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.

Keywords: WDR45B; autophagy; autosomal recessive (AR) trait; brain atrophy; neurodevelopmental disorders (NDD).

Figure 1.

Pedigrees of families included in this report. When available, genotype for family members is indicated.

Figure 2.

a: frontal view of Subject 1 (F1-II3) showing: facial asymmetry, bitemporal narrowing, thick and arched eyebrows, upslanted and narrow palpebral fissures, hypertelorism, fullness of upper eyelids, and full cheeks. b: frontal view of Subject 2 (F1-II7) showing: Broad forehead and epicanthal folds. c and d: frontal and lateral views of Subject 4 (F3-II1): long face, bitemporal narrowing, thick and arched eyebrows, downslanted palpebral fissures, large ears, long philtrum, thin upper lip, and broad chin. e and f: frontal and lateral views of Subject 6 (F4-II5) showing narrow palpebral fissures, hypertelorism, large ears, thick lips, long philtrum, and retromicrognathia. g: frontal view of Subject 9 (F5-III11) showingelongated face, bitemporal narrowing, thick and arched eyebrows with synophrys, epicanthal folds, hypertelorism, large ears, depressed nasal bridge, maxillary hypoplasia, long philtrum, and elongated jaw. h: frontal view of Subject 11 (F6-II8) showing elongated face, bitemporal narrowing, thick and arched eyebrows, hypertelorism, large ears, depressed nasal bridge, maxillary hypoplasia, long and smooth philtrum, and elongated jaw.

Figure 3.. Brain MRI images for subjects with biallelic variants in WDR45B.

Select MRI brain images of Subject 1 (a1–4), Subject 2 (b1–4), Subject 4 (c1–4), Subject 5 (d1–4), Subject 6 (e1–3), Subject 7 (f1–4), Subject 8 (g1–4), Subject 9 (h1–4), Subject 11 (i1–4), and Subject 12 (j1–4). First column represents T1-weighted mid-sagittal images; Second column represents T1-weight or T2-weight coronal images; Third column represents T1-weight axial images while the fourth column represents T2-weight axial images. The white horizontal line separates panels a and b (for Subjects 1–2 with missense variant (c.674G>A; p.R225Q) and panels c-h (for the subjects with the loss of function variants) to show the differences in the MRI features seen in both groups. The cerebral atrophy and giant cisterna magna (large white arrow heads) are seen on panels 1a-1j. Corpus callosum thinning (grey arrows) and brainstem volume loss with flattening of belly of pons (grey arrow heads) seen in 1b-1j. Dysplastic hippocampi (black arrows) can be seen on the coronal images on panels 2c-2j. The disproportionate frontal lobe atrophy (white arrows), symmetric under-opercularization (small white arrow heads), and posterior-horn predominance pattern of the ventriculomegaly (grey asterisks) are best seen on panels 3c-3j and 4c-4j.