The detection of a strong episignature for Chung-Jansen syndrome, partially overlapping with Börjeson-Forssman-Lehmann and White-Kernohan syndromes

Niels Vos; Sadegheh Haghshenas; Liselot van der Laan; Perle K M Russel; Kathleen Rooney; Michael A Levy; Raissa Relator; Jennifer Kerkhof; Haley McConkey; Saskia M Maas; Lisenka E L M Vissers; Bert B A de Vries; Rolph Pfundt; Mariet W Elting; Johanna M van Hagen; Nienke E Verbeek; Marjolijn C J Jongmans; Phillis Lakeman; Lynne Rumping; Danielle G M Bosch; Antonio Vitobello; Christel Thauvin-Robinet; Laurence Faivre; Sophie Nambot; Aurore Garde; Marjolaine Willems; David Genevieve; Gaël Nicolas; Tiffany Busa; Annick Toutain; Marion Gérard; Varoona Bizaoui; Bertrand Isidor; Giuseppe Merla; Maria Accadia; Charles E Schwartz; Katrin Ounap; Mariëtte J V Hoffer; Marjan M Nezarati; Marie-José H van den Boogaard; Matthew L Tedder; Curtis Rogers; Alfredo Brusco; Giovanni B Ferrero; Marta Spodenkiewicz; Richard Sidlow; Alessandro Mussa; Slavica Trajkova; Emma McCann; Henry J Mroczkowski; Sandra Jansen; Laura Donker-Kaat; Floor A M Duijkers; Kyra E Stuurman; Marcel M A M Mannens; Mariëlle Alders; Peter Henneman; Susan M White; Bekim Sadikovic; Mieke M van Haelst

doi:10.1007/s00439-024-02679-w

The detection of a strong episignature for Chung-Jansen syndrome, partially overlapping with Börjeson-Forssman-Lehmann and White-Kernohan syndromes

Niels Vos, Sadegheh Haghshenas, Liselot van der Laan, Perle K M Russel, Kathleen Rooney, Michael A Levy, Raissa Relator, Jennifer Kerkhof, Haley McConkey, Saskia M Maas, Lisenka E L M Vissers, Bert B A de Vries, Rolph Pfundt, Mariet W Elting, Johanna M van Hagen, Nienke E Verbeek, Marjolijn C J Jongmans, Phillis Lakeman, Lynne Rumping, Danielle G M BoschAntonio Vitobello, Christel Thauvin-Robinet, Laurence Faivre, Sophie Nambot, Aurore Garde, Marjolaine Willems, David Genevieve, Gaël Nicolas, Tiffany Busa, Annick Toutain, Marion Gérard, Varoona Bizaoui, Bertrand Isidor, Giuseppe Merla, Maria Accadia, Charles E Schwartz, Katrin Ounap, Mariëtte J V Hoffer, Marjan M Nezarati, Marie-José H van den Boogaard, Matthew L Tedder, Curtis Rogers, Alfredo Brusco, Giovanni B Ferrero, Marta Spodenkiewicz, Richard Sidlow, Alessandro Mussa, Slavica Trajkova, Emma McCann, Henry J Mroczkowski, Sandra Jansen, Laura Donker-Kaat, Floor A M Duijkers, Kyra E Stuurman, Marcel M A M Mannens, Mariëlle Alders, Peter Henneman, Susan M White, Bekim Sadikovic, Mieke M van Haelst^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

Chung-Jansen syndrome is a neurodevelopmental disorder characterized by intellectual disability, behavioral problems, obesity and dysmorphic features. It is caused by pathogenic variants in the PHIP gene that encodes for the Pleckstrin homology domain-interacting protein, which is part of an epigenetic modifier protein complex. Therefore, we hypothesized that PHIP haploinsufficiency may impact genome-wide DNA methylation (DNAm). We assessed the DNAm profiles of affected individuals with pathogenic and likely pathogenic PHIP variants with Infinium Methylation EPIC arrays and report a specific and sensitive DNAm episignature biomarker for Chung-Jansen syndrome. In addition, we observed similarities between the methylation profile of Chung-Jansen syndrome and that of functionally related and clinically partially overlapping genetic disorders, White-Kernohan syndrome (caused by variants in DDB1 gene) and Börjeson-Forssman-Lehmann syndrome (caused by variants in PHF6 gene). Based on these observations we also proceeded to develop a common episignature biomarker for these disorders. These newly defined episignatures can be used as part of a multiclass episignature classifier for screening of affected individuals with rare disorders and interpretation of genetic variants of unknown clinical significance, and provide further insights into the common molecular pathophysiology of the clinically-related Chung-Jansen, Börjeson-Forssman-Lehmann and White-Kernohan syndromes.

