Further delineation of the phenotype caused by biallelic variants in the WDR4 gene

Abstract

Microcephalic primordial dwarfisms are a group of rare Mendelian disorders characterized by severe growth retardation and microcephaly. The molecular basis is heterogeneous, with disease-causing genes implicated in different cellular functions. Recently, 2 patients were reported with the same homozygous variant in the WDR4 gene, coding for an enzyme responsible for the m⁷G₄₆ post transcriptional modification of tRNA. We report here two sisters harboring compound heterozygous variants of WDR4. Their phenotype differs from that of the first two described patients: they both have a severe microcephaly but only one of the two sisters had a head circumference at birth below −2 SD, their intellectual deficiency is less severe, and they have a GH deficiency and a partial hypogonadotropic hypogonadotropism. One of the two variants is a frameshift mutation, and the other one is a missense occurring in the same nucleotide affected by the first reported pathogenic variant, which could therefore be a mutational hot spot. The description of these two sisters allow us to confirm that biallelic variants in the WDR4 gene can lead to a specific phenotype, characterized by severe growth retardation and microcephaly.

Graphical abstract

Further delineation of theWDR4 associated phenotype.

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