A novel de novo RNF13 variant in developmental and epileptic encephalopathy 73: genotype–phenotype correlation and literature review

Abstract

Background

Developmental and epileptic encephalopathy-73 (DEE73, OMIM: #618379) is a rare autosomal dominant genetic disorder. This study reports a novel de novo RNF13 variant in a Chinese patient, aiming to assess its pathogenicity and expand understanding of the phenotypic and molecular spectrum of DEE73.

Methods

Whole-exome sequencing was performed on the patient to identify candidate variants associated with the clinical phenotype. Putative pathogenic variants were validated by Sanger sequencing. In silico prediction tools were used to assess the functional impact of the identified variant. A literature review was conducted to summarize the clinical features of the 7 previously reported cases of DEE73.

Results

A novel likely pathogenic frameshift variant, c.929del/p.(Pro310fs*3), in RNF13 was identified in the patient. The clinical presentation was consistent with the diagnostic features of DEE73, yet also exhibited phenotypic heterogeneity, including severe scoliosis and pectus carinatum. A literature review confirmed that the core clinical features of DEE73 include microcephaly, seizures, developmental delay, joint contractures, abnormal muscle tone and electroencephalogram abnormalities.

Conclusions

This study expands the known genetic spectrum of DEE73 and enhances the understanding of phenotypic characteristics associated with RNF13 variants. The findings have important implications for improving variant-based screening, genetic diagnosis, and insights into the molecular mechanisms of RNF13-related disorders.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12883-026-04651-9.

Introduction

Developmental and epileptic encephalopathy (DEE) refers to a group of neurodevelopmental disorders marked by early-onset epilepsy, abnormal electroencephalograms, and developmental delays or regression [1–3]. The DEE is recognized for its complex etiology and resistance to medication, severely affecting the development of affected children, particularly infants, and posing significant challenges in the management of pediatric neurological diseases [4]. Genetic factors play a crucial role in DEE, with more than half of the cases linked to genetic causes [5, 6]. Advances in next-generation sequencing (NGS) technologies have enabled the identification of a growing number of pathogenic genes associated with DEE. This is vital for early diagnosis and intervention. To date, 118 genes have been listed in OMIM as causing DEE, as detailed in Supplementary Table 1, which lists all the genes currently known to be associated with DEE. These genes perform various functions, including roles in neuronal ion channels, neurotransmitter synthesis and release, membrane receptors, transporters, and cellular metabolism. They also regulate processes such as the proliferation, migration, differentiation, synaptogenesis, and pruning of neuronal precursor cells [7–9]. The genes most extensively studied are those related to ion channels and neurotransmitter receptors [5, 10]. Common epileptic encephalopathies, such as Ohtahara syndrome, West syndrome, Lennox-Gastaut syndrome, Dravet syndrome, and Early Infantile Developmental and Epileptic Encephalopathy, are typically resistant to traditional antiseizure medications [11].

The RNF13 (Ring Finger Protein 13) is a protein-coding gene identified through functional gene screenings. This protein is primarily expressed in the brain, cerebellum, spinal cord, and testis [12]. The gene encodes a membrane-bound glycoprotein composed of 381 amino acids [13]. RNF13 is an E3 ubiquitin ligase containing a protease-associated domain at the N-terminus and a RING domain at the C-terminus, separated by a transmembrane region [14]. The RING domain is known to participate in protein-protein interactions. Although the precise function of RNF13 is unclear, it is hypothesized that its ubiquitination capacity regulates the stability and targeting of other proteins, which is key to its physiological function. Cellular studies show that RNF13 mediates ER stress-induced activation of the JNK pathway and apoptosis by promoting ERN1 activation and XBP1 mRNA splicing [15, 16]. It is also involved in protein transport and localization [17].

Diseases associated with RNF13 include developmental and epileptic encephalopathy 73 (DEE73, OMIM: #618379). To date, only six pathogenic variants (seven patients) have been reported globally (Table 1). In this study, we describe the case of a Chinese female patient who presented with recurrent seizures (focal seizures), facial stupor, delayed motor development, and delayed language development. These symptoms were linked to a novel de novo variant in the RNF13, located on the 3q25.1 region of the human chromosome.

Table 1.

