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

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.