Original language	English
Pages (from-to)	761-773
Number of pages	13
Journal	Human Genetics
Volume	143
Issue number	6
Early online date	24 May 2024
DOIs	https://doi.org/10.1007/s00439-024-02679-w
Publication status	Published - Jun 2024

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Vos, N., Haghshenas, S., van der Laan, L., Russel, P. K. M., Rooney, K., Levy, M. A., Relator, R., Kerkhof, J., McConkey, H., Maas, S. M., Vissers, L. E. L. M., de Vries, B. B. A., Pfundt, R., Elting, M. W., van Hagen, J. M., Verbeek, N. E., Jongmans, M. C. J., Lakeman, P., Rumping, L., ... van Haelst, M. M. (2024). The detection of a strong episignature for Chung-Jansen syndrome, partially overlapping with Börjeson-Forssman-Lehmann and White-Kernohan syndromes. Human Genetics, 143(6), 761-773. https://doi.org/10.1007/s00439-024-02679-w

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title = "The detection of a strong episignature for Chung-Jansen syndrome, partially overlapping with B{\"o}rjeson-Forssman-Lehmann and White-Kernohan syndromes",

abstract = "Chung-Jansen syndrome is a neurodevelopmental disorder characterized by intellectual disability, behavioral problems, obesity and dysmorphic features. It is caused by pathogenic variants in the PHIP gene that encodes for the Pleckstrin homology domain-interacting protein, which is part of an epigenetic modifier protein complex. Therefore, we hypothesized that PHIP haploinsufficiency may impact genome-wide DNA methylation (DNAm). We assessed the DNAm profiles of affected individuals with pathogenic and likely pathogenic PHIP variants with Infinium Methylation EPIC arrays and report a specific and sensitive DNAm episignature biomarker for Chung-Jansen syndrome. In addition, we observed similarities between the methylation profile of Chung-Jansen syndrome and that of functionally related and clinically partially overlapping genetic disorders, White-Kernohan syndrome (caused by variants in DDB1 gene) and B{\"o}rjeson-Forssman-Lehmann syndrome (caused by variants in PHF6 gene). Based on these observations we also proceeded to develop a common episignature biomarker for these disorders. These newly defined episignatures can be used as part of a multiclass episignature classifier for screening of affected individuals with rare disorders and interpretation of genetic variants of unknown clinical significance, and provide further insights into the common molecular pathophysiology of the clinically-related Chung-Jansen, B{\"o}rjeson-Forssman-Lehmann and White-Kernohan syndromes.",