Summary of clinical and molecular features of all patients with RNF13 variants

	P1[16]	P2[16]	P3[16]	P4[21]	P5[29]	P6	P7	This study	Ratio
						ClienVar Databas (https://www.ncbi.nlm.nih.gov/clinvar/)
Gender	Male	Male	Male	N.A.	N.A.	N.A.	N.A.	Female	Male: Female = 3:1
Age (Month)a	21	96	33	10	N.A.	N.A.	N.A.	4	47.22
Microcephaly (cm)	+ 29.5(-2.8SD)	+ 30.0(-2.6SD)	+ 31.5(-3SD)	+ 37(-4.7SD)	+	N.A.	N.A.	+ 38(-2SD)	100%
Seizure	+	+	+	+	+	N.A.	N.A.	+	100%
Age at First Epilepsy (Month)	2	7	1.75	1.5	N.A.	N.A.	N.A.	3	3.05 (15.25/5)
Failure to thrive	+	+	+	+	+	N.A.	N.A.	+	100%
Limb contractures	+	+	+	+	+	N.A.	N.A.	+	100%
Abnormal muscle tone	+	+	+	+	N.A.	N.A.	N.A.	+	100%
Visual impairment	+	+	+	-	N.A.	N.A.	N.A.	+	80%
Hearing impairment	+ (bilaterally)	-	+ (bilaterally)	-	N.A.	N.A.	N.A.	-	40%
Magnetic resonance imaging (MRI) abnormality	N.A.	+ (delayed myelination, thin CC, subsequent volume loss)	+ (thin CC)	+ (posterior fossa Blake’s pouch)	-	N.A.	N.A.	-	60%
Electroencephalogram (EEG) abnormality	+	+	+	+	N.A.	N.A.	N.A.	+	100%
Psychomotor retardation	+	+	+	N.A.	N.A.	N.A.	N.A.	-	75%
Other Clinical Findings	Cataract, Inguinal hernia, Scoliosis	Inguinal hernia, limb spasticity, Scoliosis, Hip dysplasia, idiopathic high B12 levels	Scoliosis	Low-set ears, High-arched Palate, Retrognathia,	Gastrointestinal dysfunction, Choreodystonic movement disorder	N.A.	N.A.	Elevated levels of lactate, Lactate Dehydrogenase, D-dimers, and blood ammonia, Scoliosis, Pectus carinatum	N.A.
Variants type	Missense	Missense	Missense	Nonsense	Frameshift	Nonsense	Nonsense	Frameshift	Missense: Nonsense: Frameshift= 1:1:0.67
Variants (NM_183381.3)	c.935T > C p.(Leu312Pro)	c.935T > C p.(Leu312Pro)	c.932T > C p.(Leu311Ser)	c.901G > T p.(Glu301*)	c.932delT p.(Leu311Tyrfs*2)	c.881_882del p.(Asp293_Ser294insTer)	c.919G > T p.(Glu307Ter)	c.929del/p.(Pro310fs*3)	N.A.
Exon (NM_183381.3)	Exon 11	Exon 11	Exon 11	Exon 11	Exon 11	Exon 11	Exon 11	Exon 11	100%
Position (GRCh37)	chr3:149678680	chr3:149678680	chr3:149678677	chr3:149678646	chr3:149678674	chr3:149678624- chr3:149678625	chr3:149678664	chr3:149678670	chr3:149678624–149,678,680
Allele origin	de novo	de novo	de novo	de novo	de novo	de novo	de novo	de novo	100%
State	Israel	Israel	Israel	Dubai	Switzerland	N.A.	N.A.	China
Significance	Pathogenic	Pathogenic	Pathogenic	Likely Pathogenic	Likely Pathogenic	Likely Pathogenic	Likely Pathogenic	Likely Pathogenic	Pathogenic: Likely Pathogenic= 1:1.67

a: Age is presented in months at the time of publication

N.A.:Not Available

Materials and methods

Next-Generation sequencing

Genomic DNA was extracted from the patient’s peripheral blood sample. Library preparation was conducted using the Agilent SureSelect Clinical Research Exome V2 Kit (Agilent Technologies, Santa Clara, CA, USA), followed by sequencing on the Illumina HiSeq 2500 platform (Illumina, San Diego, CA, USA). Raw sequencing data were aligned to the human reference genome (GRCh37/hg19) using the Burrows-Wheeler Aligner (BWA, v0.7.15). Variant detection and annotation were performed with the Genome Analysis Toolkit (GATK), while downstream refinement and prioritization of candidate variants were completed using TGex software (v5.7, LifeMap Sciences).

