DLG4-related synaptopathy: a new rare brain disorder

Agustí Rodríguez-Palmero; Melissa Maria Boerrigter; David Gómez-Andrés; Kimberly A Aldinger; Íñigo Marcos-Alcalde; Bernt Popp; David B Everman; Alysia Kern Lovgren; Stephanie Arpin; Vahid Bahrambeigi; Gea Beunders; Anne-Marie Bisgaard; V A Bjerregaard; Ange-Line Bruel; Thomas D Challman; Benjamin Cogné; Christine Coubes; Stella A de Man; Anne-Sophie Denommé-Pichon; Thomas J Dye; Frances Elmslie; Lars Feuk; Sixto García-Miñaúr; Tracy Gertler; Elisa Giorgio; Nicolas Gruchy; Tobias B Haack; Chad R Haldeman-Englert; Bjørn Ivar Haukanes; Juliane Hoyer; Anna C E Hurst; Bertrand Isidor; Maria Johansson Soller; Sulagna Kushary; Malin Kvarnung; Yuval E Landau; Kathleen A Leppig; Anna Lindstrand; Lotte Kleinendorst; Alex MacKenzie; Giorgia Mandrile; Bryce A Mendelsohn; Setareh Moghadasi; Jenny E Morton; Sebastien Moutton; Amelie J Müller; Melanie O'Leary; Marta Pacio-Míguez; Maria Palomares-Bralo; Sumit Parikh; Rolph Pfundt; Ben Pode-Shakked; Anita Rauch; Elena Repnikova; Anya Revah-Politi; Meredith J Ross; Claudia A L Ruivenkamp; Elisabeth Sarrazin; Juliann M Savatt; Agatha Schlüter; Bitten Schönewolf-Greulich; Zohra Shad; Charles Shaw-Smith; Joseph T Shieh; Motti Shohat; Stephanie Spranger; Heidi Thiese; Frederic Tran Mau-Them; Bregje van Bon; Ineke van de Burgt; Ingrid M B H van de Laar; Esmée van Drie; Mieke M van Haelst; Conny M van Ravenswaaij-Arts; Edgard Verdura; Antonio Vitobello; Stephan Waldmüller; Sharon Whiting; Christiane Zweier; Carlos E Prada; Bert B A de Vries; William B Dobyns; Simone F Reiter; Paulino Gómez-Puertas; Aurora Pujol; Zeynep Tümer

doi:10.1038/s41436-020-01075-9

DLG4-related synaptopathy: a new rare brain disorder

Agustí Rodríguez-Palmero, Melissa Maria Boerrigter, David Gómez-Andrés, Kimberly A Aldinger, Íñigo Marcos-Alcalde, Bernt Popp, David B Everman, Alysia Kern Lovgren, Stephanie Arpin, Vahid Bahrambeigi, Gea Beunders, Anne-Marie Bisgaard, V A Bjerregaard, Ange-Line Bruel, Thomas D Challman, Benjamin Cogné, Christine Coubes, Stella A de Man, Anne-Sophie Denommé-Pichon, Thomas J DyeFrances Elmslie, Lars Feuk, Sixto García-Miñaúr, Tracy Gertler, Elisa Giorgio, Nicolas Gruchy, Tobias B Haack, Chad R Haldeman-Englert, Bjørn Ivar Haukanes, Juliane Hoyer, Anna C E Hurst, Bertrand Isidor, Maria Johansson Soller, Sulagna Kushary, Malin Kvarnung, Yuval E Landau, Kathleen A Leppig, Anna Lindstrand, Lotte Kleinendorst, Alex MacKenzie, Giorgia Mandrile, Bryce A Mendelsohn, Setareh Moghadasi, Jenny E Morton, Sebastien Moutton, Amelie J Müller, Melanie O'Leary, Marta Pacio-Míguez, Maria Palomares-Bralo, Sumit Parikh, Rolph Pfundt, Ben Pode-Shakked, Anita Rauch, Elena Repnikova, Anya Revah-Politi, Meredith J Ross, Claudia A L Ruivenkamp, Elisabeth Sarrazin, Juliann M Savatt, Agatha Schlüter, Bitten Schönewolf-Greulich, Zohra Shad, Charles Shaw-Smith, Joseph T Shieh, Motti Shohat, Stephanie Spranger, Heidi Thiese, Frederic Tran Mau-Them, Bregje van Bon, Ineke van de Burgt, Ingrid M B H van de Laar, Esmée van Drie, Mieke M van Haelst, Conny M van Ravenswaaij-Arts, Edgard Verdura, Antonio Vitobello, Stephan Waldmüller, Sharon Whiting, Christiane Zweier, Carlos E Prada, Bert B A de Vries, William B Dobyns, Simone F Reiter, Paulino Gómez-Puertas, Aurora Pujol, Zeynep Tümer

