Extending the mutation spectrum for Galloway-Mowat syndrome to include homozygous missense mutations in the WDR73 gene

Abstract

Galloway-Mowat syndrome is a rare autosomal-recessive disorder classically described as the combination of microcephaly and nephrotic syndrome. Recently, homozygous truncating mutations in WDR73 (WD repeat domain 73) were described in two of 31 unrelated families with Galloway-Mowat syndrome which was followed by a report of two sibs in an Egyptian consanguineous family. In this report, seven affecteds from four families showing biallelic missense mutations in WDR73 were identified by exome sequencing and confirmed to follow a recessive model of inheritance. Three-dimensional modeling predicted conformational alterations as a result of the mutation, supporting pathogenicity. An additional 13 families with microcephaly and renal phenotype were negative for WDR73 mutations. Missense mutations in the WDR73 gene are reported for the first time in Galloway-Mowat syndrome. A detailed phenotypic comparison of all reported WDR73-linked Galloway-Mowat syndrome patients with WDR73 negative patients showed that WDR73 mutations are limited to those with classical Galloway-Mowat syndrome features, in addition to cerebellar atrophy, thin corpus callosum, brain stem hypoplasia, occasional coarse face, late-onset and mostly slow progressive nephrotic syndrome, and frequent epilepsy.

Keywords: Galloway-Mowat syndrome; WDR73; cerebellar atrophy; coarse face; nephrotic syndrome.

FIG. 1

(A) Pedigrees. Pedigrees showing autosomal recessive inheritance pattern in families. Individual 2286-II-7 shown with gray shading is not affected similarly. (B) Gestalt of the patients. Facial pictures of the affecteds showing coarse facial features such as full lips and cheeks, broad forehead, bushy eyebrows, flat nasal root with fleshy nasal tip. (C) Brain imaging studies. MR findings of affected individuals showing cerebellar atrophy, and thin corpus callosum [arrows] and brain stem hypoplasia [arrowheads]. (D) Histopathological studies. Histological slide from the renal biopsy of 1486-II-3 showing glomerular changes illustrating the collapsing variant of focal segmental glomerular sclerosis. (200× magnification, Jones silver stain-top, PAS stains-middle and bottom). [Color figure can be seen in the online version of this article, available at http://wileyonlinelibrary.com/journal/ajmga].

FIG. 2

Protein modeling. (A) Comparison of the wild-type protein and the predictions of the outcome of the missense mutations. (B) Comparison of the analyses of electrostatic potential of the wild-type and the mutated proteins. [Color figure can be seen in the online version of this article, available at http://wileyonlinelibrary.com/journal/ajmga].