Abstract
Introduction
Craniosynostosis is a common congenital disorder characterized by premature fusion of one or more cranial sutures, categorized into non-syndromic (NSCS) and syndromic craniosynostosis (SCS). SCS accounts for ∼30% of cases, often accompanied by severe clinical complications, with 20%–25% of patients lacking a clear molecular etiology.
Methods
We enrolled 18 Chinese SCS patients and analyzed their clinical and genetic data via whole-exome sequencing (WES), copy number variation (CNV) analysis, and Sanger sequencing validation.
Results
We identified 15 single nucleotide variants, 2 insertions/deletions, and one microdeletion at 11q23.3q25. Thirteen probands harbored pathogenic/likely pathogenic variants in known craniosynostosis-related genes: FGFR2 (n = 4), FGFR3 (n = 2), TWIST1 (n = 2), and one each in ERF, EFNB1, SON, HUWE1, and KRAS. Three probands carried variants in PTEN, SRCAP, PQBP1, none of which have previously been associated with craniosynostosis. Notably, a de novo nonsense variant (c.562G>T, p. Glu188Ter) was identified in NOG, a promising candidate gene for craniosynostosis.
Discussion
Our findings broaden the genotypic spectrum of craniosynostosis and further highlight the genetic heterogeneity underlying this disorder. The discovery of variants in PTEN, SRCAP, PQBP1, and NOG identifies novel candidate genes and uncovers potential disease mechanisms.
Keywords: idiosyncratically, NOG, Pqbp1, pten, SRCAP, whole-exhume sequencing
Introduction
Premature ossification of one or more cranial sutures (craniosynostosis) is a common craniofacial anomaly (1 in 2000–2500 live births), classified into syndromic (SCS, ∼30%) and non-syndromic (NSCS, >70%) subtypes based on additional extracranial abnormalities. SCS can cause severe neurological sequelae by restricting brain growth and elevating intracranial pressure (Wu and Gu, 2019). Hence, identification of causes and underlying mechanisms would aid the understanding of these conditions.
Aberrant suture fusion is driven by dysregulated signaling pathways (FGF/FGFR, TGF-β/BMP, etc.) and mutations in genes such as FGFR1-3, TWIST1, and RUNX2 (Wu and Gu, 2019; Yapijakis et al., 2023), with recent implications of chromatin modification and retinoic acid signaling genes (Timberlake et al., 2023). Over the last decades, whole-exome sequencing (WES) has identified over 50 causal/relevant genes, and OMIM (http://www.omim.org) documented 205 craniosynostosis-related syndromes by 17 April 2026. However, 20%–25% of SCS cases lack identified causative variants, highlighting genetic knowledge gaps (Kutkowska-Kazmierczak et al., 2018).
To address this gap, we retrospectively analyzed 18 SCS patients (Wuhan Children’s Hospital, 2018–2025) who underwent trio WES/copy number variation sequencing (CNVseq). We first report a de novo NOG variant (novel candidate gene) and three probands with PTEN, SRCAP, or PQBP1 variants, representing unreported phenotypic expansions (Nowaczyk et al., 1993). These findings expand craniosynostosis’ genotypic spectrum and underscore its genetic heterogeneity.
Methods
Study cohort
We retrospectively analyzed a total of 5349 patients suspected of genetic disorders who underwent WES/CNVseq in Wuhan Children’s Hospital from August 2018 to October 2025, identifying 18 SCS probands with causative genetic variants or chromosomal abnormalities (Figure 1). Craniosynostosis was confirmed by physical examination and/or three-dimensional computed tomography (3D-CT). This study was approved by the Ethics Committee of Wuhan Children’s Hospital (Approval NO: 2020R006-E05). Written informed consent was obtained from all participants’ legal guardians; consent was waived for deceased probands per IRB protocols.
FIGURE 1.
Pedigrees of 18 families and the genetic causes identified in the patients.