Sanger sequencing confirmation

Bioinformatic analysis and verification of observationsCandidate variants identified via TGex were validated through Sanger sequencing. Primer pairs (forward: 5′-ATTAGCACACCAGAAGCCAG-3′; reverse: 5′-GCACTGACAGAAGCTAAAGG-3′) targeting the RNF13 c.929del/p.(Pro310fs*3) locus were designed using Oligo7 (v7.60, Molecular Biology Insights) and synthesized by Sangon Biotech (Shanghai, China). Standard PCR conditions (annealing temperature: 58 °C, 35 cycles) were applied, and amplicons were analyzed on an ABI 3730xl sequencer (Thermo Fisher Scientific).

Bioinformatic analysis and verification of observations

To assess the functional impact of identified variants, we integrated multiple in silico prediction tools, including Molecular Evolutionary Genetics Analysis (MEGA7, https://www.megasoftware.net/), Mutation Taster (https://www.mutationtaster.org/), Provean (http://provean.jcvi.org/seq_submit.php), and RDDC (https://rddc.tsinghua-gd.org/). Together, these tools provide a comprehensive functional analysis from multiple perspectives. Variant classification adhered to the American College of Medical Genetics and Genomics (ACMG) and Association for Molecular Pathology (AMP) guidelines [18].

Results

Clinical presentation

A 4-month-old Chinese female infant presented with recurrent seizures that had persisted for one month. The infant was born at term, with healthy, non-consanguineous parents, and there were no complications during pregnancy or delivery. Physical examination revealed microcephaly (head circumference 38 cm, <−2SD), a slightly narrow forehead, low-set ears, and a short philtrum (Fig. 1-A). Neurological examination showed increased muscle tone in the limbs, decreased neck muscle tone (inability to lift her head), thumb adduction, clenched fists, a flat facial expression, and lack of social interaction.

Fig. 1.

Clinical features of the patient with RNF13 likely pathogenic variant. A: Microcephaly, flat affect (blunted emotional expression), narrow forehead, slightly low-set ears, short philtrum, and hypertonia. B-E: Brain MRI findings were unremarkable, with no significant abnormalities. F and G: Spinal imaging demonstrates severe scoliosis (thoracic Cobb angle 58°with grade III rotation) and pectus carinatum

Seizures began shortly after birth, during the neonatal period (at 3 months of age). Initial seizure episodes were focal tonic motor seizures characterized by trunk hyperextension (opisthotonus), lower limb extension, upper limb flexion with clenched fists, mouth opening with vocal arrest, while eye blinking and visual tracking were preserved. Seizures occurred frequently, about 6–7 times per day, each lasting approximately 1 min, with interictal intervals ranging from 1.5 to 8 h. No clear progression to generalized seizures was observed during hospitalization.

Neurodevelopmental assessment revealed significant delays in motor and language development. At 4 months of age, she was unable to hold her head up, did not produce vocalizations, and lacked social smiling, indicating severe neurodevelopmental impairment. The electroencephalography (EEG) showed abnormal slow waves in the posterior head regions (diffuse theta and delta rhythms), with sharp-slow wave complexes, polyspike-slow waves, and spike discharges over bilateral central, parietal, occipital, and midline areas (Cz, Pz), slightly increased during sleep (Supplementary File 1). Imaging studies revealed thoracic asymmetry with a relatively wide anteroposterior diameter. Lateral radiographs showed sternal protrusion, with the maximum distance from the posterior margin of the sternal apex to the anterior border of the spine measuring approximately 67 mm. Spinal X-rays revealed rotational scoliosis primarily in the thoracic region, convex to the right; vertebral rotation of grade I at T12 and L1–L3; grade II at T8–T9 and T11; and grade III at T4–T7 (Figs. 1: F-G). Laboratory tests showed elevated lactate (35.78 mg/dL, normal range 12–16), increased lactate dehydrogenase (LDH; 349 U/L, normal range 109–245), elevated D-dimer (6490 ng/mL FEU, normal range 0–550), and increased blood ammonia (76 µmol/L, normal range 9–47). Brainstem auditory evoked potentials (BAEP) indicated bilateral dysfunction of the central auditory pathways, whereas visual evoked potentials (VEP) showed no significant abnormalities. The urinary and reproductive systems were normal. Cardiac function, liver and kidney function, blood glucose, abdominal ultrasound, and cranial MRI all showed no abnormalities (Figs. 1: B - E). Genetic testing identified a novel heterozygous frameshift variant in exon 10 of the RNF13 : c.929del/p.(Pro310fs*3).