30 Citationer (Scopus)

Abstract

PURPOSE: Postsynaptic density protein-95 (PSD-95), encoded by DLG4, regulates excitatory synaptic function in the brain. Here we present the clinical and genetic features of 53 patients (42 previously unpublished) with DLG4 variants.

METHODS: The clinical and genetic information were collected through GeneMatcher collaboration. All the individuals were investigated by local clinicians and the gene variants were identified by clinical exome/genome sequencing.

RESULTS: The clinical picture was predominated by early onset global developmental delay, intellectual disability, autism spectrum disorder, and attention deficit-hyperactivity disorder, all of which point to a brain disorder. Marfanoid habitus, which was previously suggested to be a characteristic feature of DLG4-related phenotypes, was found in only nine individuals and despite some overlapping features, a distinct facial dysmorphism could not be established. Of the 45 different DLG4 variants, 39 were predicted to lead to loss of protein function and the majority occurred de novo (four with unknown origin). The six missense variants identified were suggested to lead to structural or functional changes by protein modeling studies.

CONCLUSION: The present study shows that clinical manifestations associated with DLG4 overlap with those found in other neurodevelopmental disorders of synaptic dysfunction; thus, we designate this group of disorders as DLG4-related synaptopathy.

Originalsprog	Engelsk
Tidsskrift	Genetics in medicine : official journal of the American College of Medical Genetics
Vol/bind	23
Udgave nummer	5
Sider (fra-til)	888-899
Antal sider	12
ISSN	1098-3600
DOI	https://doi.org/10.1038/s41436-020-01075-9
Status	Udgivet - maj 2021

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Rodríguez-Palmero, A., Boerrigter, M. M., Gómez-Andrés, D., Aldinger, K. A., Marcos-Alcalde, Í., Popp, B., Everman, D. B., Lovgren, A. K., Arpin, S., Bahrambeigi, V., Beunders, G., Bisgaard, A.-M., Bjerregaard, V. A., Bruel, A.-L., Challman, T. D., Cogné, B., Coubes, C., de Man, S. A., Denommé-Pichon, A.-S., ... Tümer, Z. (2021). DLG4-related synaptopathy: a new rare brain disorder. Genetics in medicine : official journal of the American College of Medical Genetics, 23(5), 888-899. https://doi.org/10.1038/s41436-020-01075-9

