A Recurrent De Novo PACS2 Heterozygous Missense Variant Causes Neonatal-Onset Developmental Epileptic Encephalopathy, Facial Dysmorphism, and Cerebellar Dysgenesis - Université de Bourgogne Accéder directement au contenu
Article Dans Une Revue American Journal of Human Genetics Année : 2018

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

Katrina Tatton-Brown
  • Fonction : Auteur
E. Backer
  • Fonction : Auteur
Erik-Jan Kamsteeg
  • Fonction : Auteur
Margje Sinnema
  • Fonction : Auteur
Margot R.F. Reijnders
  • Fonction : Auteur
David Bearden
  • Fonction : Auteur
Roelineke Lunsing
  • Fonction : Auteur
Lydie Burglen
Lacey Smith
  • Fonction : Auteur
Beth Sheidley
  • Fonction : Auteur
Christelle Moufawad El Achkar
  • Fonction : Auteur
Annapurna Poduri
  • Fonction : Auteur
Cara Skraban
  • Fonction : Auteur
Jennifer Tarpinian
  • Fonction : Auteur
Dietje Fransen van de Putte
  • Fonction : Auteur
Patrick Rump
  • Fonction : Auteur
David Sweetser
  • Fonction : Auteur
Jessica Waxler
  • Fonction : Auteur
Klaas Wierenga
  • Fonction : Auteur
- Ddd Study
  • Fonction : Auteur
Vinodh Narayanan
  • Fonction : Auteur
Keri Ramsey
  • Fonction : Auteur
- C4rcd Research Group
  • Fonction : Auteur

Résumé

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.

Dates et versions

hal-02064909 , version 1 (12-03-2019)

Identifiants

Citer

Heather E. Olson, Nolwenn Jean-Marçais, Edward Yang, Delphine Héron, Katrina Tatton-Brown, et al.. A Recurrent De Novo PACS2 Heterozygous Missense Variant Causes Neonatal-Onset Developmental Epileptic Encephalopathy, Facial Dysmorphism, and Cerebellar Dysgenesis. American Journal of Human Genetics, 2018, 102 (5), pp.995-1007. ⟨10.1016/j.ajhg.2018.03.005⟩. ⟨hal-02064909⟩
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