editor-In-Chief, Clinical Genetics

    Reviewer: 1

    Comments to the Author The manuscript entitled « Exome sequencing in Crisponi/CISS-like individuals reveals unpredicted alternative diagnoses » by Angius et al. deals with five patients with a clinical diagnosis of Crisponi syndrome who do not have variants in the genes previously associated with the condition. The authors found by WES two variants in NALCN, two in MAGEL2 and one in SCN2A. This work is valuable for clinical geneticists. However, the manuscript could be improved.

    Major points: The manuscript should be structured differently. Because short reports do not leave room for long descriptions of patients, they were put, along with part of the Methods, in the supporting information section, which is valuable. Patients and the methods for patients selection are briefly described in a “Case presentation” section which could be “Methods: case presentation” (completed by the Methods in Supporting information). There should be a Results section in the main text for the presentation of variants found in patients and to give support for their pathogenicity. Then, the phenotypes would be logically discussed in the Discussion section.

    In the Discussion section, the authors could discuss more thoroughly the phenotype of patient CS_239 who has a suppression burst pattern of EEG which is typically observed in Ohtahara syndrome.

    The authors should consider the authors guideline mentioning that “For WES-based studies a table must be provided as supplementary material (for review only) listing the variants found after the most obvious filtering steps (segregation, pathogenicity, frequency, etc)”.

    Minor point: p.15 l. 32: “hyperthermia of profuse sweating » ⇒ or

    Reviewer: 2

    Comments to the Author Angius, Uva and colleagues report on a genomic scan performed on five pediatric patients (3 m – 8 y) with a condition suggestive of Crisponi syndrome/cold-induced sweating syndrome (CS/CISS) but negative for mutations in the CRLF1 and CLCF1 genes. A trio-based WES analysis was performed on these subjects to identify novel CS/CISS genes, based on the consideration that approximately 40% of cases with clinical diagnosis of CS/CISS do not carry mutations in CRLF1 and CLCF1. Unexpectedly, disease-causing mutations in NALCN, MAGEL2 and SCN2A (underlying CLIFAHDD, SHFYNG and EIEE11 syndromes, respectively) were identified in these subjects. Based on these findings, the authors discuss the clinical overlap among these disorders, particularly during infancy. The report has clinical relevance, but requires revision to provide data that can be useful for clinicians managing patients affected by these disorders.

    Major issues: (1) A major message of this report concerns the clinical overlap between CS/CISS and CLIFAHDD, SHFYNG and EIEE11 syndromes, in particular during infancy. The authors should revise Table 1 to provide an overview of the features characterizing CS/CISS, and CLIFAHDD, SHFYNG and EIEE11 syndromes in the relevant time frame. This picture will allow to more clearly assess similarities and differences among disorders; (2) The authors should include a “Result” section briefly reporting on the results of the WES analysis. They should provide the ACMG criteria satisfying the pathogenic nature of the identified variants in NALCN, MAGEL2 and SCN2A; (3) The authors should also provide a summary of the WES data output (coverage, depth, and list of the other functionally/clinically relevant variants compatible with AD, AR, X-linked transmission) for individual trios; (4) Based on their findings, the authors should discuss the usefulness of the current diagnostic criteria used for CS/CISS diagnosis in the neonatal period; (5) Emphasize the relevance of the data in terms of counseling; (6) To this reviewer it is not clear the utility of reporting on the functional role of MAGEL2 and its ubiquitin ligase complex. The para does not provide any significant insight and should be removed. The authors should focus on the clinical implications of their findings.

    Decision letter by
    Cite this decision letter
    Reviewer report
    2019/01/26

    Angius, Uva and colleagues report on a genomic scan performed on five pediatric patients (3 m – 8 y) with a condition suggestive of Crisponi syndrome/cold-induced sweating syndrome (CS/CISS) but negative for mutations in the CRLF1 and CLCF1 genes. A trio-based WES analysis was performed on these subjects to identify novel CS/CISS genes, based on the consideration that approximately 40% of cases with clinical diagnosis of CS/CISS do not carry mutations in CRLF1 and CLCF1.

    Unexpectedly, disease-causing mutations in NALCN, MAGEL2 and SCN2A (underlying CLIFAHDD, SHFYNG and EIEE11 syndromes, respectively) were identified in these subjects. Based on these findings, the authors discuss the clinical overlap among these disorders, particularly during infancy.

    The report has clinical relevance, but requires revision to provide data that can be useful for clinicians managing patients affected by these disorders.

    Major issues:

    (1) A major message of this report concerns the clinical overlap between CS/CISS and CLIFAHDD, SHFYNG and EIEE11 syndromes, in particular during infancy. The authors should revise Table 1 to provide an overview of the features characterizing CS/CISS, and CLIFAHDD, SHFYNG and EIEE11 syndromes in the relevant time frame. This picture will allow to more clearly assess similarities and differences among disorders;

    (2) The authors should include a “Result” section briefly reporting on the results of the WES analysis. They should provide the ACMG criteria satisfying the pathogenic nature of the identified variants in NALCN, MAGEL2 and SCN2A;

    (3) The authors should also provide a summary of the WES data output (coverage, depth, and list of the other functionally/clinically relevant variants compatible with AD, AR, X-linked transmission) for individual trios;

    (4) Based on their findings, the authors should discuss the usefulness of the current diagnostic criteria used for CS/CISS diagnosis in the neonatal period;

    (5) Emphasize the relevance of the data in terms of counseling;

    (6) To this reviewer it is not clear the utility of reporting on the functional role of MAGEL2 and its ubiquitin ligase complex. The para does not provide any significant insight and should be removed. The authors should focus on the clinical implications of their findings.

    Reviewed by
    Cite this review
    Reviewer report
    2019/01/24

    The manuscript entitled « Exome sequencing in Crisponi/CISS-like individuals reveals unpredicted alternative diagnoses » by Angius et al. deals with five patients with a clinical diagnosis of Crisponi syndrome who do not have variants in the genes previously associated with the condition. The authors found by WES two variants in NALCN, two in MAGEL2 and one in SCN2A. This work is valuable for clinical geneticists. However, the manuscript could be improved.

    Major points:

    The manuscript should be structured differently. Because short reports do not leave room for long descriptions of patients, they were put, along with part of the Methods, in the supporting information section, which is valuable. Patients and the methods for patients selection are briefly described in a “Case presentation” section which could be “Methods: case presentation” (completed by the Methods in Supporting information). There should be a Results section in the main text for the presentation of variants found in patients and to give support for their pathogenicity. Then, the phenotypes would be logically discussed in the Discussion section.

    In the Discussion section, the authors could discuss more thoroughly the phenotype of patient CS_239 who has a suppression burst pattern of EEG which is typically observed in Ohtahara syndrome.

    The authors should consider the authors guideline mentioning that “For WES-based studies a table must be provided as supplementary material (for review only) listing the variants found after the most obvious filtering steps (segregation, pathogenicity, frequency, etc)”.

    Minor point:

    p.15 l. 32: “hyperthermia of profuse sweating » ⇒ or

    Reviewed by
    Cite this review
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