Rodríguez-Palmero, A, Boerrigter, MM, Gómez-Andrés, D, Aldinger, KA, Marcos-Alcalde, Í, Popp, B, Everman, DB, Lovgren, AK, Arpin, S, Bahrambeigi, V, Beunders, G, Bisgaard, A-M, Bjerregaard, VA, Bruel, A-L, Challman, TD, Cogné, B, Coubes, C, de Man, SA, Denommé-Pichon, A-S, Dye, TJ, Elmslie, F, Feuk, L, García-Miñaúr, S, Gertler, T, Giorgio, E, Gruchy, N, Haack, TB, Haldeman-Englert, CR, Haukanes, BI, Hoyer, J, Hurst, ACE, Isidor, B, Soller, MJ, Kushary, S, Kvarnung, M, Landau, YE, Leppig, KA, Lindstrand, A, Kleinendorst, L, MacKenzie, A, Mandrile, G, Mendelsohn, BA, Moghadasi, S, Morton, JE, Moutton, S, Müller, AJ, O'Leary, M, Pacio-Míguez, M, Palomares-Bralo, M, Parikh, S, Pfundt, R, Pode-Shakked, B, Rauch, A, Repnikova, E, Revah-Politi, A, Ross, MJ, Ruivenkamp, CAL, Sarrazin, E, Savatt, JM, Schlüter, A, Schönewolf-Greulich, B, Shad, Z, Shaw-Smith, C, Shieh, JT, Shohat, M, Spranger, S, Thiese, H, Mau-Them, FT, van Bon, B, van de Burgt, I, van de Laar, IMBH, van Drie, E, van Haelst, MM, van Ravenswaaij-Arts, CM, Verdura, E, Vitobello, A, Waldmüller, S, Whiting, S, Zweier, C, Prada, CE, de Vries, BBA, Dobyns, WB, Reiter, SF, Gómez-Puertas, P, Pujol, A & Tümer, Z 2021, 'DLG4-related synaptopathy: a new rare brain disorder', Genetics in medicine : official journal of the American College of Medical Genetics, bind 23, nr. 5, s. 888-899. https://doi.org/10.1038/s41436-020-01075-9

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abstract = "PURPOSE: Postsynaptic density protein-95 (PSD-95), encoded by DLG4, regulates excitatory synaptic function in the brain. Here we present the clinical and genetic features of 53 patients (42 previously unpublished) with DLG4 variants.METHODS: The clinical and genetic information were collected through GeneMatcher collaboration. All the individuals were investigated by local clinicians and the gene variants were identified by clinical exome/genome sequencing.RESULTS: The clinical picture was predominated by early onset global developmental delay, intellectual disability, autism spectrum disorder, and attention deficit-hyperactivity disorder, all of which point to a brain disorder. Marfanoid habitus, which was previously suggested to be a characteristic feature of DLG4-related phenotypes, was found in only nine individuals and despite some overlapping features, a distinct facial dysmorphism could not be established. Of the 45 different DLG4 variants, 39 were predicted to lead to loss of protein function and the majority occurred de novo (four with unknown origin). The six missense variants identified were suggested to lead to structural or functional changes by protein modeling studies.CONCLUSION: The present study shows that clinical manifestations associated with DLG4 overlap with those found in other neurodevelopmental disorders of synaptic dysfunction; thus, we designate this group of disorders as DLG4-related synaptopathy.",

