Skeletal dysplasia and growth disorder with SEC23A p.Arg716Cys variant-related cranio-lenticulo-sutural dysplasia

Highlights

● Here, we report a new case of heterozygous SEC23A p.Arg716Cys variant-related cranio-lenticulo-sutural dysplasia.

● This case differs from previously reported AD-CLSD with respect to delayed closure of the anterior fontanelle and lenticular phenotypes, presenting a broader phenotypic variability of SEC23A-related disorders.

● Longitudinal follow-up enabled detailed assessment of skeletal growth and pubertal progression in patients with AD-CLSD.

Introduction

Collagen, hormones, and various secretory proteins are synthesized in the endoplasmic reticulum (ER) and are subsequently transported to the Golgi apparatus for processing and secretion. This transport is mediated by vesicles coated with coat protein complex II (COPII). Dysfunction of COPII components can disrupt ER-to-Golgi trafficking, leading to congenital disorders that affect skeletal and connective tissue development (1).

Among the COPII components, the SEC23A gene encodes a core structural protein Sec23a, which is essential for vesicle formation. Pathogenic variants in SEC23A are known to cause a spectrum of disorders, including cranio-lenticulo-sutural dysplasia (CLSD, OMIM #607812), a condition characterized by delayed closure of cranial sutures, facial dysmorphism, skeletal abnormalities, and growth retardation (2). CLSD occurs in both the autosomal dominant (AD) and autosomal recessive forms. However, only a few cases of AD-CLSD have been reported to date and the phenotypic spectrum appears to be highly variable.

We report a female patient who presented with short stature and developmental delay, in whom we identified a de novo heterozygous SEC23A variant (c.2146C>T, p.Arg716Cys). This variant has been previously reported, but remains a variant of uncertain significance (3). We discuss the genotype-phenotype correlation, skeletal growth pattern, and endocrine features of the patient to provide new insights into the pathophysiology of SEC23A-related disorders.

Case Report

A 16-yr-old girl was born at 40 wk and 6 d of gestation, with a height of 48.0 cm and weight of 2,818 g. The patient’s parents were non-consanguineous. The father’s and mother’s heights were 168 and 155 cm, respectively. The patient had a healthy older sibling with no considerable family history. She showed delayed gross motor and intellectual development, and had undergone developmental rehabilitation and special educational support since early childhood. No seizures or other neurological symptoms were observed, but her limb movements were awkward, and finger stiffness was observed. Electroencephalography and brain magnetic resonance imaging performed at 6 yr of age revealed no apparent abnormalities. The typical craniofacial features of CLSD, such as delayed closure of the anterior fontanelle or frontal bossing, were absent.

She was referred to a pediatric endocrinologist for short-trunk, short stature at 4 yr of age and was followed up for growth and developmental evaluation until the age of 16 yr. At her final evaluation at age 16, her height was 132.3 cm (–4.8 SD) and body weight was 33.3 kg (–2.2 SD) (Fig. 1A). Spine radiographs (Fig. 1B) revealed irregular vertebral endplates and heterogeneous ossification of the vertebral margins, most evident in the thoracic spine, with poorly defined intervertebral boundaries and reduced vertebral body height, predominantly affecting the lumbar spine. Radiographs of the wrist (Fig. 1C) showed delayed ossification of the carpal bones and irregular contours of the epiphyseal cartilage. Endocrinological assessments throughout childhood consistently showed normal thyroid function, and serum insulin-like growth factor-1 (IGF-1) concentrations remained within the normal range for age (247 ng/mL, –1.2 SD at 14 yr). Growth hormone (GH) stimulation tests showed peak GH concentrations of 6.70 ng/mL (arginine) and 7.79 ng/mL (insulin) at 8 yr of age, and 18.0 ng/mL (levodopa) at 10 yr of age. These findings did not meet the diagnostic criteria for GH deficiency, and no hormone replacement therapy was initiated. Menarche occurred at 14 yr of age and epiphyseal closure was confirmed radiographically thereafter. In the differential diagnosis, she was considered to have skeletal dysplasias, such as hypochondroplasia and spondyloepiphyseal dysplasia (SED), as well as metabolic disorders, including mucopolysaccharidoses (MPS).

Fig. 1.

(A) Growth chart of the patient and timing of the major evaluations. A decline in growth velocity was noted at 6 yr of age, prompting brain magnetic resonance imaging and endocrine investigation. Height velocity remained low even after the onset of puberty. (B) Lateral spine radiograph at 15 yr of age showing irregular vertebral endplates and heterogeneous ossification of the vertebral margins (upper arrow) with poorly defined intervertebral boundaries and reduced vertebral body height predominantly affecting the lumbar spine (lower arrow). (C1–4) Sequential wrist radiographs revealed delayed ossification of the carpal bones and irregular contouring at the articular margins of the phalangeal joints.

Patient consent statement

Written informed consent for treatment, genetic analysis, and publication of these results was provided by the legal guardians of the patient.

Ethics approval statement

The investigation of phenotype–genotype correlations in genetically non-diagnosed diseases was approved by the institutional review board of the University of Yamanashi (no. 2437 for IRUD).

