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A Recurrent De Novo PACS2 Heterozygous Missense Variant Causes Neonatal-Onset Developmental Epileptic Encephalopathy, Facial Dysmorphism, and Cerebellar Dysgenesis

Developmental and epileptic encephalopathies (DEEs) represent a large clinical and genetic heterogeneous group of neurodevelopmental diseases. The identification of pathogenic genetic variants in DEEs remains crucial for deciphering this complex group and for accurately caring for affected individua... Full description

Journal Title: American journal of human genetics 2018-10-04, Vol.103 (4), p.631-631
Main Author: Olson, Heather E
Other Authors: Jean-Marçais, Nolwenn , Yang, Edward , Heron, Delphine , Tatton-Brown, Katrina , van der Zwaag, Paul A , Bijlsma, Emilia K , Krock, Bryan L , Backer, E , Kamsteeg, Erik-Jan , Sinnema, Margje , Reijnders, Margot R.F , Bearden, David , Begtrup, Amber , Telegrafi, Aida , Lunsing, Roelineke J , Burglen, Lydie , Lesca, Gaetan , Cho, Megan T , Smith, Lacey A , Sheidley, Beth R , El Achkar, Christelle Moufawad , Pearl, Phillip L , Poduri, Annapurna , Skraban, Cara M , Tarpinian, Jennifer , Nesbitt, Addie I , Fransen van de Putte, Dietje E , Ruivenkamp, Claudia A.L , Rump, Patrick , Chatron, Nicolas , Sabatier, Isabelle , De Bellescize, Julitta , Guibaud, Laurent , Sweetser, David A , Waxler, Jessica L , Wierenga, Klaas J , Donadieu, Jean , Narayanan, Vinodh , Ramsey, Keri M , Nava, Caroline , Rivière, Jean-Baptiste , Vitobello, Antonio , Mau-Them, Frédéric Tran , Philippe, Christophe , Bruel, Ange-Line , Duffourd, Yannis , Thomas, Laurel , Lelieveld, Stefan H , Schuurs-Hoeijmakers, Janneke , Brunner, Han G , Keren, Boris , Thevenon, Julien , Faivre, Laurence , Thomas, Gary , Thauvin-Robinet, Christel
Format: Electronic Article Electronic Article
Language: English
Subjects:
Quelle: Alma/SFX Local Collection
Publisher: Elsevier Inc
ID: ISSN: 0002-9297
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recordid: cdi_proquest_miscellaneous_2116852043
title: A Recurrent De Novo PACS2 Heterozygous Missense Variant Causes Neonatal-Onset Developmental Epileptic Encephalopathy, Facial Dysmorphism, and Cerebellar Dysgenesis
format: Article
creator:
  • Olson, Heather E
  • Jean-Marçais, Nolwenn
  • Yang, Edward
  • Heron, Delphine
  • Tatton-Brown, Katrina
  • van der Zwaag, Paul A
  • Bijlsma, Emilia K
  • Krock, Bryan L
  • Backer, E
  • Kamsteeg, Erik-Jan
  • Sinnema, Margje
  • Reijnders, Margot R.F
  • Bearden, David
  • Begtrup, Amber
  • Telegrafi, Aida
  • Lunsing, Roelineke J
  • Burglen, Lydie
  • Lesca, Gaetan
  • Cho, Megan T
  • Smith, Lacey A
  • Sheidley, Beth R
  • El Achkar, Christelle Moufawad
  • Pearl, Phillip L
  • Poduri, Annapurna
  • Skraban, Cara M
  • Tarpinian, Jennifer
  • Nesbitt, Addie I
  • Fransen van de Putte, Dietje E
  • Ruivenkamp, Claudia A.L
  • Rump, Patrick
  • Chatron, Nicolas
  • Sabatier, Isabelle
  • De Bellescize, Julitta
  • Guibaud, Laurent
  • Sweetser, David A
  • Waxler, Jessica L
  • Wierenga, Klaas J
  • Donadieu, Jean
  • Narayanan, Vinodh
  • Ramsey, Keri M
  • Nava, Caroline
  • Rivière, Jean-Baptiste
  • Vitobello, Antonio
  • Mau-Them, Frédéric Tran
  • Philippe, Christophe
  • Bruel, Ange-Line
  • Duffourd, Yannis
  • Thomas, Laurel
  • Lelieveld, Stefan H
  • Schuurs-Hoeijmakers, Janneke
  • Brunner, Han G
  • Keren, Boris
  • Thevenon, Julien
  • Faivre, Laurence
  • Thomas, Gary
  • Thauvin-Robinet, Christel
subjects:
  • Correction
  • Report
ispartof: American journal of human genetics, 2018-10-04, Vol.103 (4), p.631-631
description: Developmental and epileptic encephalopathies (DEEs) represent a large clinical and genetic heterogeneous group of neurodevelopmental diseases. The identification of pathogenic genetic variants in DEEs remains crucial for deciphering this complex group and for accurately caring for affected individuals (clinical diagnosis, genetic counseling, impacting medical, precision therapy, clinical trials, etc.). Whole-exome sequencing and intensive data sharing identified a recurrent de novo PACS2 heterozygous missense variant in 14 unrelated individuals. Their phenotype was characterized by epilepsy, global developmental delay with or without autism, common cerebellar dysgenesis, and facial dysmorphism. Mixed focal and generalized epilepsy occurred