author = "Niels Vos and Sadegheh Haghshenas and {van der Laan}, Liselot and Russel, {Perle K M} and Kathleen Rooney and Levy, {Michael A} and Raissa Relator and Jennifer Kerkhof and Haley McConkey and Maas, {Saskia M} and Vissers, {Lisenka E L M} and {de Vries}, {Bert B A} and Rolph Pfundt and Elting, {Mariet W} and {van Hagen}, {Johanna M} and Verbeek, {Nienke E} and Jongmans, {Marjolijn C J} and Phillis Lakeman and Lynne Rumping and Bosch, {Danielle G M} and Antonio Vitobello and Christel Thauvin-Robinet and Laurence Faivre and Sophie Nambot and Aurore Garde and Marjolaine Willems and David Genevieve and Ga{\"e}l Nicolas and Tiffany Busa and Annick Toutain and Marion G{\'e}rard and Varoona Bizaoui and Bertrand Isidor and Giuseppe Merla and Maria Accadia and Schwartz, {Charles E} and Katrin Ounap and Hoffer, {Mari{\"e}tte J V} and Nezarati, {Marjan M} and {van den Boogaard}, {Marie-Jos{\'e} H} and Tedder, {Matthew L} and Curtis Rogers and Alfredo Brusco and Ferrero, {Giovanni B} and Marta Spodenkiewicz and Richard Sidlow and Alessandro Mussa and Slavica Trajkova and Emma McCann and Mroczkowski, {Henry J} and Sandra Jansen and Laura Donker-Kaat and Duijkers, {Floor A M} and Stuurman, {Kyra E} and Mannens, {Marcel M A M} and Mari{\"e}lle Alders and Peter Henneman and White, {Susan M} and Bekim Sadikovic and {van Haelst}, {Mieke M}",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2024.",

year = "2024",

month = jun,

doi = "10.1007/s00439-024-02679-w",

language = "English",

volume = "143",

pages = "761--773",

journal = "Human Genetics",

issn = "0340-6717",

publisher = "Springer-Verlag",

number = "6",

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Vos, N, Haghshenas, S, van der Laan, L, Russel, PKM, Rooney, K, Levy, MA, Relator, R, Kerkhof, J, McConkey, H, Maas, SM, Vissers, LELM, de Vries, BBA, Pfundt, R, Elting, MW, van Hagen, JM, Verbeek, NE , Jongmans, MCJ, Lakeman, P, Rumping, L, Bosch, DGM, Vitobello, A, Thauvin-Robinet, C, Faivre, L, Nambot, S, Garde, A, Willems, M, Genevieve, D, Nicolas, G, Busa, T, Toutain, A, Gérard, M, Bizaoui, V, Isidor, B, Merla, G, Accadia, M, Schwartz, CE, Ounap, K, Hoffer, MJV, Nezarati, MM, van den Boogaard, M-JH, Tedder, ML, Rogers, C, Brusco, A, Ferrero, GB, Spodenkiewicz, M, Sidlow, R, Mussa, A, Trajkova, S, McCann, E, Mroczkowski, HJ, Jansen, S, Donker-Kaat, L, Duijkers, FAM, Stuurman, KE, Mannens, MMAM, Alders, M, Henneman, P, White, SM, Sadikovic, B & van Haelst, MM 2024, 'The detection of a strong episignature for Chung-Jansen syndrome, partially overlapping with Börjeson-Forssman-Lehmann and White-Kernohan syndromes', Human Genetics, vol. 143, no. 6, pp. 761-773. https://doi.org/10.1007/s00439-024-02679-w

TY - JOUR

T1 - The detection of a strong episignature for Chung-Jansen syndrome, partially overlapping with Börjeson-Forssman-Lehmann and White-Kernohan syndromes