Mutation Analysis

Chromosomal analysis using G-banding of peripheral blood lymphocytes revealed a normal female karyotype (46, XX). Targeted next-generation sequencing of a Noonan syndrome-related gene panel (Kazusa DNA Research Institute, Japan) did not reveal any pathogenic variants. The patient was subsequently enrolled in the Undiagnosed Diseases Initiative, and trio-based whole-exome sequencing (WES) was performed using DNA from the patient and her parents (4). WES was performed using genomic DNA extracted from the peripheral blood lymphocytes obtained from the patient and her parents. Library preparation was performed using the Twist Library Preparation Enzymatic Fragmentation Kit 2.0, together with the Twist Exome 2.0, Panel and Twist Mitochondrial Panel (Twist Bioscience, South San Francisco, CA, USA). Sequencing was performed on an Illumina NovaSeq 6000 platform using 151-bp paired-end reads. The sequence reads were aligned to the human reference genome (GRCh38/hg38). Variant calling, quality score recalibration, and indel realignment were performed using the exome analysis pipeline at the Osaka University. Variant filtering prioritized rare variants with an allele frequency < 0.01 in public population databases, including gnomAD, HGVD, and ToMMo (54KJPN). The patient exhibited GH-independent severe short stature, and the analysis focused on genes associated with skeletal dysplasia, such as SED/MPS. Trio-based analysis identified a heterozygous de novo missense variant in SEC23A (NM_006364.4: c.2146C>T, p.Arg716Cys), which was subsequently evaluated according to ACMG/AMP guidelines. This variant was absent from the population frequency databases, including HGVD, ToMMo (54KJPN), and gnomAD (ALL), and was classified as a variant of uncertain significance in ClinVar (January 1, 2026). The pathogenicity prediction scores showed a Combined Annotation Dependent Depletion (CADD) of 31 and a Protein Variation Effect Analyzer (PROVEAN) of 7.21. Therefore, in accordance with ACMG guidelines, the variant was classified as likely pathogenic (criteria PS2, PM2, and PP3).

Following identification of the SEC23A variant, the patient’s clinical and radiographic features were re-evaluated by an expert panel of orthopedic surgery, clinical genetics, and pediatric endocrinology clinicians. Considering the known role of Sec23a in COPII-mediated secretion and skeletal development, and through comparison with the previously reported SEC23A-related cases summarized in Table 1, the overall presentation was considered compatible with a SEC23A-related disorder.

Table 1. Reported variants in the SEC23A gene and their associations with inheritance patterns and clinical phenotypes of CLSD. Schematic representation of the functional domains and exon organization of the SEC23A gene is shown in the upper panel.

Discussion

We identified a heterozygous SEC23A variant, c.2146C>T (p.Arg716Cys), which was initially evaluated for SED and subsequently considered compatible with an SEC23A-related disorder within the AD-CLSD spectrum. This case is significant for several reasons. First, we provided new evidence supporting the reclassification of this variant as likely pathogenic. Second, compared with previously reported AD-CLSD cases, the absence of delayed closure of the anterior fontanelle and frontal bossing in our patient illustrates wide phenotypic variability within the AD-CLSD spectrum (Table 1). Third, this case is unique in that the longitudinal follow-up allowed the evaluation of skeletal growth until epiphyseal closure.

This rare missense variant is located within the gelsolin repeat domain of Sec23 (amino acids 631–718). Although the functional consequences of this specific variant remain unclear, Sec23 plays an essential role in COPII carrier formation, acting in concert with Sec31 to mediate protein transport from the ER to the Golgi apparatus (5). Several pathogenic mechanisms have been suggested in the context of AD-CLSD, such as dominant-negative disruptive effects on Sec23 multimers, presence of an undetected low-frequency second variant resulting in a compound heterozygous state, and AD inheritance with incomplete penetrance (6). Most reported variants were clustered within the gelsolin-like repeat domain of SEC23A, whereas L649P was reported to be associated with autosomal recessive (AR)-CLSD (Table 1). This domain is implicated in binding interactions with PPP (proline–repeating) motif–containing proteins such as Sec31a, raising the possibility that aberrant interactions may disrupt COPII coat assembly (5, 7). Variants in the genes encoding COPII components can impair vesicle formation, leading to abnormal protein retention or mislocalization within the ER. These disturbances result in developmental delay, skeletal abnormalities, and various congenital disorders such as CLSD.

The delayed appearance of the carpal bones, vertebral platyspondyly, and epiphyseal dysplasia observed in this patient may reflect quantitative and qualitative defects in collagen secretion from chondrocytes (Figs. 1B and 1C). Impaired COPII carrier formation due to the SEC23A variant is likely to result in endoplasmic reticulum retention of cartilage matrix proteins, leading to abnormal cartilage matrix formation (8). In the present case, the patient exhibited severe GH-independent short stature and developmental delay, compatible with the AD-CLSD phenotype. However, classical manifestations observed in previously reported cases, such as delayed closure of the anterior fontanelle, frontal bossing, and congenital cataracts, were absent in this case. These findings highlight the phenotypic variability of AD-CLSD.

Typical COPII carriers are generated through the stepwise assembly of Sar1, Sec23–Sec24 inner coat, and Sec13–Sec31 outer coat complex. Recent studies have shown that Sec31 ubiquitination is mainly involved in the formation of large COPII carriers and secretion of collagen (7). Ubiquitin-specific protease 8 (USP8) is essential in this process. Furthermore, modulation of the USP8–STAM1 complex restores the ubiquitination of Sec31 and the activity of COPII vesicles in collagen trafficking. These findings suggest a potential therapeutic strategy for the functional recovery of patients with Sec23-related disorders.

In conclusion, a comprehensive analysis of the SEC23A is useful for diagnosing patients with skeletal abnormalities including growth retardation and gross motor developmental delay. Further genetic and functional analyses of human SEC23A are required to clarify its role in COPII vesicle formation. Additionally, the use of cellular models verified the efficacy of USP8 modulation as a method of rescuing defective COPII-mediated transport in SEC23A variants.

Conflict of interests

The authors declare no conflict of interest.

Funding Statement

This work was supported by grants from the Research on the Initiative on Rare and Undiagnosed Diseases (IRUD; 25ek0109760s2002) of the Japan Agency for Medical Research and Development (AMED).