in the neonatal period, controlled with difficulty in the first year, but many improved in early childhood. PACS2 is an important PACS1 paralog and encodes a multifunctional sorting protein involved in nuclear gene expression and pathway traffic regulation. Both proteins harbor cargo(furin)-binding regions (FBRs) that bind cargo proteins, sorting adaptors, and cellular kinase. Compared to the defined PACS1 recurrent variant series, individuals with PACS2 variant have more consistently neonatal/early-infantile-onset epilepsy that can be challenging to control. Cerebellar abnormalities may be similar but PACS2 individuals exhibit a pattern of clear dysgenesis ranging from mild to severe. Functional studies demonstrated that the PACS2 recurrent variant reduces the ability of the predicted autoregulatory domain to modulate the interaction between the PACS2 FBR and client proteins, which may disturb cellular function. These findings support the causality of this recurrent de novo PACS2 heterozygous missense in DEEs with facial dysmorphim and cerebellar dysgenesis.
language: eng
source: Alma/SFX Local Collection
identifier: ISSN: 0002-9297
fulltext: fulltext
issn:
  • 0002-9297
  • 1537-6605
url: Link


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titleA Recurrent De Novo PACS2 Heterozygous Missense Variant Causes Neonatal-Onset Developmental Epileptic Encephalopathy, Facial Dysmorphism, and Cerebellar Dysgenesis
sourceAlma/SFX Local Collection
creatorOlson, Heather E ; Jean-Marçais, Nolwenn ; Yang, Edward ; Heron, Delphine ; Tatton-Brown, Katrina ; van der Zwaag, Paul A ; Bijlsma, Emilia K ; Krock, Bryan L ; Backer, E ; Kamsteeg, Erik-Jan ; Sinnema, Margje ; Reijnders, Margot R.F ; Bearden, David ; Begtrup, Amber ; Telegrafi, Aida ; Lunsing, Roelineke J ; Burglen, Lydie ; Lesca, Gaetan ; Cho, Megan T ; Smith, Lacey A ; Sheidley, Beth R ; El Achkar, Christelle Moufawad ; Pearl, Phillip L ; Poduri, Annapurna ; Skraban, Cara M ; Tarpinian, Jennifer ; Nesbitt, Addie I ; Fransen van de Putte, Dietje E ; Ruivenkamp, Claudia A.L ; Rump, Patrick ; Chatron, Nicolas ; Sabatier, Isabelle ; De Bellescize, Julitta ; Guibaud, Laurent ; Sweetser, David A ; Waxler, Jessica L ; Wierenga, Klaas J ; Donadieu, Jean ; Narayanan, Vinodh ; Ramsey, Keri M ; Nava, Caroline ; Rivière, Jean-Baptiste ; Vitobello, Antonio ; Mau-Them, Frédéric Tran ; Philippe, Christophe ; Bruel, Ange-Line ; Duffourd, Yannis ; Thomas, Laurel ; Lelieveld, Stefan H ; Schuurs-Hoeijmakers, Janneke ; Brunner, Han G ; Keren, Boris ; Thevenon, Julien ; Faivre, Laurence ; Thomas, Gary ; Thauvin-Robinet, Christel
creatorcontribOlson, Heather E ; Jean-Marçais, Nolwenn ; Yang, Edward ; Heron, Delphine ; Tatton-Brown, Katrina ; van der Zwaag, Paul A ; Bijlsma, Emilia K ; Krock, Bryan L ; Backer, E ; Kamsteeg, Erik-Jan ; Sinnema, Margje ; Reijnders, Margot R.F ; Bearden, David ; Begtrup, Amber ; Telegrafi, Aida ; Lunsing, Roelineke J ; Burglen, Lydie ; Lesca, Gaetan ; Cho, Megan T ; Smith, Lacey A ; Sheidley, Beth R ; El Achkar, Christelle Moufawad ; Pearl, Phillip L ; Poduri, Annapurna ; Skraban, Cara M ; Tarpinian, Jennifer ; Nesbitt, Addie I ; Fransen van de Putte, Dietje E ; Ruivenkamp, Claudia A.L ; Rump, Patrick ; Chatron, Nicolas ; Sabatier, Isabelle ; De Bellescize, Julitta ; Guibaud, Laurent ; Sweetser, David A ; Waxler, Jessica L ; Wierenga, Klaas J ; Donadieu, Jean ; Narayanan, Vinodh ; Ramsey, Keri M ; Nava, Caroline ; Rivière, Jean-Baptiste ; Vitobello, Antonio ; Mau-Them, Frédéric Tran ; Philippe, Christophe ; Bruel, Ange-Line ; Duffourd, Yannis ; Thomas, Laurel ; Lelieveld, Stefan H ; Schuurs-Hoeijmakers, Janneke ; Brunner, Han G ; Keren, Boris ; Thevenon, Julien ; Faivre, Laurence ; Thomas, Gary ; Thauvin-Robinet, Christel ; C4RCD Research Group ; DDD Study
