PMID- 36067010
OWN - NLM
STAT- MEDLINE
DCOM- 20230206
LR  - 20230223
IS  - 1460-2083 (Electronic)
IS  - 0964-6906 (Print)
IS  - 0964-6906 (Linking)
VI  - 32
IP  - 4
DP  - 2023 Jan 27
TI  - Germline homozygous missense DEPDC5 variants cause severe refractory early-onset 
      epilepsy, macrocephaly and bilateral polymicrogyria.
PG  - 580-594
LID - 10.1093/hmg/ddac225 [doi]
AB  - DEPDC5 (DEP Domain-Containing Protein 5) encodes an inhibitory component of the 
      mammalian target of rapamycin (mTOR) pathway and is commonly implicated in 
      sporadic and familial focal epilepsies, both non-lesional and in association with 
      focal cortical dysplasia. Germline pathogenic variants are typically heterozygous 
      and inactivating. We describe a novel phenotype caused by germline biallelic 
      missense variants in DEPDC5. Cases were identified clinically. Available records, 
      including magnetic resonance imaging and electroencephalography, were reviewed. 
      Genetic testing was performed by whole exome and whole-genome sequencing and 
      cascade screening. In addition, immunohistochemistry was performed on skin 
      biopsy. The phenotype was identified in nine children, eight of which are 
      described in detail herein. Six of the children were of Irish Traveller, two of 
      Tunisian and one of Lebanese origin. The Irish Traveller children shared the same 
      DEPDC5 germline homozygous missense variant (p.Thr337Arg), whereas the Lebanese 
      and Tunisian children shared a different germline homozygous variant 
      (p.Arg806Cys). Consistent phenotypic features included extensive bilateral 
      polymicrogyria, congenital macrocephaly and early-onset refractory epilepsy, in 
      keeping with other mTOR-opathies. Eye and cardiac involvement and severe 
      neutropenia were also observed in one or more patients. Five of the children died 
      in infancy or childhood; the other four are currently aged between 5 months and 6 
      years. Skin biopsy immunohistochemistry was supportive of hyperactivation of the 
      mTOR pathway. The clinical, histopathological and genetic evidence supports a 
      causal role for the homozygous DEPDC5 variants, expanding our understanding of 
      the biology of this gene.
CI  - (c) The Author(s) 2022. Published by Oxford University Press.
FAU - Ververi, Athina
AU  - Ververi A
AUID- ORCID: 0000-0002-8393-4444
AD  - Department of Clinical Genetics & Genomic Medicine, Great Ormond Street Hospital 
      for Children NHS Foundation Trust, London, UK.
AD  - Genetic Unit, 1st Obstetrics-Gynaecology Department, Aristotle University of 
      Thessaloniki, Papageorgiou General Hospital, Thessaloniki, Greece.
FAU - Zagaglia, Sara
AU  - Zagaglia S
AD  - Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of 
      Neurology, London, UK.
AD  - Chalfont Centre for Epilepsy, Chalfont St. Peter, UK.
FAU - Menzies, Lara
AU  - Menzies L
AD  - Department of Clinical Genetics & Genomic Medicine, Great Ormond Street Hospital 
      for Children NHS Foundation Trust, London, UK.
FAU - Baptista, Julia
AU  - Baptista J
AUID- ORCID: 0000-0003-0915-5028
AD  - Faculty of Health, University of Plymouth, Plymouth, UK.
FAU - Caswell, Richard
AU  - Caswell R
AUID- ORCID: 0000-0003-0713-4602
AD  - Exeter Genomics Laboratory, Royal Devon University Healthcare NHS Foundation 
      Trust, Exeter, UK.
FAU - Baulac, Stephanie
AU  - Baulac S
AD  - Institut du Cerveau - Paris Brain Institute - ICM, Inserm, CNRS, Sorbonne 
      Universite, F-75013 Paris, France.
FAU - Ellard, Sian
AU  - Ellard S
AD  - Exeter Genomics Laboratory, Royal Devon University Healthcare NHS Foundation 
      Trust, Exeter, UK.
