Neurological Disease Syndrome Caused by a STAG1 Gene Variant: A Case Report and Literature Review

ABSTRACT

Background

The cohesin complex is a multifunctional unit that plays a crucial role in DNA repair, replication, chromosome segregation, and gene expression. Dysfunctions in this complex can lead to a spectrum of developmental disorders collectively known as cohesinopathies.

Case

We retrospectively analysed the clinical data of a 2‐year‐old boy who was admitted to the hospital with seizures. Genetic testing identified a heterozygous de novo variant in STAG1 at the c.2549G > A (p.Gly850Asp) locus.

Methods

A comprehensive literature review was conducted to summarize previously reported STAG1 variants and their associated clinical features.

Conclusion

This study expands the molecular spectrum of STAG1 variants. This suggests that genetic testing is highly important, especially for neurodevelopmental disorders with unknown causes. It can facilitate early intervention and guide prenatal diagnosis and genetic counseling.

We present a case of a child with a neurodevelopmental disorder associated with a mutation in the STAG1 gene, aiming to raise awareness of this type of disorder.

1. Introduction

The cohesin complex is a highly conserved, multifunctional protein complex essential for DNA repair, replication, chromosome segregation, and gene expression. It consists of four core proteins—SMC1A, SMC3, RAD21 and STAG1/2—along with regulatory proteins that mediate its interaction with chromosomes. Mutations in the genes encoding these proteins have been implicated in a group of multisystem developmental disorders known as cohesinopathies. Here, we present a case of a child with a neurodevelopmental disorder associated with a mutation in the STAG1 gene, aiming to raise awareness of this type of disorder.

2. Case Report

A 2‐year‐4‐month boy was admitted to the Epilepsy Center of the Children's Hospital of Shandong University with convulsive seizures persisting for 13 days. He exhibited two distinct types of seizures:

1. His eyes deviated to the left; his limbs became stiff and trembled (especially on the left side), and he was unconscious during this period. These episodes lasted for approximately 1–2 min before resolving. He experienced three such seizures over the 13‐day period.

2. His arms lifted involuntarily, and he occasionally had clusters of seizures; each cluster consisted of 4–5 seizures, with a maximum of six clusters per day. No treatment was administered prior to hospitalization.

The child was the third‐born (G3P3) and was delivered via caesarean section at full term, with a birth weight of 3.8 kg. His mother's pregnancy and birth history were unremarkable. His developmental milestones were as follows: He raised his head and rolled over at 4 months, sat independently at 6 months, crawled at 8 months, walked at 1 year and 1 month and spoke his first words consciously (mom and dad) at 1 year and 4 months. By 2 years of age, he could run and jump. However, at the time of admission, he could only speak reduplicated words with occasional slurring, and he lagged behind his peers in both intellectual and motor development. Family history revealed that his father had a history of febrile seizures in early childhood, whereas his mother and two sisters were healthy. On physical examination, his height was 98 cm (+3 SD), and his weight was 13.5 kg (+1SD). Occipitofrontal circumference (OFC) was not reported. He could say ‘mom’ and ‘dad’, but his speech was unclear. He was unable to recognize people consistently, follow commands to identify his five senses or perform a waving gesture to say goodbye. Facial dysmorphic features included widely spaced eyes, deep sockets and a missing incisor (Figure 1). Cardiopulmonary, abdominal and neurological examinations revealed no obvious abnormalities.

FIGURE 1.

Facial phenotype of the patient with a STAG1 point mutation.

Laboratory tests, including routine blood tests, plasma ammonia, blood lactate, heart‐liver‐kidney function tests, erythrocyte sedimentation rate and calcitoninogen levels, were all within generally normal limits. No abnormalities were detected in the screening for inherited metabolic diseases. Magnetic resonance imaging of the brain revealed an abnormal signal in the right cerebellum, which was considered an artefact. No significant abnormalities were observed in the hippocampus. A 24‐h video electroencephalogram (EEG) recorded generalized seizures, epileptic spasms and multiple seizure clusters, with some episodes occurring more than 10 times or as isolated events. During the interictal period, widespread and multifocal discharges were observed, occasionally presenting as segmental‐like hypsarrhythmia. Whole‐exome sequencing (WES) (proband, mother and father) identified a heterozygous variant at NM_005862.3: c.2549G > A (p.Gly850Asp) loci in the STAG1 gene (Figure 2). The variant was a de novo missense variant, and it was classified as possibly pathogenic. The final diagnosis for the child were (1) epilepsy, epileptic spasms and hereditary (STAG1‐related); (2) intellectual and motor developmental delay. The patient was initially treated with oral topiramate at a dose of 0.9 mg/(kg·d), which was gradually increased to 5 mg/(kg·d). Corticosteroids were administered intravenously, followed by sequential oral prednisone. By the 14th day of treatment, a follow‐up EEG recorded two epileptic spasmodic seizures and widespread interictal discharges. A ketogenic diet and valproate (8 mg/kg·d) were introduced to further reduce seizure frequency. The child was followed up regularly, with the last visit occurring at 4 years and 8 months of age. He had been seizure‐free for nearly 2 years, allowing for an attempt to taper topiramate. At the last follow‐up, the child exhibited unsteady running and jumping, along with poorly organized and poorly articulated speech. He remained on convalescent treatment.

