A rare Coffin-Siris syndrome induced by SOX11: a de novo nonsense variant of short stature

Abstract

Background

Coffin-Siris syndrome is a clinically elusive and rare genetic disease characterized by a wide range of clinical manifestations. This study deeply analyzed and identified the clinical phenotype and genetic variant location in a pediatric patient with Coffin-Siris syndrome, aiming to enhance the understanding of this syndrome and assist in its screening and diagnosis.

Methods

A combination of advanced diagnostic tools, including high-throughput whole-exome sequencing (WES) and first-generation sequencing technologies, was employed to ascertain the etiology of the disease in the child.

Results

The clinical phenotype was characterized by stunted growth, reduced stature, spina bifida, enuresis, and a ventricular septal defect. WES revealed a de novo variant in the SOX11 gene locus (c.700G > T), identified as pathogenic. It is noteworthy that this variant has not been previously reported.

Conclusions

The combination of clinical presentation and genetic testing results supports that the patient suffers from Coffin-Siris syndrome due to a genetic variant in the SOX11 gene. This de novo variant expands our understanding of human gene variation, which is conducive to genetic counseling and screening for early diagnosis of Coffin-Siris syndrome.

Introduction

Coffin-Siris syndrome (CSS) is an autosomal dominant disorder characterized by inherent genetic heterogeneity. The syndrome presents with distinct clinical features, including hypoplasia of the distal phalanges or nails, atypical development of the fifth finger, distinctive facial characteristics (facial coarseness), hirsutism, sparse scalp hair, and congenital malformations in the heart, gastrointestinal tract, genitourinary system, and/or the central nervous system. Additional symptoms frequently include growth retardation, feeding difficulties, ocular abnormalities, hearing impairment, intellectual disability, and various other abnormalities [1, 2].

The pathogenesis of CSS is primarily attributed to variants in 12 related genes (ARID1A, ARID1B, ARID2, DPF2, SMARCA4, SMARCB1, SMARCC2, SMARCD1, SMARCE1, PHF6, SOX11, and SOX4) [3, 4]. The genes PHF6 and SOX11 mainly regulate the transcription of the BRM-associated complex (also known as the BAF or SWI/SNF complex), while the other genes primarily encode components of the BAF complex [5]. This ATP-dependent chromatin-remodeling complex modulates nucleosome topology, thereby controlling gene transcription and influencing protein synthesis [6].

Among these pathogenic genes, SOX11, a transcription factor, plays a crucial role in early embryogenesis and neurodevelopment [7]. Heterozygous variant in SOX11 can lead to Coffin-Siris syndrome-9 (CSS9, OMIM: 615866), characterized by growth anomalies, intellectual disability, microcephaly, facial coarseness, and hypoplastic nails of the fifth finger and/or toe [8]. This study explored a CSS9 case resulting from a variant in the SOX11 gene, as identified through whole-exome sequencing (WES). The case of CSS9 caused by SOX11 variant is rare, and its clinical manifestations are diverse. In this work, a case of CSS9 is analyzed and reported, and compared with other reported cases. This study provides a reference for clinical diagnosis of CSS9.

Case presentation

This report provides a retrospective analysis of clinical data from a child diagnosed with Coffin-Siris syndrome at Xi’an Fourth Hospital (Xi’an People’s Hospital) in 2020.

The patient, a 12-year-old girl, was admitted to the hospital due to a significantly slower growth rate compared to her peers, cognitive and motor delays, and a history of enuresis spanning more than a decade. Delivered by full-term cesarean section, she had a birth weight of 3,400 g. Her Apgar score at birth was not recorded, and there were no indications of hypoxia during the delivery. The prenatal and perinatal history included an upper respiratory tract infection early in the mother’s pregnancy, with no exposure to teratogens reported.

Upon admission, the patient had sparse scalp hair, hypoplastic nails, and no obvious facial deformity, and the physical examination revealed stunted growth and slower mass gain. One year before admission, the height of the patient was 131 cm (-2.36 SD). After taking growth hormone for one year, and her height was 138.5 cm (-2.14 SD) and her weight was 28.4 kg (-1.84 SD) on admission. She exhibited visual impairment, which is consistent with myopia at a level expected for a 10-year-old, but her hearing was normal. Auscultation showed no abnormalities in the heart, lungs, or abdomen. Muscle tone in her limbs was healthy, with both knee and heel tendon reflexes elicitable. No pathological reflexes were induced, and no significant spinal deformities were noted.