descriptionDevelopmental and epileptic encephalopathies (DEEs) represent a large clinical and genetic heterogeneous group of neurodevelopmental diseases. The identification of pathogenic genetic variants in DEEs remains crucial for deciphering this complex group and for accurately caring for affected individuals (clinical diagnosis, genetic counseling, impacting medical, precision therapy, clinical trials, etc.). Whole-exome sequencing and intensive data sharing identified a recurrent de novo PACS2 heterozygous missense variant in 14 unrelated individuals. Their phenotype was characterized by epilepsy, global developmental delay with or without autism, common cerebellar dysgenesis, and facial dysmorphism. Mixed focal and generalized epilepsy occurred in the neonatal period, controlled with difficulty in the first year, but many improved in early childhood. PACS2 is an important PACS1 paralog and encodes a multifunctional sorting protein involved in nuclear gene expression and pathway traffic regulation. Both proteins harbor cargo(furin)-binding regions (FBRs) that bind cargo proteins, sorting adaptors, and cellular kinase. Compared to the defined PACS1 recurrent variant series, individuals with PACS2 variant have more consistently neonatal/early-infantile-onset epilepsy that can be challenging to control. Cerebellar abnormalities may be similar but PACS2 individuals exhibit a pattern of clear dysgenesis ranging from mild to severe. Functional studies demonstrated that the PACS2 recurrent variant reduces the ability of the predicted autoregulatory domain to modulate the interaction between the PACS2 FBR and client proteins, which may disturb cellular function. These findings support the causality of this recurrent de novo PACS2 heterozygous missense in DEEs with facial dysmorphim and cerebellar dysgenesis.
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15Lunsing, Roelineke J
16Burglen, Lydie
17Lesca, Gaetan
18Cho, Megan T
19Smith, Lacey A
20Sheidley, Beth R
21El Achkar, Christelle Moufawad
22Pearl, Phillip L
23Poduri, Annapurna
24Skraban, Cara M
25Tarpinian, Jennifer
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27Fransen van de Putte, Dietje E
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30Chatron, Nicolas
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32De Bellescize, Julitta
33Guibaud, Laurent
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35Waxler, Jessica L
36Wierenga, Klaas J
37Donadieu, Jean
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39Ramsey, Keri M
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44Philippe, Christophe
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47Thomas, Laurel
48Lelieveld, Stefan H
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51Keren, Boris
52Thevenon, Julien
53Faivre, Laurence
54Thomas, Gary
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0A Recurrent De Novo PACS2 Heterozygous Missense Variant Causes Neonatal-Onset Developmental Epileptic Encephalopathy, Facial Dysmorphism, and Cerebellar Dysgenesis
1American journal of human genetics
descriptionDevelopmental and epileptic encephalopathies (DEEs) represent a large clinical and genetic heterogeneous group of neurodevelopmental diseases. The identification of pathogenic genetic variants in DEEs remains crucial for deciphering this complex group and for accurately caring for affected individuals (clinical diagnosis, genetic counseling, impacting medical, precision therapy, clinical trials, etc.). Whole-exome sequencing and intensive data sharing identified a recurrent de novo PACS2 heterozygous missense variant in 14 unrelated individuals. Their phenotype was characterized by epilepsy, global developmental delay with or without autism, common cerebellar dysgenesis, and facial dysmorphism. Mixed focal and generalized epilepsy occurred in the neonatal period, controlled with difficulty in the first year, but many improved in early childhood. PACS2 is an important PACS1 paralog and encodes a multifunctional sorting protein involved in nuclear gene expression and pathway traffic regulation. Both proteins harbor cargo(furin)-binding regions (FBRs) that bind cargo proteins, sorting adaptors, and cellular kinase. Compared to the defined PACS1 recurrent variant series, individuals with PACS2 variant have more consistently neonatal/early-infantile-onset epilepsy that can be challenging to control. Cerebellar abnormalities may be similar but PACS2 individuals exhibit a pattern of clear dysgenesis ranging from mild to severe. Functional studies demonstrated that the PACS2 recurrent variant reduces the ability of the predicted autoregulatory domain to modulate the interaction between the PACS2 FBR and client proteins, which may disturb cellular function. These findings support the causality of this recurrent de novo PACS2 heterozygous missense in DEEs with facial dysmorphim and cerebellar dysgenesis.