FIGURE 2.

One‐generation sequencing of the NM_005862.3: c.2549G > A (p.Gly850Asp) locus of the STAG1 gene. In order, a, b, and c are the first witness, the father of the first witness, and the mother of the first witness.

3. Discussion

STAG1 is a constituent subunit of the nuclear phosphoprotein RAD21, a key component of the chromosomal cohesin complex (Cheng et al. 2020). This complex plays an important role in sister chromatid cohesion and segregation, with each subunit participating in essential cohesion‐related processes, including chromosome cohesion during the S phase, gene transcription regulation during interphase and DNA damage repair. STAG1, one of the subunits, has a specific role in telomere cohesion. Lesions in any component of this complex can impair neurodevelopment. A group of disorders with overlapping clinical manifestations, collectively termed ‘cohesinopathies’, arise from mutations affecting the cohesin complex. Among these, two of the most well‐characterized syndromes are Cornelia de Lange syndrome (CdLS) (OMIM 122470, 300590, 610759, 614701 and 300882) and Roberts syndrome (OMIM 268300) (Piché et al. 2019). A study by Lehalle et al. (2017) reviewed 17 patients with STAG1 gene variants and identified a distinctive set of clinical features, including wide mouths, deep concave eyes and mental retardation. Approximately 50% of these patients experienced seizures, and a smaller percentage had microcephaly. These findings suggest that STAG1 gene variants may underlie a distinct class of neurodevelopmental disorders. Similarly, a study by Di Muro et al. (2021) provided further evidence that STAG1 mutations contribute to an emerging syndrome characterized by neurodevelopmental disorders. Additionally, Casa et al. (2020) investigated the functional roles of STAG1 and STAG2 in gene regulation and chromatin looping using HCT116 cells with an auxin‐inducible degron tag fused to either STAG1 or STAG2. Their findings confirmed the involvement of the STAG1 gene in endosomal function, reinforcing its role in neurodevelopmental disorders.

In this case, the child initially presented with seizures and neurodevelopmental delay. Additionally, he exhibited distinct craniofacial abnormalities, hypertelorism (wide spacing between the eyes), deep‐set eye sockets and missing incisors. WES revealed a heterozygous variant at NM_005862.3: c.2549G > A (p.Gly850Asp) in the STAG1 gene. This variant, a de novo missense mutation, resulted in the substitution of glycine with aspartic acid at position 850 (p.Gly850Asp). This variant was absent in both parents. To date, this variant has not been recorded in the Genome Aggregation Database (gnomAD) for minimum allele frequency, nor has it been reported in the ClinVar database. According to the American College of Medical Genetics and Genomics (ACMG) guidelines:

1. This sequence variation results in an amino acid substitution at position 850 (p.Gly850Asp).

2. The variant is de novo in the patient, with no family history, as confirmed by parental testing (PS2).

3. The variant is not found in normal control populations, including the Elasticsearch Service Platform (ESP database), the 1000 Genomes Project database or the Exome Aggregation Consortium (EXAC) database (or is extremely rare in recessive genetic disorders) (PM2).

Based on these findings, this mutation is classified as potentially pathogenic (family pedigree analysis, protein conservation analysis and 3D protein structure modelling are shown in Figure 3). Tests have linked STAG1 mutations to autosomal dominant mental retardation type 47 (MRD47; OMIM: 617635). Therefore, the clinical phenotypes observed in this child—epileptic seizures, cognitive impairment and motor delay—are consistent with STAG1‐related neurodevelopmental disorder syndromes.

FIGURE 3.

(a) Family pedigree, arrows indicate precertifiers; +/+ indicate wild type; m/+ indicate heterozygous type. (b) Analysis of protein conservation of STAG1 gene. (c) Three‐dimensional protein structure of the wild‐type STAG1 gene; the red box shows the position of the amino acid before the gene mutation. (d) Amino acid structure at position 850 of the wild‐type STAG1 gene. (e) Predicted amino acid structure at position 850 of the mutant STAG1 gene.

The findings of this study are consistent with those reported by Di Muro et al. (2021). However, the child's epileptic seizures represent a distinct form of epileptic syndrome—specifically, an epileptic encephalopathy with a poor prognosis. At the last follow‐up, he had been seizure‐free for nearly 2 years. Despite this, there remains a high likelihood of seizure recurrence in the future. Furthermore, the specific seizure type observed in this patient, along with the mutation site identified in this case, has not been previously reported. To date, the available data on known STAG1 genotypes and associated phenotypes are summarized in Table 1 (Lehalle et al. 2017; Di Muro et al. 2021; Cipriano et al. 2024; Seymour et al. 2024). All patients exhibited growth retardation to varying degrees; the majority had craniofacial abnormalities, and approximately 30% experienced seizures. However, the specific seizure subtypes were not described. The identified STAG1 mutations were predominantly missense or deletion variants, with most occurring de novo.

