Domingo-Gallego et al. BMC Nephrology (2019) 20:126 https://doi.org/10.1186/s12882-019-1317-y CASE REPORT Open Access Novel homozygous OSGEP gene pathogenic variants in two unrelated patients with Galloway-Mowat syndrome: case report and review of the literature Andrea Domingo-Gallego1,2, Mónica Furlano2, Marc Pybus1,2, Daniel Barraca3, Ana Belén Martínez3, Emiliano Mora Muñoz4, Roser Torra2† and Elisabet Ars1,2*† 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: Galloway-Mowat syndrome, Nephrotic syndrome, OSGEP, KEOPS complex, Genetic testing, Case report Background present dysmorphic facial features, including hypertelor- Galloway-Mowat syndrome (GAMOS) (OMIM #251300) ism, ear abnormalities, and micrognathia. Most affected is a rare autosomal recessive syndrome first described in individuals die in early childhood [1, 2]. The estimated 1968. It is a clinically heterogeneous condition character- prevalence is < 1/1,000,000 but it is likely that many cases ized by early-onset nephrotic syndrome associated with remain misdiagnosed or undiagnosed. microcephaly, gyral abnormalities of the brain, and Truncating variants in WDR73 gene were described as delayed psychomotor development. Most patients also the first monogenic cause of GAMOS in two families [3]. The protein encoded by this gene is implicated in * Correspondence: ears@fundacio-puigvert.es the regulation of the microtubule network during cell † Roser Torra and Elisabet Ars contributed equally to this work. cycle progression, proliferation, and survival [3–5]. 1 Molecular Biology Laboratory, Fundació Puigvert, Instituto de Investigaciones Biomédicas Sant Pau (IIB-Sant Pau), Universitat Autònoma de Homozygous missense variants in the WDR73 gene were Barcelona, REDinREN, Instituto de Investigación Carlos III, Cartagena 340-350, later reported [6, 7]. Recently, pathogenic variants in the 08025 Barcelona, Catalonia, Spain 2 OSGEP, LAGE3, TP53RK, and TPRKB genes have been Nephrology Department, Fundació Puigvert, Instituto de Investigaciones Biomédicas Sant Pau (IIB-Sant Pau), Universitat Autònoma de Barcelona, identified as novel monogenic causes of GAMOS. These REDinREN, Instituto de Investigación Carlos III, Barcelona, Catalonia, Spain genes encode four subunits of the evolutionary highly Full list of author information is available at the end of the article © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Domingo-Gallego et al. BMC Nephrology (2019) 20:126 Page 2 of 8 conserved KEOPS (kinase, endopeptidase, and other tubular atrophy, and primitive glomeruli (Fig. 1C). The pa- proteins of small size) complex. This complex plays tient progressed to end-stage renal disease and required an important role in brain and renal development. To peritoneal dialysis. He also presented left eye evisceration, date, the genetic cause of GAMOS has been reported dry right eye, and gastroesophageal reflux. At 5 months of in 54 families: OSGEP in 26 (48.15%), WDR73 in 19 age, the neurological examination revealed microcephaly (35.18%), TP53RK in 4 (7.40%), LAGE3 in 3 (5.55%), with a head circumference of 38.5 cm (percentile < 1, − and TPRKB in 2 (3.70%) [2–11]. 4.72 SD), severe psychomotor delay for his age, and axial Here, we report two unrelated patients with GAMOS hypotonia. Cranial magnetic resonance imaging (CMRI) carrying homozygous pathogenic variants in the newly revealed brain atrophy and absence of normal myelination identified OSGEP gene. of the brainstem, cerebellar white matter, bilateral hemi- spheric white matter, internal capsules, and corpus callo- Case presentation sum as well as abnormal intensity signal in the dentate Patient 1 was a first-child male born to healthy consan- nucleus and thalamus (Fig. 1D). In view of the congenital guineous parents from Spain with no previous family nephrotic syndrome and microcephaly with brain anomal- history of kidney disease (Table 1, Fig. 1A). He was born ies, a clinical diagnosis of GAMOS was suspected. The pa- at 39.4 weeks of gestation. Birth weight was 3400 g, tient presented progressive neurological deterioration and height was 51 cm, and head circumference was 34 cm, died at 8 months of age. with no dysmorphic features. Forty-five days after birth, Patient 2 was a female infant with normal karyotype the patient was diagnosed as having congenital nephrotic (46, XX) born to healthy consanguineous parents from syndrome with severe proteinuria, hypertension, and Pakistan. The patient had two healthy sisters and there hypothyroidism. He also presented edema, hyperkalemia, was no family history of kidney disease (Table 1, Fig. 2a). hyponatremia, and hypomagnesemia. Renal ultrasound She was born at 