FAU - Lynch, Sally
AU  - Lynch S
AD  - Academic Centre on Rare Diseases, University College Dublin School of Medicine 
      and Medical Science, Dublin, Ireland.
AD  - Department of Clinical Genetics, Children's Health Ireland (CHI) at Crumlin, 
      Dublin, Ireland.
CN  - Genomics England Research Consortium
FAU - Jacques, Thomas S
AU  - Jacques TS
AD  - Developmental Biology and Cancer Research and Teaching Department, UCL Great 
      Ormond Street Institute of Child Health, London, UK.
AD  - Department of Histopathology, Great Ormond Street Hospital for Children NHS 
      Foundation Trust, London, UK.
FAU - Chawla, Maninder Singh
AU  - Chawla MS
AD  - Department of Neuroradiology, Oslo University Hospital, Oslo, Norway.
FAU - Heier, Martin
AU  - Heier M
AD  - Department of Clinical Neuroscience for Children, Oslo University Hospital, Oslo, 
      Norway.
FAU - Kulseth, Mari Ann
AU  - Kulseth MA
AD  - Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
FAU - Mero, Inger-Lise
AU  - Mero IL
AD  - Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
FAU - Vatevik, Anne Katrine
AU  - Vatevik AK
AD  - National Center for Epilepsy-SSE, Oslo Univeristy Hospital, Oslo, Norway.
FAU - Kraoua, Ichraf
AU  - Kraoua I
AD  - Research Laboratory LR18SP04, Department of Child and Adolescent Neurology, 
      National Institute Mongi Ben Hmida of Neurology, Tunis, Tunisia. Faculty of 
      Medicine of Tunis, University of Tunis El Manar, Tunis, Tunisia.
FAU - Ben Rhouma, Hanene
AU  - Ben Rhouma H
AD  - Research Laboratory LR18SP04, Department of Child and Adolescent Neurology, 
      National Institute Mongi Ben Hmida of Neurology, Tunis, Tunisia. Faculty of 
      Medicine of Tunis, University of Tunis El Manar, Tunis, Tunisia.
FAU - Ben Younes, Thouraya
AU  - Ben Younes T
AD  - Research Laboratory LR18SP04, Department of Child and Adolescent Neurology, 
      National Institute Mongi Ben Hmida of Neurology, Tunis, Tunisia. Faculty of 
      Medicine of Tunis, University of Tunis El Manar, Tunis, Tunisia.
FAU - Miladi, Zouhour
AU  - Miladi Z
AD  - Research Laboratory LR18SP04, Department of Child and Adolescent Neurology, 
      National Institute Mongi Ben Hmida of Neurology, Tunis, Tunisia. Faculty of 
      Medicine of Tunis, University of Tunis El Manar, Tunis, Tunisia.
FAU - Ben Youssef Turki, Ilhem
AU  - Ben Youssef Turki I
AD  - Research Laboratory LR18SP04, Department of Child and Adolescent Neurology, 
      National Institute Mongi Ben Hmida of Neurology, Tunis, Tunisia. Faculty of 
      Medicine of Tunis, University of Tunis El Manar, Tunis, Tunisia.
FAU - Jones, Wendy D
AU  - Jones WD
AD  - Department of Clinical Genetics & Genomic Medicine, Great Ormond Street Hospital 
      for Children NHS Foundation Trust, London, UK.
FAU - Clement, Emma
AU  - Clement E
AD  - Department of Clinical Genetics & Genomic Medicine, Great Ormond Street Hospital 
      for Children NHS Foundation Trust, London, UK.
FAU - Eltze, Christin
AU  - Eltze C
AD  - Department of Paediatric Neurology, Great Ormond Street Hospital for Children NHS 
      Foundation Trust, London, UK.
FAU - Mankad, Kshitij
AU  - Mankad K
AD  - Department of Radiology, Great Ormond Street Hospital for Children NHS Foundation 
      Trust, London, UK.
