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Hum Mutat. 2019 Jan;40(1):42-47. doi: 10.1002/humu.23675. Epub 2018 Nov 18.

Early infantile-onset epileptic encephalopathy 28 due to a homozygous microdeletion involving the WWOX gene in a region of uniparental disomy.

Author information

1
NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, NIH, Bethesda, Maryland.
2
Office of the Clinical Director, NHGRI, NIH, Bethesda, Maryland.

Abstract

The genetic etiologies of many rare disorders, including early infantile epileptic encephalopathies, are largely undiagnosed. A 6-year-old girl was admitted to the National Institutes of Health Undiagnosed Diseases Program with profound intellectual disability, infantile-onset seizures, chronic respiratory failure, facial dysmorphisms, skeletal abnormalities, and atrial septum defect. A large region of homozygosity was discovered on chromosome 16, spanning 16q22.1-16q24.3' caused by uniparental disomy (UPD) that included a maternally inherited homozygous microdeletion covering exon 6 of WWOX (NM_016373.3). mRNA expression analysis revealed that the deletion led to nonsense-mediated decay of the NM_016373.3 transcript; the exon 6 of an alternative transcript (NM_130791.3), lacking the short-chain dehydrogenase, was utilized. The microdeletion in WWOX explains the seizures and intellectual disability, while pathogenic variants in another gene, HSPG2, are likely responsible for the patient's skeletal abnormalities. This report describes a rare autosomal recessive disorder with multiple genetic etiologies, one of which involves UPD.

KEYWORDS:

blended phenotype; epileptic encephalopathy; perlecan; rare diseases; uniparental disomy

PMID:
30362252
PMCID:
PMC6296882
[Available on 2020-01-01]
DOI:
10.1002/humu.23675

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