Inspired by a patient
Yang C, Zhang Y, Song Z, Yi Z, Li F. Novel compound heterozygous mutations in the WWOX gene cause early infantile epileptic encephalopathy. Int J Dev Neurosci. 2019 Oct 24;79:45-48. doi: 10.1016/j.ijdevneu.2019.10.003. [Epub ahead of print]
Defects of WW domain-containing oxidoreductase (WWOX) has been associated with autosomal recessive spinocerebellar ataxia type 12 (SCAR12) and severe early-onset epileptic encephalopathy. The mutations in this gene can lead to global developmental delay, acquired microcephaly, and epilepsy. We report an infant with an autosomal recessive severe early-onset epileptic encephalopathy. Whole exome sequencing analysis was applied to the patient. Novel compound heterozygous mutations in the WWOX gene, c.173-2A > G and c.775 T > C (p.Ser259Pro), were identified. The present study expands our knowledge of WWOX mutations and related phenotypes, and provides new information on the genetic defects associated with this disease for clinical diagnosis.
Mori T, Goji A, Toda Y, Ito H, Mori K, Kohmoto T, Imoto I, Kagami S. A 16q22.2-q23.1 deletion identified in a male infant with West syndrome. Brain Dev. 2019 Nov;41(10):888-893.
In partial monosomy of the distal part of chromosome 16q, abnormal facial features, intellectual disability (ID), and feeding dysfunction are often reported. However, seizures are not typical and the majority of them were seizure-free. Here we present the case of a 16q22.2-q23.1 interstitial deletion identified in a male patient with severe ID, facial anomalies including forehead protrusions and flat nose bridge, patent ductus arteriosus, bilateral vocal cord atresia treated by tracheotomy, and West syndrome, which were developed 10 months after birth. Although phenobarbital, sodium valproate (VPA), and zonisamide were not effective as monotherapies or combination therapies, the patient's epileptic seizures and electroencephalogram anomalies disappeared following combined therapy with lamotrigine and VPA. Although WW Domain Containing Oxidoreductase (WWOX), which is known as a cause of autosomal recessive epileptic encephalopathy, was included within the 6.8-Mb deleted region which identified by targeted panel sequencing and validated by chromosomal microarray analysis, no pathogenic variants were detected in the other allele of WWOX. Therefore, it is possible that other genes within or outside of the long deleted region or their interactions may cause West syndrome in this patient.
Ben-Salem S, Al-Shamsi AM, John A, Ali BR, Al-Gazali L. A novel whole exon deletion in WWOX gene causes early epilepsy, intellectual disability and optic atrophy. J Mol Neurosci. 2015 May; 56(1):17-23.
Recent studies have implicated the WW domain-containing oxidoreductase encoding gene (WWOX) in a severe form of autosomal recessive neurological disorder. This condition showed an overlapping spectrum of clinical features including spinocerebellar ataxia associated with generalized seizures and delayed psychomotor development to growth retardation, spasticity, and microcephaly. We evaluated a child from a consanguineous Emirati family that presented at birth with growth retardation, microcephaly, epileptic seizures, and later developed spasticity and delayed psychomotor development. Screening for deletions and duplications using whole-chromosomal microarray analysis identified a novel homozygous microdeletion encompassing exon 5 of the WWOX gene. Analysis of parental DNA indicated that this deletion was inherited from both parents and lies within a large region of homozygosity. Sanger sequencing of the cDNA showed that the deletion resulted in exon 5 skipping leading to a frame-shift and creating a premature stop codon at amino acid position 212. Quantification of mRNA revealed striking low level of WWOX expression in the child and moderate level of expression in the mother compared to a healthy control. To the best of our knowledge, this is the first homozygous germline structural variation in WWOX gene resulting in truncated transcripts that were presumably subject to NMD pathway. Our findings extend the clinical and genetic spectrum of WWOX mutations and support a crucial role of this gene in neurological development.
Peter B, Dinu V, Liu L, Huentelman M, Naymik M, Lancaster H, Vose C, Schrauwen I. Exome Sequencing of Two Siblings with Sporadic Autism Spectrum Disorder and Severe Speech Sound Disorder Suggests Pleiotropic and Complex Effects. Behav Genet. 2019 Jul;49(4):399-414.
Recent studies of autism spectrum disorder (ASD) and childhood apraxia of speech (CAS) have resulted in conflicting conclusions regarding the comorbidity of these disorders on phenotypic grounds. In a nuclear family with two dually affected and one unaffected offspring, whole-exome sequences were evaluated for single nucleotide and indel variants and CNVs. The affected siblings but not the unaffected sibling share a rare deleterious compound heterozygous mutation in WWOX, implicated both in ASD and motor control. In addition, one of the affected children carries a rare deleterious de novo mutation in the ASD candidate gene RIMS1. The two affected children but not their unaffected sibling inherited deleterious variants with relevance for ASD and/or CAS. WWOX, RIMS1, and several of the genes harboring the inherited variants are expressed in the brain during prenatal and early postnatal development. Results suggest compound heterozygosity as a cause of ASD and CAS, pleiotropic gene effects, and potentially additional, complex genetic effects.