WDR73 Mutations Cause Infantile Neurodegeneration and Variable Glomerular Kidney Disease

Abstract

Infantile-onset cerebellar atrophy (CA) is a clinically and genetically heterogeneous trait. Galloway-Mowat syndrome (GMS) is a rare autosomal recessive disease, characterized by microcephaly with brain anomalies including CA in some cases, intellectual disability, and early-infantile-onset nephrotic syndrome. Very recently, WDR73 deficiency was identified as the cause of GMS in five individuals. To evaluate the role of WDR73 mutations as a cause of GMS and other forms of syndromic CA, we performed Sanger or exome sequencing in 51 unrelated patients with CA and variable brain anomalies and in 40 unrelated patients with a diagnosis of GMS. We identified 10 patients from three CA and from two GMS families with WDR73 mutations including the original family described with CA, mental retardation, optic atrophy, and skin abnormalities (CAMOS). There were five novel mutations, of which two were truncating and three were missense mutations affecting highly conserved residues. Individuals carrying homozygous WDR73 mutations mainly presented with a pattern of neurological and neuroimaging findings as well as intellectual disability, while kidney involvement was variable. We document postnatal onset of CA, a retinopathy, basal ganglia degeneration, and short stature as novel features of WDR73-related disease, and define WDR73-related disease as a new entity of infantile neurodegeneration.

Keywords: Galloway-Mowat; SCAR5; WDR73; basal ganglia; cerebellar atrophy; intellectual disability; optic atrophy; retinopathy.

Figure 1

Detection of WDR73 mutations in five families. A, Simplified pedigrees of unrelated families segregating WDR73 mutations. All marriages with affected offspring were consanguineous. Note that affected individuals were present in three branches of family 2 (complete pedigree can be found in Nicolas et al., 2010). Individuals II-6 in family 2, II-1 in family 3, and II-1 in family 4 were reportedly affected, but neither sufficient clinical information nor DNA samples were available for confirmation of mutations and genotype-phenotype correlation analysis. B, Sequence chromatograms displaying homozygous mutations in affected patients (P) from each family compared with wild-type (WT). Nucleotide numbering uses +1 as the A of the ATG translation initiation codon in the reference sequence, with the initiation codon as codon 1. C, The three identified missense mutations affect invariantly conserved amino acids in WDR73 orthologues. D, Linkage intervals of family 1 and the reported linkage region for family 2 (Delague et al., 2002) on chromosome 15q show a shared interval harboring WDR73. Scheme of the WDR73 gene with exons displayed as blocks and of the WDR73 protein with predicted domains. Mutations identified by Colin et al. (2014), Ben-Omran et al. (2015) and in this study are indicated in black and red, respectively (triangles denote missense mutations, hexagons denote truncating mutations); all reported mutations were observed in homozygous state in patients.

Figure 2

Progressive cerebellar atrophy and basal ganglia involvement in two siblings homozygous for WDR73 mutation p.(Trp136fs2*). Serial brain MRIs show progression of cerebellar atrophy in patient II-2 from family 1: Brain MRI demonstrate mild enlargement of outer cerebrospinal fluid spaces and normal signal intensity of basal ganglia at three months of age (A, D), but displays severe cerebellar atrophy as indicated by an arrow in (B) and shows bilateral T2-weighed hyperintensities of putamina (arrows in E) at one year and four months of age. Most severe cerebellar atrophy as indicated by an arrow in (C) and T2-weighed hyperintensities of putamina as indicated by arrows in (F) are present in the affected sister (II-1) at 9.5 years of age.