Two brothers presented with rare clinical characteristics with a novel LAGE3 variant: a case report and literature review

Abstract

Background

Variants in the LAGE3 gene can lead to Galloway-Mowat syndrome (GAMOS), a rare genetic disease. Currently, there have been a total of 6 reported cases worldwide, all occurring in children under the age of 3 years old. The main features of LAGE3 variants include early-onset nephrotic syndrome, microcephaly, developmental delay, and neurological abnormalities, with a poor prognosis. However, there are few reports on mild clinical manifestations and prognosis associated with LAGE3 variants.

Case presentation

Here, we report two brothers, aged 9 and 5 years old respectively, from a family, both presenting with nephrotic syndrome with different types of renal pathology. They both had a high-arched palate and were treated with steroids and tacrolimus, resulting in negative urine protein. Genetic sequencing revealed that both siblings carried a hemizygous variant in the LAGE3 gene: c.389T > G (p.V130G). However, neither of them exhibited the typical features of microcephaly, developmental delay, or neurological abnormalities associated with LAGE3 gene variants. Currently, both siblings have normal renal function and are being regularly followed up with a good prognosis.

Conclusions

This report is the first to document patients with LAGE3 variants who do not exhibit microcephaly, developmental delay, or neurological abnormalities. Additionally, it is the first case where proteinuria manifested at an older age and had a positive prognosis. The two siblings represent the 7th and 8th cases of children with LAGE3 variants, expanding the genotype and phenotype spectrum of LAGE3 variants, providing new insights for clinical diagnosis and risk assessment.

Background

Galloway-Mowat syndrome (GAMOS) is a rare autosomal or X-linked recessive genetic disease characterized by nephrotic syndrome combined with microcephaly, intellectual and motor developmental delay as the main clinical features [1, 2]. Recent advancements in high-throughput sequencing technology have led to the discovery of new pathogenic genes associated with this syndrome, including WDR73, LAGE3, OSGEP, TP53RK, TPRKB, GON7, WDR4, and NUP133 [3]. Among these, LAGE3, as an important subunit of the KEOPS complex, plays a crucial role in RNA modification and protein translation. Variants in the LAGE3 gene have been linked to severe kidney dysfunction and neurological damage in GAMOS patients. However, there have been some cases that exhibit milder clinical phenotypes and a favorable prognosis [4]. LAGE3 variants related to nephrotic syndrome (NS) or GAMOS are extremely rare, with only 6 reported cases worldwide. Further research is needed to better understand the genotype-phenotype correlation in this disease. Here, we report two cases of NS patients with LAGE3 variants who did not present typical features such as microcephaly, developmental delay, or neurological abnormalities. Both patients received treatment with steroids and tacrolimus, resulting in negative urine protein and a good prognosis.

Case presentation

Patient 1

Patient 1 is a 9-year-old male who presented to our hospital in February 2023 due to “proteinuria discovered for 3 months.” He is the older brother in the family and was born via cesarean section at full term. His mother has congenital heart disease. The patient’s prenatal history, birth history, and past medical history are unremarkable. Upon physical examination, the patient’s height is 131 cm, head circumference is 50 cm, and weight is 31.2 kg. He appears alert with a normal head shape and a high-arched palate (Fig. 1C). Furthermore, we did not find any significant presence of high-arched palate in his parents (Fig. 1A-B). There is no significant edema in his body. Lung sounds are coarse, heart sounds are strong and regular, the abdomen is soft with negative shifting dullness, muscle tone is normal, and there are no abnormalities in the nervous system.

Fig. 1.

Identification of a novel hemizygous LAGE3 variant in a family with a high-arched palate and nephrotic syndrome. a-d The clinical presentation of a high-arched palate in the proband and their family members. e-i The image of the renal biopsy from the proband. j The pedigree diagram of the Chinese family. k Chromatograms show the results of Sanger sequencing of the LAGE3 variant c.389T > G for the proband (II-1) and his family members. K = G/T

Laboratory findings show a white blood cell count of 9.67 × 109/L, hemoglobin of 125 g/L, serum albumin of 24.6 g/L, total cholesterol of 4.71 mmol/L, and serum creatinine of 17.3 µmol/L. A 24-hour urine protein quantification test revealed 3.538 g/24 h of protein, with 3 + protein in the urine. The renal ultrasound indicated normal kidney size. Imaging studies including a chest X-ray, an abdominal ultrasound, a cardiac ultrasound, and an electrocardiogram were all normal.