author = "Agust{\'i} Rodr{\'i}guez-Palmero and Boerrigter, {Melissa Maria} and David G{\'o}mez-Andr{\'e}s and Aldinger, {Kimberly A} and {\'I}{\~n}igo Marcos-Alcalde and Bernt Popp and Everman, {David B} and Lovgren, {Alysia Kern} and Stephanie Arpin and Vahid Bahrambeigi and Gea Beunders and Anne-Marie Bisgaard and Bjerregaard, {V A} and Ange-Line Bruel and Challman, {Thomas D} and Benjamin Cogn{\'e} and Christine Coubes and {de Man}, {Stella A} and Anne-Sophie Denomm{\'e}-Pichon and Dye, {Thomas J} and Frances Elmslie and Lars Feuk and Sixto Garc{\'i}a-Mi{\~n}a{\'u}r and Tracy Gertler and Elisa Giorgio and Nicolas Gruchy and Haack, {Tobias B} and Haldeman-Englert, {Chad R} and Haukanes, {Bj{\o}rn Ivar} and Juliane Hoyer and Hurst, {Anna C E} and Bertrand Isidor and Soller, {Maria Johansson} and Sulagna Kushary and Malin Kvarnung and Landau, {Yuval E} and Leppig, {Kathleen A} and Anna Lindstrand and Lotte Kleinendorst and Alex MacKenzie and Giorgia Mandrile and Mendelsohn, {Bryce A} and Setareh Moghadasi and Morton, {Jenny E} and Sebastien Moutton and M{\"u}ller, {Amelie J} and Melanie O'Leary and Marta Pacio-M{\'i}guez and Maria Palomares-Bralo and Sumit Parikh and Rolph Pfundt and Ben Pode-Shakked and Anita Rauch and Elena Repnikova and Anya Revah-Politi and Ross, {Meredith J} and Ruivenkamp, {Claudia A L} and Elisabeth Sarrazin and Savatt, {Juliann M} and Agatha Schl{\"u}ter and Bitten Sch{\"o}newolf-Greulich and Zohra Shad and Charles Shaw-Smith and Shieh, {Joseph T} and Motti Shohat and Stephanie Spranger and Heidi Thiese and Mau-Them, {Frederic Tran} and {van Bon}, Bregje and {van de Burgt}, Ineke and {van de Laar}, {Ingrid M B H} and {van Drie}, Esm{\'e}e and {van Haelst}, {Mieke M} and {van Ravenswaaij-Arts}, {Conny M} and Edgard Verdura and Antonio Vitobello and Stephan Waldm{\"u}ller and Sharon Whiting and Christiane Zweier and Prada, {Carlos E} and {de Vries}, {Bert B A} and Dobyns, {William B} and Reiter, {Simone F} and Paulino G{\'o}mez-Puertas and Aurora Pujol and Zeynep T{\"u}mer",

year = "2021",

month = may,

doi = "10.1038/s41436-020-01075-9",

language = "English",

volume = "23",

pages = "888--899",

journal = "Genetics in medicine : official journal of the American College of Medical Genetics",