40.3 weeks of gestation. Birth weight showed poor corticomedullary differentiation in the right was 2940 g, height was 49 cm, and head circumference kidney. Renal biopsy showed diffuse mesangial sclerosis, was 32 cm with signs of microcephaly. Screening for Table 1 Clinical data of patients 1 and 2 Clinical features Patient 1 Patient 2 Sex Male Female Age at death 8 months 7 months Origin Spanish Pakistani Neonatal profile (at birth) Gestational period (weeks) 39.4 40.3 Weight (g) 3400 (58th percentile) 2940 (17th percentile) Height (cm) 51 (70th percentile) 49 (30th percentile) Head circumference (cm) 34 (28th percentile) 32 (3rd percentile) Renal phenotype Onset of NS (days) 45 75 Renal biopsy DMS, tubular atrophy, primitive glomeruli Increased glomerular mesangial matrix Renal ultrasound Poor corticomedullary differentiation Cortical hyperechogenicity Hyperkalemia Yes No Hypomagnesemia Yes No Neurological involvement Brain MRI Microcephaly, brain atrophy, poor myelination Microcephaly, brain atrophy Developmental delay Yes Yes Axial hypotonia Yes Yes Skeletal abnormalities No Arachnodactyly Dysmorphic features No Yes (wide nasal bridge, retrognathia, low set ears) Others Dry right eye Epileptiform activity Gastroesophageal reflux Seizures DMS Diffuse mesangial sclerosis, NS nephrotic syndrome Domingo-Gallego et al. BMC Nephrology (2019) 20:126 Page 3 of 8 a b c d 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) metabolic disorders and cerebral ultrasound were normal. Seventy-five days after birth, she presented with nephrotic The patient presented dysmorphic features (wide nasal range proteinuria, hypoproteinemia with severe hypoal- bridge, aquiline nose and retrognathia, low set ears, and buminemia, hypertriglyceridemia and hypercholesterol- arachnodactyly) with axial hypotonia and poor eye contact. emia. Serum creatinine and urea were normal. Abdominal Domingo-Gallego et al. BMC Nephrology (2019) 20:126 Page 4 of 8 a 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 ultrasound showed normal-sized kidneys and correct cor- with 100% of the bases covered at least 100X. Predic- ticomedullary differentiation with cortical hyperechogeni- tion of pathogenicity was evaluated using different bio- city, bilateral pleural effusion, and a discrete amount of informatic algorithms (DANN, GERP, dbNSFP.FATHMM, fluid in the abdominal cavity. Renal biopsy showed one LRT, MetaLR, MetaSVM, MutationAssessor, PROVEAN, glomerulus with increased mesangial matrix and two nor- SIFT, and MutationTaster). Clinical interpretation of vari- mal glomeruli; fibrosis and tubular atrophy were absent. ants was based on American College of Medical Genetics CMRI revealed severe brain atrophy with normal cerebel- (ACMG) recommendations [15]. All candidate pathogenic lum and brainstem. Electroencephalogram showed normal variants were validated by conventional polymerase chain brain activity with low-amplitude brain waves and occa- reaction amplification and Sanger sequencing. Familial sional frontal left epileptiform activity. The patient evolved segregation analysis was assessed. Analysis of copy num- with failure to thrive, anemia, and electrolyte disorders ber variations (CNVs) was performed using CoNVaDING and finally died from cardiorespiratory arrest in a sepsis (copy number variation detection in next-generation context at 7 months of age. sequencing gene panels) software [16]. Patient 1 carried a homozygous missense variant Genetic study c.81C > G p.(Asn27Lys) in exon 1 of the OSGEP gene Variant analyses of patients 1 and 2 were performed by (NM_017807), not previously described in the literature. targeted massive parallel sequencing using an updated This variant was predicted to be pathogenic by seven version of our kidney disease gene panel that includes prediction tools (DANN, GERP, LRT, MutationAssessor, more than 200 genes causative of or associated with MutationTaster, SIFT, and PROVEAN) and benign by inherited kidney diseases (including WDR73, TPRKB, three (dbNSFP.FATHMM, MetaLR, and MetaSVM). TP53RK, LARGE3, and OSGEP genes) [12]. This variant altered an evolutionarily highly conserved Briefly, libraries were prepared according to the manu- residue and was absent from the population databases facturer’s standard protocol, NimbleGen SeqCap EZ Genome Aggregation Database (gnomAD) and 1000 Library SR version 4.3. Patients’ DNAs were fragmented Genomes (Fig. 1B). Segregation analysis showed that and hybridized to the custom NimbleGen SeqCap EZ both parents were heterozygous carriers of this OSGEP Choice gene panel and sequenced on a NextSeq 500 variant (Fig. 1A). We concluded that this variant was instrument (Illumina). Sequence data analysis was per- likely pathogenic (Table 2). formed using an open-source in-house bioinformatic Patient 2 carried a homozygous missense variant pipeline, as previously reported [12–14]. The mean depth c.157A > T p.