The infant was initially treated with levetiracetam and sodium valproate, but the overall therapeutic effect was unsatisfactory, with limited progress observed in neurodevelopment.

Genetic analysis of whole exome sequencing

Genetic factors play a significant role in the development of epilepsy, with studies indicating that over 50% of epilepsy cases have a genetic basis [19]. More than 1,000 genes have been identified as related to monogenic epilepsy [20]. To elucidate the molecular basis, we conducted a genomic investigation using whole exome sequencing (WES), which has become a powerful tool for identifying pathogenic variants in genetic disorders.

Exome capture kit was employed for whole-exome sequencing of the patient’s genomic DNA. The exome capture enriched the exonic regions within a 67 Mb capture area, achieving an average Q30 score of ≥ 98%. We obtained 22.1 GB of clean data with uniform base distribution and negligible GC bias, achieving 99.2% coverage of the targeted exome region (≥ 20x coverage). WES identified 107,090 variants, including 14,218 amino acid alterations. Using the TGex software (LifeMap Sciences, USA), we identified the variants of eight genes most closely associated with the patient’s phenotype from the OMIM database: NCDN, KCNN3, ASH1L, TMEM63A, TBP, SCN11A, SYNE2, and RNF13. Subsequently, after applying filters based on population frequency, inheritance patterns (autosomal dominant or recessive), and predicted pathogenicity, the heterozygous variant c.929del/p.(Pro310fs*3) in the RNF13 (NM_183381.3, GRCh37/hg19) emerged as the most likely causative variant. Sanger sequencing confirmed the non-parental origin of the variant (ACMG-PS2; Fig. 2). The Pro310 has no natural variants recorded in the 1000 Genomes Project, the Human Gene Mutation Database, ClinVar, or LOVD, fulfilling the PM2 criterion according to ACMG guidelines for pathogenicity classification. The variant was supported by multiple computational evidence lines indicating deleterious impacts on gene products (ACMG-PP3; Fig. 3). Heterozygous variants in key regions of the RNF13 have been reported in the literature to cause congenital microcephaly, epileptic encephalopathy, blindness, and growth retardation, primarily through gain-of-function effects. Therefore, this frameshift variant does not qualify for PVS1 (Pathogenic Very Strong) evidence. Based on the available evidence, the observed frameshift variant in the patient has been classified as “likely pathogenic” (PS2 + PM2 + PP3 + PP4), which is considered equivalent to a “pathogenic variant” in clinical contexts. Consequently, this variant is applicable for clinical diagnosis and decision-making.

Fig. 2.

The The pedigree and sanger sequencing results. A The pedigree shows shows a nuclear family structure, with II-1 being the affected female individual (indicated by a half-shaded circle). Squares represent males, and circles represent females. B The Sanger sequencing chromatogram illustrates the DNA sequences of core family members. No variants were detected in the parents (I-1 and I-2), while the patient (II-1) carries a heterozygous de novo variant

Fig. 3.

Functional Impact and Conservation Analysis of the Pro310fs*3 variant in RNF13. A Conservation analysis: The region highlighted by the red box shows that the Pro310 site is highly conserved across a range of species, emphasizing its critical role in maintaining protein function. B Protein structure model: The 3D structural model of the RNF13 protein shows the location of the Pro310 residue. The variant (c.929del/p.(Pro310fs*3)) may alter the protein’s structure or function. C In silico predictions: Multiple bioinformatics tools consistently predict this variant to be damaging or pathogenic, further supporting its potential deleterious effects on protein function

Literature review

To explore the genetic and clinical landscape of Developmental and Epileptic Encephalopathy 73, our research included a comprehensive review of the literature concerning the clinical manifestations and genetic profiles of patients with RNF13 variants (Table 1). The literature review reveals that, to date, there have been seven reported cases of Developmental and Epileptic Encephalopathy 73 worldwide. The potentially pathogenic variant identified in this study has not been previously documented.

Discussion

The autosomal dominant disorder later designated DEE73, initially delineated by Edvardson et al. in 2019, presents in three unrelated pediatric cases characterized by profound neurodevelopmental and neurodegenerative pathologies [16]. Since this initial case, DEE73 has been identified in 7 individuals of diverse ethnicities worldwide (Table 1). In this study, we report the first case in the East Asian region and the eighth case worldwide of a patient affected by DEE73. Utilizing WES and Sanger sequencing, we identified a novel de novo frameshift variant c.929del/p.(Pro310fs*3) in RNF13. This discovery not only expands the clinical spectrum of RNF13-related disorders but also enhances our understanding of the genetic basis of DEE73.

