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

TitleEl-Hattab-Alkuraya syndrome caused by biallelic WDR45B pathogenic variants: Further delineation of the phenotype and genotype.
Publication TypeJournal Article
Year of Publication2022
AuthorsAlmannai, M, Marafi, D, Abdel-Salam, GMH, Zaki, MS, Duan, R, Calame, D, Herman, I, Levesque, F, Elbendary, HM, Hegazy, I, Chung, WK, Kavus, H, Saeidi, K, Maroofian, R, AlHashim, A, Al-Otaibi, A, Madhi, AAl, Al-Seood, HMAbou, Alasmari, A, Houlden, H, Gleeson, JG, Hunter, JV, Posey, JE, Lupski, JR, El-Hattab, AW
JournalClin Genet
Volume101
Issue5-6
Pagination530-540
Date Published2022 May
ISSN1399-0004
KeywordsAtrophy, Bone Diseases, Metabolic, Congenital Disorders of Glycosylation, Homozygote, Humans, Microcephaly, Nervous System Malformations, Pedigree, Phenotype, Quadriplegia, Seizures
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.

DOI10.1111/cge.14132
Alternate JournalClin Genet
PubMed ID35322404
PubMed Central IDPMC9359317
Grant ListT32 GM007526 / GM / NIGMS NIH HHS / United States
UM1 HG006542 / HG / NHGRI NIH HHS / United States
R35 NS105078 / NS / NINDS NIH HHS / United States
K08 HG008986 / HG / NHGRI NIH HHS / United States
T32 NS043124 / NS / NINDS NIH HHS / United States
R01 GM106373 / GM / NIGMS NIH HHS / United States
U01 HG011758 / HG / NHGRI NIH HHS / United States

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