TABLE 1.

Comparison of clinical, cytogenetic and molecular data; F: female; M: male.

Patient	Sex	Clinical phenotype		Epilepsy	Nucleotide change	Amino acid change	Mutation type	Inheritance
		Growth retardation	Facial dysmorphisms
1	F	+	+	−	c.2769_2770del	p.(Ile924Serfs*8)	Frameshift	De novo
2–3	M	+	+	−	c.1279G > A	p.(Val427Ile)	Missense	De novo
4	M	+	+	−	Chr3: 135979743–136510812	−	Deletion	De novo
5	F	+	+	+	Chr3: 136035522–136412948	−	Deletion	De novo
6	F	+	+	−	Chr3: 135983184–136383429	−	Deletion	De novo
7	M	+	+	+	Chr3: 136109538–136310711	−	Deletion	Absent in the mother (father N/A)
8–9	F M	+	+	−	Chr3: 136254742–136427833	−	Deletion	Inherited
10	M	+	+	+	Chr3: 135969755–136305476	−	Deletion	N/A
11	M	+	+	−	c.641A > G	p.(Gln214Arg)	Missense	De novo
12	M	+	+	+	c.1433A > C	p.(His478Pro)	Missense	De novo
13	F	+	+	−	c.646A > G	p.(Arg216Gly)	Missense	De novo
14	M	+	−	+	c.1118G > A	p.(Arg373Gln)	Missense	De novo
15	F	+	+	−	c.1460_1464dup	p.(Trp489Valfs*10)	Frameshift	De novo
16	F	+	+	+	c.659A > G	p.(His220Arg)	Missense	De novo
17	M	+	+	−	c.997A > C	p.(Lys333Gln)	Missense	De novo
18	F	+	+	−	c.2936A > G	p.(Lys979Arg)	Missense	De novo
19	M	+	−	−	c.1052 T > G	p.(Leu351Trp)	Missense	De novo
20	F	+	+	+	c.1736dup	p.(Ser580Valfs*21)	Frameshift	De novo
21	M	+	+	N/A	c.17 T > G	p.(Leu6Ter)	Nonsense	N/A

Patients with STAG1 variants typically present with varying degrees of neurodevelopmental delay, often sharing common clinical phenotypes. The most frequently reported features include intellectual disability, developmental delay, feeding difficulties, seizures, autism spectrum disorder and growth retardation (Bo et al. 2019). In this case, the child exhibited intellectual and motor developmental delay, seizures, and distinctive craniofacial features, findings that align with previously reported cases. Since most identified STAG1 variants have been documented only in case reports, additional studies on patient cohorts and genotype–phenotype correlations are necessary to validate these observations and further refine the clinical spectrum of STAG1‐related disorders.

Notably, the STAG1 variant reported in this case has not been previously reported in the medical literature and is absent from public genomic databases. Thus, this case contributes to expanding the known molecular spectrum of STAG1 pathogenic variants.

4. Conclusion

In this study, we report new STAG1 variants and their associated clinical features. Moreover, our case showed a clinical phenotype similar to those described in previous studies on STAG1 variants, thereby contributing to the growing body of clinical data on this rare and poorly characterized syndrome. To further elucidate the role of STAG1 variants in neurodevelopmental disorders, comprehensive WES of familial cases with unexplained developmental delay should be prioritized in clinical practice. Establishing an extensive database of STAG1 variants through larger cohort studies will enable more precise characterization of the pathogenesis and clinical manifestations of this disorder.

5. Limitations

This paper presents a case report along with a literature review to discuss STAG1 variants and their associated clinical phenotypes. However, the level of evidence provided is inherently lower than that of large‐scale clinical studies, such as randomized controlled trials.

Author Contributions

Conception and design of the study: Qi Zhang. Acquisition and analysis of data: Qi Zhang, Ying Ren, Song Su and Wandong Hu. Drafting of a significant portion of the manuscript, script or figures: Qi Zhang. Writing – review and editing: Hongwei Zhang and Tong Zhang. All authors have read and approved the manuscript.

Ethics Statement

This study was approved by the Medical Ethics Committee of the Children's Hospital Affiliated to Shandong University (Approval No. SDFE‐IRB/T‐2025025). All procedures were performed in accordance with the ethical standards of the Declaration of Helsinki.

Consent

Informed consent was obtained from all participants in the study.

Conflicts of Interest

The authors declare no conflicts of interest.

Zhang, Q. , Ren Y., Su S., Hu W., Zhang H., and Zhang T.. 2025. “Neurological Disease Syndrome Caused by a STAG1 Gene Variant: A Case Report and Literature Review.” International Journal of Developmental Neuroscience 85, no. 5: e70030. 10.1002/jdn.70030.

Data Availability Statement

The datasets generated and analysed during the current study are all shown in the manuscript.