WES and variant validation
Genomic DNA was extracted from leukocytes using the QIAamp DNA Blood Maxi Kit (Qiagen, Germany). WES and subsequent variant analysis were performed at Chigene (Beijing) Translational Medical Research Center, following protocols similar to our previous studies (Tan et al., 2021; Huang et al., 2024). Bioinformatics analysis involved raw read trimming (Trimmomatic v0.39), alignment to GRCh37/hg19 (BWA-MEM v0.7.17), duplicate marking (Picard v2.19.0), base recalibration, and germline variant calling (GATK HaplotypeCaller v4.5). Variants were annotated (ANNOVAR v2021-05–20), filtered against population databases (gnomAD v3.1.2, 1000 Genomes Phase three), and assessed for functional impact using ten prediction algorithms (SIFT, PolyPhen-2, PROVEAN, CADD v1.6, etc.), then classified per American College of Medical Genetics and Genomics/Association of Molecular Pathology (ACMG/AMP) guidelines or ClinGen PTEN Variant Curation Expert Panel (VCEP) specifications (Kalia et al., 2017) into five categories: Pathogenic, Likely Pathogenic, Variant of Uncertain Significance, Likely Benign, and Benign. All candidate variants were confirmed via bidirectional Sanger sequencing (ABI 3730xl, Thermo Fisher). The variants were described according to current Human Genome Variation Society (HGVS) recommendations and report variants using the Matched Annotation from NCBI and EMBL-EBI (MANE) Select transcripts. Patient clinical phenotypes were annotated using standardized HPO terms, which were implemented for phenotype-driven variant prioritization and filtering throughout the WES analysis workflow.
CNVseq
The CNVseq methodology employed in this study is similar to WES but utilizes a low-coverage whole-genome sequencing (WGS) strategy to achieve comprehensive genomic coverage. This approach enables the detection of large-scale CNVs across the genome. The detailed protocol was as previously described (Luo et al., 2021).
Functional enrichment analysis
Protein-protein interaction (PPI) network analysis using the STRING database (https://string-db.org/), a comprehensive resource that integrates experimentally validated interactions, computational predictions, literature mining, and co-expression data across thousands of species. The Metascape database (https://metascape.org) was used to perform GO functional enrichment analysis for the key module genes (Zhou et al., 2019). The criteria of the analyses were p-values <0.01, min (overlap) = 3, and min (enrichment) = 1.5, and the outcomes were visualized using enrichment network, sankey diagram and dot bubble.
Results
Clinical description
A total of 18 unrelated probands with SCS were included. Detailed clinical information, including the clinical types and manifestations of craniosynostosis, family history, brain CT/MRI, and other relevant examinations, were summarized in Table 1.
TABLE 1.
Clinical features of the 18 craniosynostosis probands.