FAU - Merve, Ashirwad
AU  - Merve A
AD  - Department of Histopathology, Great Ormond Street Hospital for Children NHS 
      Foundation Trust, London, UK.
FAU - Parker, Jennifer
AU  - Parker J
AD  - North Thames Genomic Laboratory Hub, Great Ormond Street Hospital for Children 
      NHS Foundation Trust, London, UK.
FAU - Hoskins, Bethan
AU  - Hoskins B
AD  - North Thames Genomic Laboratory Hub, Great Ormond Street Hospital for Children 
      NHS Foundation Trust, London, UK.
FAU - Pressler, Ronit
AU  - Pressler R
AD  - Department of Clinical Neurophysiology, Great Ormond Street Hospital for Children 
      NHS Foundation Trust, London, UK.
FAU - Sudhakar, Sniya
AU  - Sudhakar S
AD  - Department of Radiology, Great Ormond Street Hospital for Children NHS Foundation 
      Trust, London, UK.
FAU - DeVile, Catherine
AU  - DeVile C
AD  - Department of Paediatric Neurology, Great Ormond Street Hospital for Children NHS 
      Foundation Trust, London, UK.
FAU - Homfray, Tessa
AU  - Homfray T
AD  - SW Thames Regional Genetics Service, St George's Hospital, St George's University 
      of London, London, UK.
FAU - Kaliakatsos, Marios
AU  - Kaliakatsos M
AD  - Department of Paediatric Neurology, Great Ormond Street Hospital for Children NHS 
      Foundation Trust, London, UK.
CN  - Ponnudas (Prab) Prabhakar
FAU - Robinson, Robert
AU  - Robinson R
AD  - Department of Paediatric Neurology, Great Ormond Street Hospital for Children NHS 
      Foundation Trust, London, UK.
FAU - Keim, Sara Margrete Boen
AU  - Keim SMB
AD  - Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
FAU - Habibi, Imen
AU  - Habibi I
AD  - Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.
FAU - Reymond, Alexandre
AU  - Reymond A
AUID- ORCID: 0000-0003-1030-8327
AD  - Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.
FAU - Sisodiya, Sanjay M
AU  - Sisodiya SM
AD  - Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of 
      Neurology, London, UK.
AD  - Chalfont Centre for Epilepsy, Chalfont St. Peter, UK.
FAU - Hurst, Jane A
AU  - Hurst JA
AD  - Department of Clinical Genetics & Genomic Medicine, Great Ormond Street Hospital 
      for Children NHS Foundation Trust, London, UK.
LA  - eng
GR  - Medical Research Council/United Kingdom
GR  - Department of Health/United Kingdom
GR  - Wellcome Trust/United Kingdom
GR  - Cancer Research UK/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Hum Mol Genet
JT  - Human molecular genetics
JID - 9208958
RN  - 0 (GTPase-Activating Proteins)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - 0 (DEPDC5 protein, human)
SB  - IM
MH  - Humans
MH  - Mutation
MH  - *Polymicrogyria
MH  - GTPase-Activating Proteins/genetics
MH  - TOR Serine-Threonine Kinases/genetics
MH  - *Epilepsies, Partial/genetics
MH  - *Megalencephaly/genetics
MH  - *Epileptic Syndromes
PMC - PMC9896472
EDAT- 2022/09/07 06:00
MHDA- 2023/02/07 06:00
PMCR- 2022/09/06
CRDT- 2022/09/06 12:22
PHST- 2022/06/19 00:00 [received]
PHST- 2022/08/16 00:00 [revised]
PHST- 2022/08/31 00:00 [accepted]
PHST- 2022/09/07 06:00 [pubmed]
PHST- 2023/02/07 06:00 [medline]
PHST- 2022/09/06 12:22 [entrez]
PHST- 2022/09/06 00:00 [pmc-release]
AID - 6693142 [pii]
AID - ddac225 [pii]
AID - 10.1093/hmg/ddac225 [doi]
PST - ppublish
SO  - Hum Mol Genet. 2023 Jan 27;32(4):580-594. doi: 10.1093/hmg/ddac225.