The DEE should be considered when clinical features include refractory seizures, severe EEG recording abnormalities, and developmental stagnation or regression (cognitive impairment, motor dysfunction, behavioral problems). However, it must be emphasized that genetic analysis remains the gold standard for diagnosing DEE73. This case underscores the importance of clinical assessment combined with WES in diagnosing rare genetic disorders. Among patients with DEE73, seven individuals with DEE73 carrying six distinct de novo variants in the RNF13 (refer to Table 1; Fig. 4). The observed male predominance (3:1 ratio) in reported cases likely reflects the small sample size, rather than a true sex-linked difference, given DEE73’s autosomal dominant inheritance. The age of onset for DEE73 ranges from 1.5 to 7 months, with most cases presenting epilepsy in infancy and early childhood (mean age of onset: 3.05 months). Patients consistently exhibit defining features of DEE73, including seizures, hypotonia, and growth delay.

Fig. 4.

The pathogenic and likely pathogenic variants of the RNF13. The figure illustrates the exons (exons 1–11), functional domains (PA, TM, RING), and variants in the RNF13 as recorded in the ClinVar database. The variants highlighted in red are those identified in this study. These variants are predominantly localized between amino acids 292–312, which may suggest a critical region for the gene’s function

Based on available data in the literature, the core clinical manifestations of DEE73 caused by RNF13 are seizures (100%), microcephaly (head circumference ranging from − 4.7 to -2SD, 100%), growth retardation (100%), limb contractures (100%), and abnormal muscle tone (100%), along with EEG abnormalities (100%). Additional clinical features may include visual impairment (present in 80% of cases), intellectual disability (75%), magnetic resonance imaging abnormalities (60%), and hearing impairment (40%). Additionally, the case reported in this study presents with non-specific phenotypic features, including elevated levels of lactate, lactate dehydrogenase, D-dimers, and blood ammonia. A report by Simon Edvardson noted that urinary organic acid analysis repeatedly showed increased lactate excretion in one of the three affected individuals [16]. It is currently unclear whether the non-specific biochemical abnormalities exhibited by this child are associated with RNF13. We will pay particular attention to the reproducibility of these indicators in subsequent follow-up. According to literature reports, the neurocognitive phenotype of DEE73 may be attributed to altered apoptosis levels. Mutant cells exhibit enhanced endoplasmic reticulum (ER) stress signaling and increased ER stress-induced apoptosis. Apoptosis regulates stem cell populations, and in mice, an increase in neuronal apoptosis has been observed, leading to the depletion of intermediate neuronal progenitor pools. These findings suggest that alleviating ER stress and controlling apoptosis in a precise spatiotemporal manner are critical for normal brain development. Furthermore, RNF13, identified as an E3 ubiquitin ligase, plays a key role in early-onset progressive epilepsy. variants in RNF13 impair its ubiquitin ligase activity, which normally promotes the ubiquitination of SNARE-associated protein (snapin). This process enhances its interaction with synaptosome-associated protein 25 (SNAP-25), strengthening the binding between synaptotagmin I and SNAP-25. Such interactions are crucial for the assembly of the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex and the release of neurotransmitters into the synaptic cleft. Based on available data, the prognosis for DEE73 patients is generally poor, with the maximum recorded age of survival being 8 years old (patient 2).

Alan Taylor and colleagues have suggested a potential link between the clinical manifestations of DEE73 and variants in the amino acid sequence 292–312 of the RNF13 [21]. Current evidence indicates that this region may exert a negative regulatory (inhibitory) effect on downstream targets, and thus, its alteration—either through truncating variants or missense variants—could result in a gain-of-function (GOF) effect [21]. The variant reported in this study falls within this region, with the highly conserved proline residue at position 310 (Fig. 3: B, Fig. 4), suggesting its importance for protein function. According to the VarSite database (https://www.ebi.ac.uk/thornton-srv/-databases/VarSite), the proline at position 310 in this protein has a rigid side chain that restricts protein conformation at this site. Generally speaking, such frameshift variants located in terminal exons are likely to remove critical regions of protein function while escaping nonsense-mediated decay, thereby leading to a gain-of-function effect [22].