The patient initially received a full course of steroids for 8 weeks, but his urine protein levels remained high. A renal biopsy performed in February 2023 showed minimal change disease (MCD) (Fig. 1E-I). He started oral immunosuppressive therapy (tacrolimus) that same month and tapered off steroids in October 2023. We performed genetic testing on the patient’s family using whole-exome sequencing and found that the proband carries a novel heterozygous missense variant in the LAGE3 gene (NM_006014:c.389T > G, p.V130G), which he inherited from his mother, which he inherited from his mother. His younger brother also carries the same genetic variant, consistent with the phenomenon of genetic segregation in family inheritance (Fig. 1J-K). Currently, the patient’s 24-hour urine protein quantification is within the normal range, his renal function is normal, and he is undergoing regular follow-up visits at our outpatient clinic.

Patient 2

Patient 2 is the younger brother, a 5-year-old male who presented to our hospital in May 2023 with a 3-day history of fever and foamy urine. He is the second child of the family, born at full term via cesarean section. There were no abnormalities in maternal history, birth history, or past medical history. Physical examination upon admission: Height 113.5 cm, head circumference 49.5 cm, weight 20.4 kg; alert, normal facial appearance and head shape, high-arched palate (Fig. 1D); no obvious edema, normal muscle tone; no abnormalities in the heart, lungs, abdomen, or limbs.

Laboratory findings: White blood cell count 10.16 × 109/L, hemoglobin 132 g/L, serum albumin 20.3 g/L, total cholesterol 6.74 mmol/L, blood creatinine 18.7 µmol/L, 24-hour urine protein quantification 2.647 g/24 h, urine protein 2+, abdominal ultrasound showed slightly enlarged left kidney (98.9 mm×45.2 mm) and right kidney (86.2 mm×39.2 mm) with increased parenchymal echogenicity. Chest X-ray, liver gallbladder pancreas spleen ultrasound, echocardiogram, and electrocardiogram were all normal.

Despite six weeks of steroid-induced remission therapy, the 24-hour urine protein quantification remained high. The parents refused a renal biopsy. In June 2023, the patient started oral immunosuppressive therapy (tacrolimus), and the steroids were tapered and stopped in April 2024. Currently, the patient has normal kidney function and negative urine protein. He is regularly followed up in our outpatient clinic.

Discussion and conclusions

Here, we report two brothers carrying the same novel LAGE3 variant (c.389T > G; p.V130G) causing GAMOS, without typical features such as microcephaly, developmental delay, and neurological abnormalities. The age of onset of proteinuria was later, clinical symptoms were mild, and prognosis was good. The LAGE3 gene consists of three exons, encoding one of the five subunits of the KEOPS complex, with a functional domain Pcc1 (Fig. 2A-B). Pcc1 tightly binds to the active site of Kae1 in the KEOPS complex, possibly activating Kae1 or promoting its dimerization, although the exact function of Pcc1 remains unknown [5–8]. GAMOS caused by a LAGE3 variant is a rare disease with a wide range of phenotypes, including NS, microcephaly, intellectual and motor developmental delay, distinctive facial features, skeletal abnormalities, hypotonia, epilepsy, low eye pressure, and hypothyroidism (Table 1) [2, 3, 9]. The prognosis of this disease is usually poor. Recently, there has been increasing attention on the relationship between LAGE3 variants and GAMOS phenotype. Chen et al. reported that patients with GAMOS caused by classical splice site variants (c.188 + 1 C > T; NM_006014) have milder symptoms and a better prognosis, providing new insights into the molecular mechanisms and clinical impact of LAGE3 variants [3]. Additionally, the co-occurrence of other pathogenic LAGE3 variants with variants in other genes, such as TRPC6 and NUP160, may lead to multisystem involvement and a more complex disease presentation [10]. Therefore, different types and locations of LAGE3 variants may have significant differences in molecular mechanisms, resulting in marked heterogeneity in clinical manifestations.

