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

Galloway-Mowat syndrome (GAMOS) (OMIM #251300) is a rare autosomal recessive syndrome first described in 1968. It is a clinically heterogeneous condition characterized by early-onset nephrotic syndrome associated with microcephaly, gyral abnormalities of the brain, and delayed psychomotor development. Most patients also present dysmorphic facial features, including hypertelorism, ear abnormalities, and micrognathia. Most affected individuals die in early childhood [1, 2]. The estimated prevalence is < 1/1,000,000 but it is likely that many cases remain misdiagnosed or undiagnosed.

Truncating variants in WDR73 gene were described as the first monogenic cause of GAMOS in two families [3]. The protein encoded by this gene is implicated in the regulation of the microtubule network during cell cycle progression, proliferation, and survival [3‐5]. Homozygous missense variants in the WDR73 gene were later reported [6, 7]. Recently, pathogenic variants in the OSGEP, LAGE3, TP53RK, and TPRKB genes have been identified as novel monogenic causes of GAMOS. These genes encode four subunits of the evolutionary highly conserved KEOPS (kinase, endopeptidase, and other proteins of small size) complex. This complex plays an important role in brain and renal development. To date, the genetic cause of GAMOS has been reported in 54 families: OSGEP in 26 (48.15%), WDR73 in 19 (35.18%), TP53RK in 4 (7.40%), LAGE3 in 3 (5.55%), and TPRKB in 2 (3.70%) [2‐11].

Patient 1 was a first-child male born to healthy consanguineous parents from Spain with no previous family history of kidney disease (Table 1, Fig. 1A). He was born at 39.4 weeks of gestation. Birth weight was 3400 g, height was 51 cm, and head circumference was 34 cm, with no dysmorphic features. Forty-five days after birth, the patient was diagnosed as having congenital nephrotic syndrome with severe proteinuria, hypertension, and hypothyroidism. He also presented edema, hyperkalemia, hyponatremia, and hypomagnesemia. Renal ultrasound showed poor corticomedullary differentiation in the right kidney. Renal biopsy showed diffuse mesangial sclerosis, tubular atrophy, and primitive glomeruli (Fig. 1C). The patient progressed to end-stage renal disease and required peritoneal dialysis. He also presented left eye evisceration, dry right eye, and gastroesophageal reflux. At 5 months of age, the neurological examination revealed microcephaly with a head circumference of 38.5 cm (percentile < 1, − 4.72 SD), severe psychomotor delay for his age, and axial hypotonia. Cranial magnetic resonance imaging (CMRI) revealed brain atrophy and absence of normal myelination of the brainstem, cerebellar white matter, bilateral hemispheric white matter, internal capsules, and corpus callosum as well as abnormal intensity signal in the dentate nucleus and thalamus (Fig. 1D). In view of the congenital nephrotic syndrome and microcephaly with brain anomalies, a clinical diagnosis of GAMOS was suspected. The patient presented progressive neurological deterioration and died at 8 months of age.

Patient 2 was a female infant with normal karyotype (46, XX) born to healthy consanguineous parents from Pakistan. The patient had two healthy sisters and there was no family history of kidney disease (Table 1, Fig. 2a). She was born at 40.3 weeks of gestation. Birth weight was 2940 g, height was 49 cm, and head circumference was 32 cm with signs of microcephaly. Screening for metabolic disorders and cerebral ultrasound were normal. The patient presented dysmorphic features (wide nasal bridge, aquiline nose and retrognathia, low set ears, and arachnodactyly) with axial hypotonia and poor eye contact. Seventy-five days after birth, she presented with nephrotic range proteinuria, hypoproteinemia with severe hypoalbuminemia, hypertriglyceridemia and hypercholesterolemia. Serum creatinine and urea were normal. Abdominal ultrasound showed normal-sized kidneys and correct corticomedullary differentiation with cortical hyperechogenicity, bilateral pleural effusion, and a discrete amount of fluid in the abdominal cavity. Renal biopsy showed one glomerulus with increased mesangial matrix and two normal glomeruli; fibrosis and tubular atrophy were absent. CMRI revealed severe brain atrophy with normal cerebellum and brainstem. Electroencephalogram showed normal brain activity with low-amplitude brain waves and occasional frontal left epileptiform activity. The patient evolved with failure to thrive, anemia, and electrolyte disorders and finally died from cardiorespiratory arrest in a sepsis context at 7 months of age.

We report two patients who presented with nephrotic syndrome with onset at < 3 months old, primary microcephaly, and developmental delay, which are hallmarks of GAMOS. Both patients carried homozygous likely disease-causing variants in the OSGEP gene. This gene was recently identified as causative of GAMOS in a large cohort of 907 individuals with nephrotic syndrome [2]. Pathogenic variants in one of the four genes TP53RK, TPRKB, LAGE3, and OSGEP, encoding KEOPS complex subunits, were found in 37 out of 91 patients with GAMOS. Independently, a homozygous pathogenic variant in the OSGEP gene was reported in two siblings with a similar renal-neurological phenotype, also by whole exome sequencing [8].

