Novel homozygous OSGEP gene pathogenic variants in two unrelated patients with Galloway-Mowat syndrome: case report and review of the literature

Abstract

Background: Galloway-Mowat syndrome (GAMOS) is a rare autosomal recessive disorder characterized by early-onset nephrotic syndrome and microcephaly with brain anomalies. WDR73 pathogenic variants were described as the first genetic cause of GAMOS and, very recently, four novel causative genes, OSGEP, LAGE3, TP53RK, and TPRKB, have been identified.

Case presentation: We present the clinical and genetic characteristics of two unrelated infants with clinical suspicion of GAMOS who were born from consanguineous parents. Both patients showed a similar clinical presentation, with early-onset nephrotic syndrome, microcephaly, brain atrophy, developmental delay, axial hypotonia, and early fatality. We identified two novel likely disease-causing variants in the OSGEP gene. These two cases, in conjunction with the findings of a literature review, indicate that OSGEP pathogenic variants are associated with an earlier onset of nephrotic syndrome and shorter life expectancy than WDR73 pathogenic variants.

Conclusions: Our findings expand the spectrum of pathogenic variants in the OSGEP gene and, taken in conjunction with the results of the literature review, suggest that the OSGEP gene should be considered the main known monogenic cause of GAMOS. Early genetic diagnosis of GAMOS is of paramount importance for genetic counseling and family planning.

Keywords: Case report; Galloway-Mowat syndrome; Genetic testing; KEOPS complex; Nephrotic syndrome; OSGEP.

Fig. 1

a Pedigree of patient 1 with a likely pathogenic OSGEP variant, c.81C > G p.(Asn27Lys), in homozygosity while his consanguineous parents are healthy heterozygous carriers. b The identified missense variant c.81C > G p.(Asn27Lys) affects a totally conserved amino acid N27 in OSGEP orthologs. c Silver-stained renal biopsy from patient 1 showed glomerular collapse with mesangial matrix increase, atrophic tubules, and interstitial fibrosis on light microscopy. d CMRI performed in patient 1 at 8 months of age: sagittal 3 Dimensional Imaging T1 sequence (a), axial reconstructions (b–e), and axial Turbo Spin Echo (TSE) T2 (f–j). k–o: Sequence TSE T2 of normal control individual. MRI revealed craniofacial disproportion in relation to microcephaly (a); supratentorial cortico-subcortical atrophy with increased extra-axial space, prominence of the frontal horns, and thinning of the corpus callosum (red arrow in a); bilateral subdural frontoparietal hygromas (red asterisks in h–j); and atrophy of the basal ganglia (h). A decrease in the number and depth of the grooves was observed (h–j) and there was an absence of normal myelination of the brainstem (red arrow in f), cerebellar peduncles (blue arrow in f), internal capsules (red arrow in h), and white bihemispheric substance (arrows in i and j). Hypointense T2 signal of the thalamus was evident (blue arrow in h). Enucleation of the left eye is denoted by the yellow arrow in f. Finally, there was an increase in the thickness of the cranial and facial subcutaneous cellular tissue (green arrows in a and b)

Fig. 2

a Pedigree of the family of patient 2 with a likely pathogenic OSGEP variant c.157A > T p.(Ile53Phe) in homozygosity in the proband (arrow) and heterozygosity in her healthy parents. b Conservation of I53 in OSGEP orthologs to C. elegans