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16Burglen, Lydie
17Lesca, Gaetan
18Cho, Megan T
19Smith, Lacey A
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21El Achkar, Christelle Moufawad
22Pearl, Phillip L
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25Tarpinian, Jennifer
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27Fransen van de Putte, Dietje E
28Ruivenkamp, Claudia A.L
29Rump, Patrick
30Chatron, Nicolas
31Sabatier, Isabelle
32De Bellescize, Julitta
33Guibaud, Laurent
34Sweetser, David A
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titleA Recurrent De Novo PACS2 Heterozygous Missense Variant Causes Neonatal-Onset Developmental Epileptic Encephalopathy, Facial Dysmorphism, and Cerebellar Dysgenesis
authorOlson, Heather E ; Jean-Marçais, Nolwenn ; Yang, Edward ; Heron, Delphine ; Tatton-Brown, Katrina ; van der Zwaag, Paul A ; Bijlsma, Emilia K ; Krock, Bryan L ; Backer, E ; Kamsteeg, Erik-Jan ; Sinnema, Margje ; Reijnders, Margot R.F ; Bearden, David ; Begtrup, Amber ; Telegrafi, Aida ; Lunsing, Roelineke J ; Burglen, Lydie ; Lesca, Gaetan ; Cho, Megan T ; Smith, Lacey A ; Sheidley, Beth R ; El Achkar, Christelle Moufawad ; Pearl, Phillip L ; Poduri, Annapurna ; Skraban, Cara M ; Tarpinian, Jennifer ; Nesbitt, Addie I ; Fransen van de Putte, Dietje E ; Ruivenkamp, Claudia A.L ; Rump, Patrick ; Chatron, Nicolas ; Sabatier, Isabelle ; De Bellescize, Julitta ; Guibaud, Laurent ; Sweetser, David A ; Waxler, Jessica L ; Wierenga, Klaas J ; Donadieu, Jean ; Narayanan, Vinodh ; Ramsey, Keri M ; Nava, Caroline ; Rivière, Jean-Baptiste ; Vitobello, Antonio ; Mau-Them, Frédéric Tran ; Philippe, Christophe ; Bruel, Ange-Line ; Duffourd, Yannis ; Thomas, Laurel ; Lelieveld, Stefan H ; Schuurs-Hoeijmakers, Janneke ; Brunner, Han G ; Keren, Boris ; Thevenon, Julien ; Faivre, Laurence ; Thomas, Gary ; Thauvin-Robinet, Christel
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pages631-631
issn0002-9297
eissn1537-6605
abstractDevelopmental and epileptic encephalopathies (DEEs) represent a large clinical and genetic heterogeneous group of neurodevelopmental diseases. The identification of pathogenic genetic variants in DEEs remains crucial for deciphering this complex group and for accurately caring for affected individuals (clinical diagnosis, genetic counseling, impacting medical, precision therapy, clinical trials, etc.). Whole-exome sequencing and intensive data sharing identified a recurrent de novo PACS2 heterozygous missense variant in 14 unrelated individuals. Their phenotype was characterized by epilepsy, global developmental delay with or without autism, common cerebellar dysgenesis, and facial dysmorphism. Mixed focal and generalized epilepsy occurred in the neonatal period, controlled with difficulty in the first year, but many improved in early childhood. PACS2 is an important PACS1 paralog and encodes a multifunctional sorting protein involved in nuclear gene expression and pathway traffic regulation. Both proteins harbor cargo(furin)-binding regions (FBRs) that bind cargo proteins, sorting adaptors, and cellular kinase. Compared to the defined PACS1 recurrent variant series, individuals with PACS2 variant have more consistently neonatal/early-infantile-onset epilepsy that can be challenging to control. Cerebellar abnormalities may be similar but PACS2 individuals exhibit a pattern of clear dysgenesis ranging from mild to severe. Functional studies demonstrated that the PACS2 recurrent variant reduces the ability of the predicted autoregulatory domain to modulate the interaction between the PACS2 FBR and client proteins, which may disturb cellular function. These findings support the causality of this recurrent de novo PACS2 heterozygous missense in DEEs with facial dysmorphim and cerebellar dysgenesis.
pubElsevier Inc
pmid
029656858
130290155
doi10.1016/j.ajhg.2018.09.002
oafree_for_read