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Eur J Paediatr Neurol. 2019 Feb 19. pii: S1090-3798(18)30411-2. doi: 10.1016/j.ejpn.2019.02.003. [Epub ahead of print]

Novel WWOX deleterious variants cause early infantile epileptic encephalopathy, severe developmental delay and dysmorphism among Yemenite Jews.

Author information

1
Pediatric Genetics Unit, Schneider Children's Medical Center of Israel, Petach Tikva, Israel; Raphael Recanati Genetic Institute, Rabin Medical Center, Petach Tikva, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. Electronic address: hubshman@bcm.edu.
2
Pediatric Neurology Unit, Kaplan Medical Center Rehovot, Israel.
3
Shaare Zedek Medical Center, Hebrew University School of Medicine, Jerusalem, Israel.
4
Laboratory of Molecular Medicine, Rambam Health Care Campus, Haifa, Israel.
5
Laboratory of Molecular Medicine, Rambam Health Care Campus, Haifa, Israel; Genomic Research Department, Emedgene Technologies, Tel-Aviv, Israel.
6
Gene by Gene, Genomic Research Center, Houston, TX, USA.
7
Variantyx, Inc, Framingham, MA, USA.
8
Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; Variantyx, Inc, Framingham, MA, USA.
9
Institute of Medical Genetics, Kaplan Medical Center, Rehovot, Israel.
10
Pediatric Genetics Unit, Schneider Children's Medical Center of Israel, Petach Tikva, Israel; Raphael Recanati Genetic Institute, Rabin Medical Center, Petach Tikva, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
11
Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; Radiology Unit, Schneider Children's Medical Center of Israel, Petach Tikva, Israel.
12
Metabolic Diseases Unit, Safra Children Hospital, Sheba Medical Center, Tel Hashomer, Israel.
13
Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
14
Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; Metabolic Neurogenetic Clinic, Wolfson Medical Center, Holon, Israel; Institute of Medical Genetics, Wolfson Medical Center, Holon, Israel.
15
Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; Metabolic Neurogenetic Clinic, Wolfson Medical Center, Holon, Israel.
16
Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; Institute of Rare Diseases, The Danek Gertner Institute of Human Genetics, Sheba Medical Center, Tel Hashomer, Israel.
17
Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; Pediatric Neurology Unit, Safra Children Hospital, Sheba Medical Center, Tel Hashomer, Israel.
18
Pediatric Genetics Unit, Schneider Children's Medical Center of Israel, Petach Tikva, Israel; Raphael Recanati Genetic Institute, Rabin Medical Center, Petach Tikva, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; Felsenstein Medical Research Center, Petach Tikva, Israel.
19
Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; Pediatric Neurology Unit, Safra Children Hospital, Sheba Medical Center, Tel Hashomer, Israel; The Pinchas Borenstein Talpiot Medical Leadership Program, The Chaim Sheba Medical Center, 52621, Ramat Gan, Israel.

Abstract

The human WW Domain Containing Oxidoreductase (WWOX) gene was originally described as a tumor suppressor gene. However, recent reports have demonstrated its cardinal role in the pathogenesis of central nervous systems disorders such as epileptic encephalopathy, intellectual disability, and spinocerebellar ataxia. We report on six patients from three unrelated families of full or partial Yemenite Jewish ancestry exhibiting early infantile epileptic encephalopathy and profound developmental delay. Importantly, four patients demonstrated facial dysmorphism. Exome sequencing revealed that four of the patients were homozygous for a novel WWOX c.517-2A > G splice-site variant and two were compound heterozygous for this variant and a novel c.689A > C, p.Gln230Pro missense variant. Complementary DNA sequencing demonstrated that the WWOX c.517-2A > G splice-site variant causes skipping of exon six. A carrier rate of 1:177 was found among Yemenite Jews. We provide the first detailed description of patients harboring a splice-site variant in the WWOX gene and propose that the clinical synopsis of WWOX related epileptic encephalopathy should be broadened to include facial dysmorphism. The increased frequency of the c.517-2A > G splice-site variant among Yemenite Jews coupled with the severity of the phenotype makes it a candidate for inclusion in expanded preconception screening programs.

KEYWORDS:

3′ splice site; Early infantile epileptic encephalopathy; Intellectual disability; WW Domain Containing Oxidoreductase

PMID:
30853297
DOI:
10.1016/j.ejpn.2019.02.003

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