(Ile53Phe) localized in exon 2 of the OSGEP of coverage per exon of OSGEP ranged from 153 to 433, gene. This variant has not been previously reported in Domingo-Gallego et al. BMC Nephrology (2019) 20:126 Table 2 Information of the two identified variants in the OSGEP gene Population Databases Predictor scores Patient Variant dbSNP 1000G gnomAD ƒ DANN GERP LRT MA MT SIFT PROVEAN dbNSFP.FATHMM MetaLR MetaSVM Parental segregation ACMG (Variant confirmed classification) Patient 1 c.81C > G p.(Asn27Lys) No 0 0 P P P P P P P B B B Yes LP (PM2, PM3, PP1, PP2, PP3, PP4) Patient 2 c.157A > T p.(Ile53Phe) rs780944919 0 0.0000979 P B P P P B P B B B Yes LP (PM2, PM3, PP1, (South Asians) PP2, PP4) 1000G 1000 Genomes Project, ƒ Allele Frequency, B Benign, gnomAD genome Aggregation Database, LP Likely Pathogenic, MA MutationAssessor, MT MutationTaster, P Pathogenic Page 5 of 8 Domingo-Gallego et al. BMC Nephrology (2019) 20:126 Page 6 of 8 literature. The variant c.157A > T p.(Ile53Phe) was pre- indicates that OSGEP causes earlier onset of nephrotic syn- dicted to be pathogenic by five prediction tools (DANN, drome than WDR73 [2–4, 6–10]. Eighty percent (25/31) of LRT, MutationAssessor, MutationTaster, and PROVEAN) patients with OSGEP pathogenic variants developed neph- and benign by five (GERP, dbNSFP.FATHMM, MetaLR, rotic syndrome with a mean age at onset of 10.36 months SIFT, and MetaSVM). This variant was conserved in (ranging onset from birth to 13 years). In comparison, OSGEP orthologs to C. elegans and is extremely rare in the 35% (8/23) of patients with WDR73 pathogenic vari- general population (Fig. 2b), with a minor allele frequency ants presented nephrotic syndrome at a mean age of in South Asians is 0.00009799 (3 of 30,782 sequenced 7.7 years (ranging from 0.5 to 16 years). Our two pa- alleles, no homozygous individuals) in the gnomAD data- tients carrying OSGEP pathogenic variants presented base. The global allele frequency was lower than the 0.0001 with nephrotic syndrome before 3 months of age. threshold for recessive gene OSGEP. The parents were Renal manifestations described in GAMOS patients confirmed to be heterozygous carriers (Fig. 2a). We classi- vary from isolated proteinuria to steroid-resistant neph- fied this variant as likely pathogenic (Table 2). rotic syndrome, and some patients even have no renal alterations during follow-up period [2–8]. Intrafamilial Discussion and conclusions clinical variability has also been described in GAMOS. We report two patients who presented with nephrotic For instance, two siblings carrying a WDR73 pathogenic syndrome with onset at < 3 months old, primary micro- variant manifested contrasting renal phenotype [3]. One cephaly, and developmental delay, which are hallmarks of the affected siblings presented with nephrotic syn- of GAMOS. Both patients carried homozygous likely drome at the age of 5 years, rapidly developed chronic disease-causing variants in the OSGEP gene. This gene renal insufficiency, and died after a month, while the was recently identified as causative of GAMOS in a large other had no renal symptoms at the age of 7 years [3]. A cohort of 907 individuals with nephrotic syndrome [2]. homozygous OSGEP pathogenic variant, c.974A > G Pathogenic variants in one of the four genes TP53RK, p.(Arg325Gln), has also been associated with renal tubu- TPRKB, LAGE3, and OSGEP, encoding KEOPS complex lar anomalies [10]. It was detected in a girl with subunits, were found in 37 out of 91 patients with magnesium-wasting tubulopathy and partial Fanconi GAMOS. Independently, a homozygous pathogenic vari- syndrome with a normal glomerular filtration rate who ant in the OSGEP gene was reported in two siblings with never developed nephrotic syndrome [10]. Interestingly, a similar renal-neurological phenotype, also by whole ex- this variant was previously identified in two siblings with ome sequencing [8]. severe hypomagnesemia, hypercalciuria, and proteinuria The OSGEP gene encodes the O-sialoglycoprotein endo- but normal albumin levels [8]. The authors raised the peptidase enzyme, which regulates the second biosynthetic question of whether these patients should be considered step in the formation of N-6-threonylcarbamoyladenosine to be affected by a different clinical entity [8, 10]. in the cytosol, essential for mRNA translational initiation The review of the literature also indicates that patients and efficiency. The highly conserved