Laboratory examinations post-admission showed normal results for blood, urine, and fecal routines, as well as liver and kidney functions, thyroid function, electrolytes, and blood lipid levels. Imaging examinations, including X-rays and CT scans, identified a non-visible spina bifida.The result of echocardiogram revealed a perimembranous ventricular septal defect, while cranial magnetic resonance imaging (MRI) showed no abnormalities. Key terms extracted for report interpretation included dwarfism, growth retardation, short stature, cognitive delay, spina bifida, enuresis, ventricular septal defect, myopia, and respiratory tract infection.

At present, the patient is 16 years old, and her secondary sexual characteristics have not developed. The result of B-ultrasound shows that the uterus and ovaries are small. Through the telephone follow-up of the parents of patient, the photo of hands of patient (Fig. 1) is obtained with the consent of her parents. As the consideration of the protection of patient privacy, the facial photograph of the patient is not disclosed.

Fig. 1

Photo of patients’ hands

Given that the growth retardation, cognitive and motor delays of patient, non-visible spina bifida, and congenital heart disease, a hereditary disease was suspected. To elucidate the etiology, whole exome sequencing (WES) was performed on peripheral blood samples obtained from the patient and her parents, who provided their consent and signed the informed consent form. The examination was approved by the hospital’s medical ethics committee.

Test results

WES results identified a variant in the SOX11 gene locus. According to the guidelines of the American College of Medical Genetics and Genomics (ACMG) [9], and recommendations from the ClinGen Sequence Variant Interpretation (SIV) expert group [10], the c.700G > T variant in the SOX11 gene locus is classified as a pathogenic variant site associated with the autosomal dominant genetic disease CSS9.

SOX11: NM_003108.4: c.700G > T: p.E234* variant: pathogenic (PVS1 + PM2 + PM6). The highly pathogenic evidence, PVS1, demonstrates that the corresponding codon of this variant is mutated to a termination codon, resulting in the changes in protein function. The moderately pathogenic evidence, PM2, indicates that this variation has not been found in the Chinese Genome Database, the Human Exon Database (ExAC), the reference population 1000 genomes (100G), or the Human Genome Mutation Frequency Database (gnomAD). The moderately pathogenic evidence, PM6, confirms that this mutation is a novel variant not previously verified for parentage (Table 1).

Table 1 Results of SNV and InDel detection of the child

Public databases indicate that a variant in the SOX11 gene locus (OMIM:600898) can induce Coffin-Siris syndrome 9 (CSS9), an autosomal dominant genetic disorder. This condition is primarily characterized by short stature, micro-nails, hypoplasia of the fifth toenails, a short nose, small palpebral fissures, puberty and gonadal issues, thick lips, short phalanges, hypertrichosis, finger (toe) inversion, intellectual disability, supinated ears, arched eyebrows, microcephaly, a long nose, a small chin, nasal alar dysplasia, lip infrared inversion, full cheeks, mouth opening, nasal abnormalities, nasal columella abnormalities, midface retrusion, nasal bridge depression, supraorbital ridge dysplasia, skeletal system abnormalities, ptosis, abnormal facial shape, long eyelashes, growth hormone deficiency, intrauterine growth retardation, and low-set ears. These characteristics of disease partially align with the phenotype observed in this case.

The results of pedigree verification indicate that there is a heterozygous variant, c.700G > T, in the patient’s SOX11 gene. As this variant is not found in her parents, it is considered as a de novo variant (Fig. 2).

Fig. 2

Gene sequencing map of the patient and her parents. (The patient: 20Y04639; Father: 20Y04639FUO; Mother: 20Y04639MUO)

Discussion

CSS is primarily induced by neonatal variants and exhibits a wide range of clinical phenotypes, which may vary at different growth stages of a child and tend to become more pronounced with age. Consequently, uniform diagnostic criteria for this disease are lacking. The suspected diagnosis is based on specific clinical features of CSS, including: (i) dysplasia of the fifth toenail, hypoplasia of the distal phalanx or nail, and even scoliosis or pectus excavatum in severe cases; (ii) developmental delay or cognitive impairment of varying degrees, which may encompass hearing, vision, and language impairments; (iii) distinctive facial features such as a coarse face, flattened nasal bridge, wide mouth, thick eyebrows, and sparse hair; (iv) atypical symptoms such as excessive back hair, facial hirsutism, growth hormone deficiency, hypothyroidism, and congenital heart diseases (e.g., atrial septal defect, ventricular septal defect, and patent ductus arteriosus) [11]. The patient was hospitalized for growth retardation. Upon reviewing her medical history, she presented with a body weight below that of her peers, short stature, mental and motor retardation, and visual impairment. Imaging examinations revealed non-visible spina bifida and a perimembranous ventricular septal defect, a type of congenital heart disease. The clinical manifestations were partially consistent with CSS, leading to a suspected diagnosis.