Fig. 2.

Analysis of the position of LAGE3 variants in mRNA and protein structural diagrams and amino acid conservation of these missense variants among different species. a-b The distribution of LAGE3 variants in the gene structure and protein domains. c Multiple amino acid sequence alignments of LAGE3 among different species for missense variants (p.V130G, p.F137S, and p.V106F)

Table 1.

Clinical features of patients with LAGE3 variants

Patients	P1	P2	3 (IV-1)	4 (16M0417)	5 (B65)	6 (B60)	7 (Younger brother of B60)	8
Sex	Male	Male	Male	Male	Male	Male	Male	Male
Nucleotide change	c.389T > G	c.389T > G	c.188 + 1G > A	c.188 + 1G > A	c.316G > T	c.410T > C	c.410T > C	c.317 + 4 A > G
Amino acid change	p.V130G	p.V130G	Splice	Splice	p.V106F	p.F137S	p.F137S	Splice
Family history	+	+	+	-	+	+	+	-
Clinvar	ND	ND	P	P	P	P	P	ND
ACMG	VUS	VUS	P	P	ND	ND	ND	ND
Renal biopsy	MCD	NP	FSGS	FSGS	MCD	FSGS	Segmental increase in mesangial cellularity and matrix; IgM and C3 deposits	NP
Ethnicity	China	China	China	China	European	Japanese	Japanese	American
Source of variation	Mother	Mother	Mother	ND	Mother	Mother	Mother	De novo
Renal phenotype	NS	NS	NS	Infantile NS	Infantile NS	NS	NS	Infantile NS
Age of onset of proteinuria	9Y	5Y11M	2Y	3 M	4 M	3Y	2Y	9 M
ESRD at last follow-up	-	-	-	+	+	+	+	-
Time from proteinuria to ERSD	-	-	-	4 M	1 M	5Y	6Y	-
Primary microcephaly	-	-	+	+	+	+	+	+
Abnormal brain MRI	NP	NP	+	+	+	+	+	+
Developmental delay	-	-	+	+	+	+	+	+
Neurologic abnormality	-	-	+	+	+	+	+	+
Gothic arch	+	+	-	-	-	+	+	-
References	This study	This study	Chen et al.	Liu et al.	Braun et al.	Malakasioti et al.	Malakasioti et al.	Baker et al.

Note: +, yes;-, no; ND, no data; P, pathogenic; VUS, uncertain significance; MCD, minimal change disease; NP, not performed; FSGS, focal segmental glomerulosclerosis; NS, nephrotic syndrome; Y, year; M, month

In comparison with the aforementioned report, this study identified a new LAGE3 variant c.389T > G (p.V130G). Multiple bioinformatics tools such as SIFT, Provean, and M-CAP predicted this variant as pathogenic, while other tools such as DEOGEN2, LIST_S2, MetaSVM, and PrimateAI predicted it as tolerated (see table - source GeneBe https://genebe.net/). Therefore, the variant’s pathogenicity needs to be evaluated in conjunction with clinical features and analyzed by functional validation. Comparison of the amino acid sequences of the LAGE3 protein in different species revealed that this variant, along with the p.F137S and p.V106F variants reported by Braun et al. [2]. is located in highly conserved regions of the LAGE3 protein (Fig. 2B-C). The affected brothers are both hemizygous, with their mother carrying the same variant, consistent with X-linked recessive (XR) disease and familial genetic co-segregation. The symptoms caused by the LAGE3 variant in this study are milder than previously reported, with the patient having good renal function and neurological status, leading to a better prognosis. This may be due to the p.V130G variant only partially weakening the LAGE3 protein function, rather than completely inactivating it. However, further functional validation of different variants is still needed using biological methods.