AU - Vos, Niels

AU - Haghshenas, Sadegheh

AU - van der Laan, Liselot

AU - Russel, Perle K M

AU - Rooney, Kathleen

AU - Levy, Michael A

AU - Relator, Raissa

AU - Kerkhof, Jennifer

AU - McConkey, Haley

AU - Maas, Saskia M

AU - Vissers, Lisenka E L M

AU - de Vries, Bert B A

AU - Pfundt, Rolph

AU - Elting, Mariet W

AU - van Hagen, Johanna M

AU - Verbeek, Nienke E

AU - Jongmans, Marjolijn C J

AU - Lakeman, Phillis

AU - Rumping, Lynne

AU - Bosch, Danielle G M

AU - Vitobello, Antonio

AU - Thauvin-Robinet, Christel

AU - Faivre, Laurence

AU - Nambot, Sophie

AU - Garde, Aurore

AU - Willems, Marjolaine

AU - Genevieve, David

AU - Nicolas, Gaël

AU - Busa, Tiffany

AU - Toutain, Annick

AU - Gérard, Marion

AU - Bizaoui, Varoona

AU - Isidor, Bertrand

AU - Merla, Giuseppe

AU - Accadia, Maria

AU - Schwartz, Charles E

AU - Ounap, Katrin

AU - Hoffer, Mariëtte J V

AU - Nezarati, Marjan M

AU - van den Boogaard, Marie-José H

AU - Tedder, Matthew L

AU - Rogers, Curtis

AU - Brusco, Alfredo

AU - Ferrero, Giovanni B

AU - Spodenkiewicz, Marta

AU - Sidlow, Richard

AU - Mussa, Alessandro

AU - Trajkova, Slavica

AU - McCann, Emma

AU - Mroczkowski, Henry J

AU - Jansen, Sandra

AU - Donker-Kaat, Laura

AU - Duijkers, Floor A M

AU - Stuurman, Kyra E

AU - Mannens, Marcel M A M

AU - Alders, Mariëlle

AU - Henneman, Peter

AU - White, Susan M

AU - Sadikovic, Bekim

AU - van Haelst, Mieke M

PY - 2024/6

Y1 - 2024/6

N2 - Chung-Jansen syndrome is a neurodevelopmental disorder characterized by intellectual disability, behavioral problems, obesity and dysmorphic features. It is caused by pathogenic variants in the PHIP gene that encodes for the Pleckstrin homology domain-interacting protein, which is part of an epigenetic modifier protein complex. Therefore, we hypothesized that PHIP haploinsufficiency may impact genome-wide DNA methylation (DNAm). We assessed the DNAm profiles of affected individuals with pathogenic and likely pathogenic PHIP variants with Infinium Methylation EPIC arrays and report a specific and sensitive DNAm episignature biomarker for Chung-Jansen syndrome. In addition, we observed similarities between the methylation profile of Chung-Jansen syndrome and that of functionally related and clinically partially overlapping genetic disorders, White-Kernohan syndrome (caused by variants in DDB1 gene) and Börjeson-Forssman-Lehmann syndrome (caused by variants in PHF6 gene). Based on these observations we also proceeded to develop a common episignature biomarker for these disorders. These newly defined episignatures can be used as part of a multiclass episignature classifier for screening of affected individuals with rare disorders and interpretation of genetic variants of unknown clinical significance, and provide further insights into the common molecular pathophysiology of the clinically-related Chung-Jansen, Börjeson-Forssman-Lehmann and White-Kernohan syndromes.

AB - Chung-Jansen syndrome is a neurodevelopmental disorder characterized by intellectual disability, behavioral problems, obesity and dysmorphic features. It is caused by pathogenic variants in the PHIP gene that encodes for the Pleckstrin homology domain-interacting protein, which is part of an epigenetic modifier protein complex. Therefore, we hypothesized that PHIP haploinsufficiency may impact genome-wide DNA methylation (DNAm). We assessed the DNAm profiles of affected individuals with pathogenic and likely pathogenic PHIP variants with Infinium Methylation EPIC arrays and report a specific and sensitive DNAm episignature biomarker for Chung-Jansen syndrome. In addition, we observed similarities between the methylation profile of Chung-Jansen syndrome and that of functionally related and clinically partially overlapping genetic disorders, White-Kernohan syndrome (caused by variants in DDB1 gene) and Börjeson-Forssman-Lehmann syndrome (caused by variants in PHF6 gene). Based on these observations we also proceeded to develop a common episignature biomarker for these disorders. These newly defined episignatures can be used as part of a multiclass episignature classifier for screening of affected individuals with rare disorders and interpretation of genetic variants of unknown clinical significance, and provide further insights into the common molecular pathophysiology of the clinically-related Chung-Jansen, Börjeson-Forssman-Lehmann and White-Kernohan syndromes.

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U2 - 10.1007/s00439-024-02679-w

DO - 10.1007/s00439-024-02679-w

M3 - Article

C2 - 38787418

SN - 0340-6717

VL - 143

SP - 761

EP - 773

JO - Human Genetics

JF - Human Genetics

IS - 6

ER -

The detection of a strong episignature for Chung-Jansen syndrome, partially overlapping with Börjeson-Forssman-Lehmann and White-Kernohan syndromes

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