El‐Hattab‐Alkuraya syndrome caused by biallelic WDR45B pathogenic variants: Further delineation of the phenotype and genotype

Abstract

Homozygous pathogenic variants in WDR45B were first identified in six subjects from three unrelated families with global development delay, refractory seizures, spastic quadriplegia, and brain malformations. Since the initial report in 2018, no further cases have been described. In this report, we present 12 additional individuals from seven unrelated families and their clinical, radiological, and molecular findings. Six different variants in WDR45B were identified, five of which are novel. Microcephaly and global developmental delay were observed in all subjects, and seizures and spastic quadriplegia in most. Common findings on brain imaging include cerebral atrophy, ex vacuo ventricular dilatation, brainstem volume loss, and symmetric under‐opercularization. El‐Hattab‐Alkuraya syndrome is associated with a consistent phenotype characterized by early onset cerebral atrophy resulting in microcephaly, developmental delay, spastic quadriplegia, and seizures. The phenotype appears to be more severe among individuals with loss‐of‐function variants whereas those with missense variants were less severely affected suggesting a potential genotype–phenotype correlation in this disorder. A brain imaging pattern emerges which is consistent among individuals with loss‐of‐function variants and could potentially alert the neuroradiologists or clinician to consider WDR45B‐related El‐Hattab‐Alkuraya syndrome.

WIPI proteins: Biological functions and related syndromes

“…Recently, our group published detailed clinical, molecular, and radiological features of 12 new subjects with El-Hattab-Alkuraya syndrome (Almannai et al, 2022). Similar to what was observed in the initial report, the main features of this syndrome in this cohort are GDD, spastic quadriplegia, microcephaly, and early onset and refractory epilepsy (Almannai et al, 2022).…”

“…Recently, our group published detailed clinical, molecular, and radiological features of 12 new subjects with El-Hattab-Alkuraya syndrome (Almannai et al, 2022). Similar to what was observed in the initial report, the main features of this syndrome in this cohort are GDD, spastic quadriplegia, microcephaly, and early onset and refractory epilepsy (Almannai et al, 2022). Furthermore, neuroradiological findings in this syndrome are homogenous, especially among individuals with loss-offunction variants and therefore four criteria were proposed that could suggest the diagnosis of El-Hattab-Alkuraya syndrome.…”

“…These include: cerebral atrophy that is disproportionately most prominent in frontal lobes, ex-vacuo ventricular dilatation with notable posterior-horn predominance, brainstem atrophy with flattening of belly of the pons, and symmetric underopercularization. A possible genotype-phenotype correlation was demonstrated as two individuals with a homozygous missense variant had a milder phenotype with less prominent clinical and radiological features compared to the rest of subjects with complete loss-of-function variants (Almannai et al, 2022).…”

A homozygous variant of WDR45B results in global developmental delay: Additional case and literature review

“…As WDR45 and WDR45B were also reported associated with development delay, for example, J Suleiman et al described a homozygous pathogenic variant (c.673C>T, p.R225*) in two families. The probands exhibited profound development delay, early‐onset refractory epilepsy, progressive spastic quadriplegia, contractures, and brain malformations (Suleiman et al, 2018); Najmabadi et al reported a homozygous missense variant (R109Q) from three members of a closely related family with intellectual disability and microcephaly (Najmabadi et al, 2011); Almannai et al presented 12 individuals from seven unrelated families with microcephaly, global developmental delay, seizures, and spastic quadriplegia (Almannai et al, 2022). These studies demonstrated the role of WDR45B in neurodevelopmental diseases.…”

“…To date, variants in WDR45B are rare, and clinical features are relatively heterogeneous. Only two homozygous nonsense variants (c.799C>T (p. Q267*); c.673C>T (p. R225*)), three splicing variants (c.619‐3A>G; c.427+4A>G; c.67+1G>T), one frameshift variant (c.428‐10_435del18), and two missense variants (p. R109Q; p.R225Q) of WDR45B have been identified in 11 families (Almannai et al, 2022; Najmabadi et al, 2011; Suleiman et al, 2018).…”