KEOPS complex is with OSGEP pathogenic variants have a shorter life ex- implicated in several cell processes, such as control of telo- pectancy than those with WDR73 pathogenic variants. mere length, telomere-associated DNA damage response Seventy-one percent (22/31) of patients with OSGEP signaling, and genome maintenance. Zebrafish larvae pathogenic variants died at a mean age of 1.5 years (ran- knockout of the osgep gene resulted in primary microceph- ging from 6 weeks to 8 years). In line with these reported aly, with increased apoptosis in the brain compared with cases, our patients died at 8 and 7 months of age. However, controls and early lethality. Knockout mouse embryos also seven patients with OSGEP pathogenic variants were alive showed microcephaly compared with wild-type embryos. at 13 (2), 10.5 (1), 7 (1), 3.5 (1), and 2 (1) years and at 7 (1) Neither mutant fish nor mice showed any renal phenotype, months [2, 10]. It should be noted that four of them car- possibly due to embryonic early lethality [2]. ried the above-mentioned OSGEP variant, c.974A > G Great strides have been made in the understanding of p.(Arg325Gln), associated with renal tubular anomalies GAMOS disease over the past 4 years, with the identifi- [10]. Twenty-two percent (5/23) of patients carrying patho- cation of its genetic bases in some patients. However, genic variants in the WDR73 gene died at a mean age of the genetic etiology of more than three-quarters of 8.1 years (ranging from 2.5 to 17 years). patients with a clinical diagnosis of GAMOS remains Nearly all OSGEP variants reported as causative of elusive, suggesting that additional causative genes re- GAMOS are missense, except for two splicing variants main to be identified. Currently, the principal known [2, 8]. These variants are located throughout the OSGEP causative genes of GAMOS are OSGEP and WDR73. gene. By contrast, different types of variant in WDR73 A review of the literature based on 31 patients (26 causative of GAMOS have been reported in the litera- families) bearing OSGEP pathogenic variants and 23 ture, including nonsense (3), frameshift (3), and missense patients (13 families) with WDR73 pathogenic variants (4). No correlation seems to exist between the type or Domingo-Gallego et al. BMC Nephrology (2019) 20:126 Page 7 of 8 position of the variant and particular clinical fea- Consent for publication tures. Identification of the causative pathogenic vari- The parents of the patients provided written informed consent to publish this case report, including case description, medical data, and images, ant in patients 1 and 2 confirmed the initial clinical maintaining anonymity. suspicion of GAMOS and allowed precise genetic counseling to their parents. In particular, it allowed Competing interests RT is the Editorial Board Member of BMC Nephrology. The other authors prenatal diagnosis of a baby girl without GAMOS declare that they have no competing interests. for the parents of patient 1. In conclusion, we report two patients with GAMOS Publisher’s Note caused by OSGEP pathogenic variants. These two Springer Nature remains neutral with regard to jurisdictional claims in cases, in conjunction with the reported cases in the published maps and institutional affiliations. literature, add evidence that OSGEP pathogenic vari- Author details ants are the most prevalent cause of GAMOS and are 1 Molecular Biology Laboratory, Fundació Puigvert, Instituto de associated with a more severe phenotype than WDR73 Investigaciones Biomédicas Sant Pau (IIB-Sant Pau), Universitat Autònoma de Barcelona, REDinREN, Instituto de Investigación Carlos III, Cartagena 340-350, pathogenic variants. For these reasons, OSGEP variant 08025 Barcelona, Catalonia, Spain. 2Nephrology Department, Fundació analysis should be considered as the first step in gen- Puigvert, Instituto de Investigaciones Biomédicas Sant Pau (IIB-Sant Pau), etic diagnosis of patients with clinical suspicion of Universitat Autònoma de Barcelona, REDinREN, Instituto de Investigación Carlos III, Barcelona, Catalonia, Spain. 3Hospital General Universitario Gregorio GAMOS; this is especially true for those labs that do Marañón, Madrid, Spain. 4Hospital Universitario Mutua de Terrassa, Barcelona, not perform massive parallel sequencing and for those Catalonia, Spain. cases with early and severe onset of the disease. Gen- Received: 28 November 2018 Accepted: 29 March 2019 etic diagnosis of GAMOS is of paramount importance for genetic counseling and family planning and allows prenatal or preimplantation genetic diagnosis for fu- References 1. Galloway WH, Mowat AP. 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