To date, only 5 types of LAGE3 variants have been found in the reported 6 GAMOS families (Table 1) [2–4, 9, 11]. These patients all exhibit kidney phenotypes, with some also showing a high-arched palate. Proteinuria appeared as early as 3 months and as late as 3 years, accompanied by microcephaly, developmental delay, and neurological symptoms. However, the patients in this study presented with proteinuria at a significantly later time compared to previous reports, showing steroid-resistant nephrotic syndrome (SRNS) with a high-arched palate. Due to the absence of developmental delay, intellectual disability, or neurological abnormalities in the proband and his brother, a complete cranial MRI was not performed, suggesting a milder form of GAMOS caused by a LAGE3 variant. Chen et al. reported a family with the largest number of cases of GAMOS, showing mild overall symptoms despite clear neurological and kidney phenotypes [3]. Mann et al. found that variants in the GAMOS-related gene PRDM15 can also cause isolated nephrotic syndrome, indicating that not all variants in GAMOS-related genes lead to neurological abnormalities and microcephaly [12]. In conclusion, LAGE3 variants exhibit a wide spectrum of clinical manifestations, ranging from isolated nephrotic syndrome to more complex forms of GAMOS.

LAGE3 variants can lead to different types of NS, mainly focal segmental glomerulosclerosis (FSGS) and MCD. In this study, Patient 1 was diagnosed with MCD, similar to the renal pathology of B65a’s brother reported by Braun et al. [2]. The severity extent of GAMOS kidney symptoms can range from mild non-nephrotic proteinuria to SRNS. The prognosis of GAMOS patients may be related to the age of onset of kidney disease. Currently, there are no specific treatment guidelines for NS caused by LAGE3 gene variants. The use of calcineurin inhibitors in genetic kidney diseases or GAMOS is not clearly defined. Takashi et al. reported that patients with LAGE3 variants did not achieve control of NS after treatment with corticosteroids and cyclophosphamide [11]; Georgia et al. found that up to 27.6% of children with single-gene causes of SRNS who received calcineurin inhibitors (CNIs) therapy can expect at least partial remission and a reduced risk of renal failure [13]. It is worth noting that in the two cases we reported, after treatment with CNIs, the patients’ urine protein gradually turned negative, successfully achieving a smooth reduction of steroids until discontinuation. Throughout the treatment process, their renal function remained normal. However, there are few reports on children with LAGE3 variants, and further research is needed on their diagnosis and treatment.

In conclusion, this study found that two brothers carrying the LAGE3 c.389T > G (p.V130G) variant did not exhibit microcephaly, developmental delay, or neurological disorders, further expanding the understanding of the genotype and phenotype spectrum. Additionally, the condition was controlled after immunosuppressive therapy, indicating a close association between this variant and mild clinical symptoms with a good prognosis. This suggests that in the management of diseases caused by LAGE3 variants in the future, the phenotypic differences caused by different variants should be comprehensively considered for risk assessment and treatment planning. This provides a new theoretical basis and practical guidance for early diagnosis and personalized treatment of GAMOS patients.

Abbreviations

GAMOS

Galloway-Mowat syndrome

NS

Nephrotic syndrome

MCD

Minimal change disease

FSGS

Focal segmental glomerulosclerosis

SRNS

Steroid-resistant nephrotic syndrome

CNIs

Calcineurin inhibitors

Author contributions

JL and CL conceived the study. JW and GZ wrote the original draft. JL and CL reviewed and edited the manuscript. LL searched for relevant literature and provided comments. All authors have read and approved the final manuscript.

Funding

This work was supported by the Key Scientific Research Project of Colleges and Universities in Henan Province (No. 22A310028) and the Zhengzhou Medical Research Project (No. ZZYK2024091).

Data availability

The datasets generated and analysed during the current study are available in the ClinVar repository, and the ClinVar accession number is SCV006081069.

Declarations

Ethics approval and consent to participate

This study has been approved by the Ethics Committee of the Children’s Hospital Affiliated to Zhengzhou University (2023-K-L010), and written informed consent has been obtained from the children and their parents.

Consent for publication

Written informed consent was obtained from the patients and their parents for the publication of this case report.

Competing interests

The authors declare no competing interests.