The OSGEP gene encodes the O-sialoglycoprotein endopeptidase enzyme, which regulates the second biosynthetic step in the formation of N-6-threonylcarbamoyladenosine in the cytosol, essential for mRNA translational initiation and efficiency. The highly conserved KEOPS complex is implicated in several cell processes, such as control of telomere length, telomere-associated DNA damage response signaling, and genome maintenance. Zebrafish larvae knockout of the osgep gene resulted in primary microcephaly, with increased apoptosis in the brain compared with controls and early lethality. Knockout mouse embryos also showed microcephaly compared with wild-type embryos. Neither mutant fish nor mice showed any renal phenotype, possibly due to embryonic early lethality [2].

Great strides have been made in the understanding of GAMOS disease over the past 4 years, with the identification of its genetic bases in some patients. However, the genetic etiology of more than three-quarters of patients with a clinical diagnosis of GAMOS remains elusive, suggesting that additional causative genes remain to be identified. Currently, the principal known causative genes of GAMOS are OSGEP and WDR73.

A review of the literature based on 31 patients (26 families) bearing OSGEP pathogenic variants and 23 patients (13 families) with WDR73 pathogenic variants indicates that OSGEP causes earlier onset of nephrotic syndrome than WDR73 [2‐4, 6‐10]. Eighty percent (25/31) of patients with OSGEP pathogenic variants developed nephrotic syndrome with a mean age at onset of 10.36 months (ranging onset from birth to 13 years). In comparison, 35% (8/23) of patients with WDR73 pathogenic variants presented nephrotic syndrome at a mean age of 7.7 years (ranging from 0.5 to 16 years). Our two patients carrying OSGEP pathogenic variants presented with nephrotic syndrome before 3 months of age.

Renal manifestations described in GAMOS patients vary from isolated proteinuria to steroid-resistant nephrotic syndrome, and some patients even have no renal alterations during follow-up period [2‐8]. Intrafamilial clinical variability has also been described in GAMOS. For instance, two siblings carrying a WDR73 pathogenic variant manifested contrasting renal phenotype [3]. One of the affected siblings presented with nephrotic syndrome at the age of 5 years, rapidly developed chronic renal insufficiency, and died after a month, while the other had no renal symptoms at the age of 7 years [3]. A homozygous OSGEP pathogenic variant, c.974A > G p.(Arg325Gln), has also been associated with renal tubular anomalies [10]. It was detected in a girl with magnesium-wasting tubulopathy and partial Fanconi syndrome with a normal glomerular filtration rate who never developed nephrotic syndrome [10]. Interestingly, this variant was previously identified in two siblings with severe hypomagnesemia, hypercalciuria, and proteinuria but normal albumin levels [8]. The authors raised the question of whether these patients should be considered to be affected by a different clinical entity [8, 10].

The review of the literature also indicates that patients with OSGEP pathogenic variants have a shorter life expectancy than those with WDR73 pathogenic variants. Seventy-one percent (22/31) of patients with OSGEP pathogenic variants died at a mean age of 1.5 years (ranging from 6 weeks to 8 years). In line with these reported cases, our patients died at 8 and 7 months of age. However, seven patients with OSGEP pathogenic variants were alive at 13 (2), 10.5 (1), 7 (1), 3.5 (1), and 2 (1) years and at 7 (1) months [2, 10]. It should be noted that four of them carried the above-mentioned OSGEP variant, c.974A > G p.(Arg325Gln), associated with renal tubular anomalies [10]. Twenty-two percent (5/23) of patients carrying pathogenic variants in the WDR73 gene died at a mean age of 8.1 years (ranging from 2.5 to 17 years).

Nearly all OSGEP variants reported as causative of GAMOS are missense, except for two splicing variants [2, 8]. These variants are located throughout the OSGEP gene. By contrast, different types of variant in WDR73 causative of GAMOS have been reported in the literature, including nonsense (3), frameshift (3), and missense (4). No correlation seems to exist between the type or position of the variant and particular clinical features. Identification of the causative pathogenic variant in patients 1 and 2 confirmed the initial clinical suspicion of GAMOS and allowed precise genetic counseling to their parents. In particular, it allowed prenatal diagnosis of a baby girl without GAMOS for the parents of patient 1.

In conclusion, we report two patients with GAMOS caused by OSGEP pathogenic variants. These two cases, in conjunction with the reported cases in the literature, add evidence that OSGEP pathogenic variants are the most prevalent cause of GAMOS and are associated with a more severe phenotype than WDR73 pathogenic variants. For these reasons, OSGEP variant analysis should be considered as the first step in genetic diagnosis of patients with clinical suspicion of GAMOS; this is especially true for those labs that do not perform massive parallel sequencing and for those cases with early and severe onset of the disease. Genetic diagnosis of GAMOS is of paramount importance for genetic counseling and family planning and allows prenatal or preimplantation genetic diagnosis for future pregnancies.