El-Hattab-Alkuraya syndrome caused by biallelic WDR45B pathogenic variants: Further delineation of the phenotype and genotype.
Mohammed AlmannaiDana MarafiGhada M H Abdel-SalamMaha Saad ZakiRuizhi DuanDaniel CalameIsabella HermanFelix LevesqueHasnaa M ElbendaryIbrahim HegazyWendy K ChungHaluk KavusKolsoum SaeidiReza MaroofianAqeela AlHashimAli Al-OtaibiAsma Al MadhiHager M Abou Al-SeoodAli AlasmariHenry HouldenJoseph G GleesonJill V HunterJennifer E PoseyJames R LupskiAyman W. El-HattabPublished in: Clinical genetics (2022)
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.
Keyphrases
- copy number
- early onset
- intellectual disability
- zika virus
- resting state
- high resolution
- white matter
- cerebral ischemia
- cerebral palsy
- late onset
- botulinum toxin
- subarachnoid hemorrhage
- functional connectivity
- heart failure
- autism spectrum disorder
- left ventricular
- multiple sclerosis
- gene expression
- single molecule
- atrial fibrillation
- climate change
- cord blood