Approximately 200 cases of CSS have been reported globally, with 12 related genes identified, including 10 BAF-regulating and encoding genes (ARID1A, ARID1B, ARID2, DPF2, SMARCA4, SMARCB1, SMARCC2, SMARCD1, SMARCE1, and SOX4), and 2 transcription-regulating genes (PHF6 and SOX11). Among these, the ARID1B gene, associated with CSS1, has the highest variant frequency [12]. The WES results in this case revealed a rare heterozygous variant, c.700G > T, in the SOX11 gene. Since Yoshinori Tsurusaki first reported in 2014 that variants in the SOX11 gene could cause CSS, only 14 cases of SOX11 deletion or de novo variants have been documented, including 6 severe chromosomal deletions, 1 nonsense variant, and 7 missense variants [13]. Abnormalities in the SOX11 gene lead to CSS9 syndrome, which is milder in clinical manifestations compared to other types of CSS, often features more prevalent developmental abnormalities in the nervous system. The case described stems from the c.700G > T variant in the SOX11 gene. The corresponding codon of this variant mutates to a termination codon, which alter the corresponding protein, thus resulting in this disease. Clinically, this patient exhibits developmental delays but lack abnormalities in the fifth finger, significant vision disorder, or hearing impairments, leading to an erroneous diagnosis of dwarfism.

The SOX11 gene is located in the 2p25.2 region of human chromosome and is crucial for neural development. Deletion of the SOX11 gene in early embryos disrupts the normal development of human central nervous system [14]. Experiments in zebrafish have demonstrated that knocking down SOX11a/b leads to brain abnormalities, potentially explaining the brain phenotype observed in CSS [15]. SOX11 is also pivotal in the Pax6-BAF complex within the transcriptional cross-regulation network, which influences the transformation of glial cells into neurons [16]. The interaction between Brg1 and the promoter of the SOX11 gene, along with its interaction with Pax6,triggers the activation of SOX11 expression, crucial for neuron formation. This underlines the significance of the BAF complex and SOX11 in brain development, shedding light on why CSS9 syndrome is often marked by developmental delays [17].

Globally, few cases of CSS9 have been reported, and their varied clinical presentations make diagnosis challenging. The documented CSS9 cases are listed in Table 2. As detailed in Table 2, almost all reported cases exhibit developmental delays and intellectual disabilities, and part of cases own the seizures and vision problems, etc [18,19,20]. But for the patient in this study, in addition to short stature, developmental delay, it is also manifested with the enuresis, absent ventricular septum, scoliosis, and abnormal reproductive system, which are differ from most other patients. What’s more, this patient also lacks the facial features that common to CSS9, and has no abnormalities of the fifth finger, only shows the sparse hair and abnormal nails. The differences of the patient in this case further illustrate the complexity of the clinical manifestations of CSS9. Therefore, clinically, it is recommended that children suspected of having CSS9 receives high-throughput whole-exome sequencing to aid in making a definitive diagnosis [21, 22]. Comprehensive multi-system assessments are also advised, including evaluations of the gastrointestinal, skeletal, urinary systems, vision, growth, and cognitive development. Currently, there has been no effective treatment for CSS9; the management primarily is focused on symptomatic relief and preventing long-term complications [23, 24]. Children with CSS9 often experience feeding difficulties, necessitating timely nutritional supplementation and systematic, comprehensive evaluations to prevent complications. For congenital heart disease, visual impairment, and malformations of the urinary and skeletal systems, early detection and treatment are crucial, with surgery performed as necessary [25].

Table 2 Comparison of identified variants and phenotypic of patients

Conclusion

In this study, the c.700G > T variant of the SOX11 gene documented in this case is a new variant previously unreported. The clinical characteristics of patient are manifested as the developmental delay and short stature, specifically accompanied by scoliosis, enuresis and ventricular septal defect, which are differ from those of almost other reported CSS9 syndromes. This new variant further enriches the database of human gene variations and supports genetic counseling for affected families, aiding in prenatal diagnosis in similar cases in the future.