The phenotypic spectrum of WWOX-related disorders: 20 additional cases of WOREE syndrome and review of the literature

Abstract

Purpose: Germline WWOX pathogenic variants have been associated with disorder of sex differentiation (DSD), spinocerebellar ataxia (SCA), and WWOX-related epileptic encephalopathy (WOREE syndrome). We review clinical and molecular data on WWOX-related disorders, further describing WOREE syndrome and phenotype/genotype correlations.

Methods: We report clinical and molecular findings in 20 additional patients from 18 unrelated families with WOREE syndrome and biallelic pathogenic variants in the WWOX gene. Different molecular screening approaches were used (quantitative polymerase chain reaction/multiplex ligation-dependent probe amplification [qPCR/MLPA], array comparative genomic hybridization [array-CGH], Sanger sequencing, epilepsy gene panel, exome sequencing), genome sequencing.

Results: Two copy-number variations (CNVs) or two single-nucleotide variations (SNVs) were found respectively in four and nine families, with compound heterozygosity for one SNV and one CNV in five families. Eight novel missense pathogenic variants have been described. By aggregating our patients with all cases reported in the literature, 37 patients from 27 families with WOREE syndrome are known. This review suggests WOREE syndrome is a very severe epileptic encephalopathy characterized by absence of language development and acquisition of walking, early-onset drug-resistant seizures, ophthalmological involvement, and a high likelihood of premature death. The most severe clinical presentation seems to be associated with null genotypes.

Conclusion: Germline pathogenic variants in WWOX are clearly associated with a severe early-onset epileptic encephalopathy. We report here the largest cohort of individuals with WOREE syndrome.

Keywords: WWOX; encephalopathy; epilepsy.

Fig. 1

WWOX germline pathogenic variants identified in patients with constitutional WWOX-related disorders (SCAR12, WOREE syndrome, and DSD). a Copy-number variations (n = 12). DSD disorder of sex development, IF in frame, OOF out of frame, WOREE WWOX-related epileptic encephalopathy. b Single-nucleotide variations (n = 23). MTS mitochondrial targeting sequence, NLS nuclear localization signal, SRD short-chain dehydrogenase reductase.

Fig. 2

Photographs of individuals with WWOX-related epileptic encephalopathy (WOREE) syndrome. Note major axial hypotonia (P4 and P17); hypotonic facial appearance (all patients); round face, full cheeks, and short neck (P2, P4, P7, P11, P12, P13, P14, P17, and P18).

Fig. 3

Brain magnetic resonance image (MRI) of individuals with WWOX-related epileptic encephalopathy (WOREE) syndrome. a–j Hypoplastic corpus callosum on sagittal planes. k–q Cerebral atrophy and enlarged subarachnoid spaces on axial planes (P4, P6, P14) and coronal planes (P3, P7, P17). r–t Symmetric white matter hypersignal on axial T2. u–v Plagiocephaly and asymmetric lateral ventricle on axial T2 planes. w P19 sagittal T1 circular lesions (hyposignal) of the medial part of the corpus callosum. m month, P patient, y year old.