issn = "1098-3600",

publisher = "Elsevier BV",

number = "5",

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TY - JOUR

T1 - DLG4-related synaptopathy

T2 - a new rare brain disorder

AU - Rodríguez-Palmero, Agustí

AU - Boerrigter, Melissa Maria

AU - Gómez-Andrés, David

AU - Aldinger, Kimberly A

AU - Marcos-Alcalde, Íñigo

AU - Popp, Bernt

AU - Everman, David B

AU - Lovgren, Alysia Kern

AU - Arpin, Stephanie

AU - Bahrambeigi, Vahid

AU - Beunders, Gea

AU - Bisgaard, Anne-Marie

AU - Bjerregaard, V A

AU - Bruel, Ange-Line

AU - Challman, Thomas D

AU - Cogné, Benjamin

AU - Coubes, Christine

AU - de Man, Stella A

AU - Denommé-Pichon, Anne-Sophie

AU - Dye, Thomas J

AU - Elmslie, Frances

AU - Feuk, Lars

AU - García-Miñaúr, Sixto

AU - Gertler, Tracy

AU - Giorgio, Elisa

AU - Gruchy, Nicolas

AU - Haack, Tobias B

AU - Haldeman-Englert, Chad R

AU - Haukanes, Bjørn Ivar

AU - Hoyer, Juliane

AU - Hurst, Anna C E

AU - Isidor, Bertrand

AU - Soller, Maria Johansson

AU - Kushary, Sulagna

AU - Kvarnung, Malin

AU - Landau, Yuval E

AU - Leppig, Kathleen A

AU - Lindstrand, Anna

AU - Kleinendorst, Lotte

AU - MacKenzie, Alex

AU - Mandrile, Giorgia

AU - Mendelsohn, Bryce A

AU - Moghadasi, Setareh

AU - Morton, Jenny E

AU - Moutton, Sebastien

AU - Müller, Amelie J

AU - O'Leary, Melanie

AU - Pacio-Míguez, Marta

AU - Palomares-Bralo, Maria

AU - Parikh, Sumit

AU - Pfundt, Rolph

AU - Pode-Shakked, Ben

AU - Rauch, Anita

AU - Repnikova, Elena

AU - Revah-Politi, Anya

AU - Ross, Meredith J

AU - Ruivenkamp, Claudia A L

AU - Sarrazin, Elisabeth

AU - Savatt, Juliann M

AU - Schlüter, Agatha

AU - Schönewolf-Greulich, Bitten

AU - Shad, Zohra

AU - Shaw-Smith, Charles

AU - Shieh, Joseph T

AU - Shohat, Motti

AU - Spranger, Stephanie

AU - Thiese, Heidi

AU - Mau-Them, Frederic Tran

AU - van Bon, Bregje

AU - van de Burgt, Ineke

AU - van de Laar, Ingrid M B H

AU - van Drie, Esmée

AU - van Haelst, Mieke M

AU - van Ravenswaaij-Arts, Conny M

AU - Verdura, Edgard

AU - Vitobello, Antonio

AU - Waldmüller, Stephan

AU - Whiting, Sharon

AU - Zweier, Christiane

AU - Prada, Carlos E

AU - de Vries, Bert B A

AU - Dobyns, William B

AU - Reiter, Simone F

AU - Gómez-Puertas, Paulino

AU - Pujol, Aurora

AU - Tümer, Zeynep

PY - 2021/5

Y1 - 2021/5

N2 - PURPOSE: Postsynaptic density protein-95 (PSD-95), encoded by DLG4, regulates excitatory synaptic function in the brain. Here we present the clinical and genetic features of 53 patients (42 previously unpublished) with DLG4 variants.METHODS: The clinical and genetic information were collected through GeneMatcher collaboration. All the individuals were investigated by local clinicians and the gene variants were identified by clinical exome/genome sequencing.RESULTS: The clinical picture was predominated by early onset global developmental delay, intellectual disability, autism spectrum disorder, and attention deficit-hyperactivity disorder, all of which point to a brain disorder. Marfanoid habitus, which was previously suggested to be a characteristic feature of DLG4-related phenotypes, was found in only nine individuals and despite some overlapping features, a distinct facial dysmorphism could not be established. Of the 45 different DLG4 variants, 39 were predicted to lead to loss of protein function and the majority occurred de novo (four with unknown origin). The six missense variants identified were suggested to lead to structural or functional changes by protein modeling studies.CONCLUSION: The present study shows that clinical manifestations associated with DLG4 overlap with those found in other neurodevelopmental disorders of synaptic dysfunction; thus, we designate this group of disorders as DLG4-related synaptopathy.

AB - PURPOSE: Postsynaptic density protein-95 (PSD-95), encoded by DLG4, regulates excitatory synaptic function in the brain. Here we present the clinical and genetic features of 53 patients (42 previously unpublished) with DLG4 variants.METHODS: The clinical and genetic information were collected through GeneMatcher collaboration. All the individuals were investigated by local clinicians and the gene variants were identified by clinical exome/genome sequencing.RESULTS: The clinical picture was predominated by early onset global developmental delay, intellectual disability, autism spectrum disorder, and attention deficit-hyperactivity disorder, all of which point to a brain disorder. Marfanoid habitus, which was previously suggested to be a characteristic feature of DLG4-related phenotypes, was found in only nine individuals and despite some overlapping features, a distinct facial dysmorphism could not be established. Of the 45 different DLG4 variants, 39 were predicted to lead to loss of protein function and the majority occurred de novo (four with unknown origin). The six missense variants identified were suggested to lead to structural or functional changes by protein modeling studies.CONCLUSION: The present study shows that clinical manifestations associated with DLG4 overlap with those found in other neurodevelopmental disorders of synaptic dysfunction; thus, we designate this group of disorders as DLG4-related synaptopathy.

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U2 - 10.1038/s41436-020-01075-9

DO - 10.1038/s41436-020-01075-9

M3 - Journal article

C2 - 33597769

SN - 1098-3600

VL - 23

SP - 888

EP - 899

JO - Genetics in medicine : official journal of the American College of Medical Genetics

JF - Genetics in medicine : official journal of the American College of Medical Genetics

IS - 5

ER -

DLG4-related synaptopathy: a new rare brain disorder

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