The specific role of RNF13 pathogenic variants in DEEs is primarily reflected in their gain-of-function variants. Currently, more than a hundred monogenic diseases have been reported to be caused by gain-of-function variants in various genes. For example, ROSAH Syndrome is caused by variants in the ALPK1 gene [23]. Cardio-facio-cutaneous syndrome results from variants in the BRAF gene [24], and Muckle-Wells syndrome is caused by variants in the NLRP3 gene [25].

Although much attention has been given to how variants disrupt protein structure and cause loss-of-function (LOF), alternative mechanisms—such as dominant-negative (DN) and gain-of-function (GOF) effects—are less well understood [26]. These diseases typically manifest as dominantly inherited conditions, with genetic variants leading to an abnormal enhancement or increase in protein expression, thereby triggering a variety of clinical symptoms.

Cellular function studies have shown that RNF13 is prominently expressed in both embryonic and adult brain tissues. Additionally, it plays a crucial role in neuronal development [13]. Genetic variations cause abnormal increases in endoplasmic reticulum stress-induced apoptosis (apoptosis can lead to human neurological diseases [27, 28]. It is hypothesized that the mechanism involves the introduction of new post-translational modification (PTM) sites by the variant or the modification of the amino acid sequences flanking natural PTM target sites, altering the function of RNF13 [16]. This modification could affect RNF13 protein function, either by altering its half-life or by changing its interactions with key regulatory proteins, such as IRE1α, which are involved in apoptosis regulation [29].

Conclusions

In our study, Whole Exome Sequencing, Sanger sequencing, and bioinformatics analysis were utilized to identify a novel likely pathogenic variant in the RNF13 in a Chinese girl with DEE73. This finding broadens the known spectrum of RNF13 variants. Moreover, we conducted a review and analysis of the clinical manifestations and molecular genetic characteristics of DEE73 patients reported globally. This work aims to enhance our understanding of DEE73’s genetic landscape across different populations. The discovery’s significance is its potential to improve DEE73’s genetic diagnosis and clinical management, offering a more comprehensive global perspective on this rare inherited disorder.

We recognize the limitations of a single - case report. Future research should increase the sample size and include more functional studies, such as in vitro and in vivo experiments. These studies will help evaluate the identified variant’s biological effects and provide insights into DEE73’s molecular mechanisms. They will also help delineate the phenotypic spectrum linked to RNF13 variants. Overall, these efforts will contribute to more accurate genetic diagnosis, better clinical management, and ultimately improving patient outcomes.

Authors’ contributions

Conceptualization, Qiang Zhang and Jingsi Luo; Funding acquisition, Qiang Zhang, Qi Yang and Jingsi Luo; Investigation, Qi Yang, Xunzhao Zhou and Yiyan Ruan; Project administration, Jingsi Luo; Resources, Yiyan Ruan; Supervision, Jingsi Luo; Validation, Shujie Zhang; Writing – original draft, Qiang Zhang; Writing – review & editing, Qiang Zhang and Qi Yang.

Funding

The research received financial support from the Guangxi Key Laboratory of reproductive health and birth defect prevention (21-220-22), the Guangxi Zhuang Region Health Department(Z20190311, Z-A20230305, Z20220256), Guangxi Key Laboratory of Birth Defects and Stem Cell Biobank (ZTJ2020002), the Guangxi Clinical Research Center for Pediatric Diseases (Guike AD22035121) and Liaoning Province Applied Basic Research Program Project (2023JH2/101300044).

Data availability

The original contributions presented in the study are included in the article and Supplementary Materials, further inquiries can be directed to the corresponding author. The data are deposited in the NCBI Sequence Read Archive repository, accession number PRJNA1274519 (https://www.ncbi.nlm.nih.gov/sra/PRJNA1274519).

Declarations

Ethics approval and consent to participate

The studies involving humans were approved by the Institutional Review Board and Ethics Committee of Guangxi Maternal and Child Health Hospital (No. [2017-2-11]) in accordance with the ethical principles of the Declaration of Helsinki. The studies were conducted in compliance with local legislation and institutional requirements. This study obtained written informed consent from all participants, as well as from the parents or legal guardians of participants under the age of 16.

Consent for publication

Written informed consent for the publication of the patient’s clinical details, identifying information, and clinical images was obtained from the patient’s parents (or legal guardians) in this study.

Consent for publication

All the authors agree to publish this study.

Competing interests

The authors declare no competing interests.