| No. | Gender | Age | Suture(s) | Craniofacial futures | Neurological symptoms | Ocular abnormalities | Cardiovascular defects | Genitourinary anomalies | Others | CT | MRI | Surgical treatment |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| P1 | F | 1Y2M | Metopic | Abnormal head shape, ocular proptosis, orbital hypertelorism, mild flattened nose, blepharotosis, hydrocephalus | Developmental delay | No | No | No | Lacrimal duct eobstruction, congenital choanael stenosis | Proximal occlusion of the four ventricles | Occipital venous anomaly, enlarged third and bilateral lateral ventricles | Yes, 2Y |
| P2 | F | 10D | Sagittal | Microcephaly, frontal bossing, ocular proptosis | Too young to assess | No | Patent ductus arteriosus, atrial septal defect (oval hole) | No | Neonatal necrotizing enterocolitis, neonatal gastric bleeding | Partially fused sagittal suture narrow cranial cavity | Slightly larger triangular area of bilateral lateral ventricle | Yes, 2 M |
| P3 | F | 1Y | Coronal, sagittal, rhomboid | Abnormal head shape, frontal bossing, low-set ears, open-mouth posture, sialorhea, entropion complicated with trichiasis | Developmental delay, syringomyelia | No | No | No | No | Frontal apical cranial protrusion; coronal, sagittal and rhomboid suture closure | Frontoparietal white matter signal abnormality, bilateral ventriculomegaly, septum pellucidum agenesis, C5–C7 vertebral signal abnormality, syringomyelia | Yes, 4Y |
| P4 | M | 10M28D | Bilateral coronal | Sharp head, ocular proptosis | No | Exotropia | No | No | No | Cerebellar tonsil descends; unclear the coronal suture and the bilateral squamosal sutures | Chiari deformity, abnormal signals in bilateral frontal white matter, slightly larger bilateral lateral ventricles | Yes, 1Y |
| P5 | F | 3Y7M | Coronal | Craniofacial asymmetry (asymmetric frontal, unequal palpebral fissures, left eye hypotelorism) | Developmental delay, speech delay, cognitive impairment | Strabismus | Central atrial septal defect (oval hole type) | No | No | Fused right coronal suture, smaller right frontal cranial cavity than the left | Abnormal signal shadow in bilateralfrontal parietal lobe, smaller right frontal cranial cavity | No |
| P6 | M | 11M16D | Coronal | Abnormal head shape, microcephaly, blepharoptosis, congenital narrow posterior nostrils, and low-set ears | Developmental delay | No | No | No | No | Fused coronal suture, wide anterior fontanelle | NA | Yes, 1Y |
| P7 | F | 1M17D | Sagittal | Abnormal head shape, hydrocephalus | Developmental delay | No | No | Unilateral kidney | No | Cerebellar subtonsillar hernia, fused sagittal suture | Slightly widened bilateral frontotemporal extracerebral space, slightly enlarged bilateral lateral ventricles, abnormal head shape | Yes, NA |
| P8 | F | 5D | NA | Dysmorphic features, auricular malformation, multiple swollen, deformed and stiff joints | Developmental delay | No | No | Malformation of external genitalia | No | NA | Abnormal brain morphology and multiple abnormal intracranial signal foci | Yes, 2Y |
| P9 | M | 1Y1M | Coronal | Right frontal flattening, right orbit retraction, left head tilt | Developmental delay, motor developmental delay, cognitive impairment, epilepsy | Strabismus | No | Cryptorchidism | Flat and outward-turned feet | Partially fused right coronal suture, smaller right cranial cavity than the left | Larger cisterna magna, bilateral lateral ventriculomegaly, widened right posterior fossa and bilateral temporal extracranial spaces, hypoplastic right anterior cranial fossa | Yes, 2Y |
| P10 | M | 4 M | NA | Microcephaly, premature fontanelle closure, prominent ears, micronathia, brachyury | Developmental delay (fetal growth restriction and DD), epilepsy | No | No | No | Short stature, feeding difficulty | NA | Slightly larger cisterna magna | No |
| P11 | M | 3 M | Frontal, sagittal, right coronal | Scaphocephaly | No | No | No | Hypospadias, undescended right testicle | Radial deviation deformity of the little finger, hypertonia | Abnormal skull morphology, long anterior posterior diameter, inward depression of bilateral cranial bones, fused frontal, sagittal and right coronal sutures | NA | Yes, 4 M |
| P12 | M | 1Y3M | NA | Abnormal head shape, dysmorphic features | Developmental delay | No | Pulmonary valve stenosis, patent ductus arteriosus, interventricular septal and right ventricular wall hypertrophy | NO | Hypomyotonia, dysphagia, malnutrition, thin subcutaneous fat | NA | NA | No |
| P13 | M | 6Y2M | NA | Dysmorphic features (long face, high-arched eyebrows, flat nasal bridge, ocular hypertelorism, anteverted nares, long philtrum, thin upper lip, low-set ears, posteriorly rotated ears), prominent eyes, ptosis, scaphocephaly | Developmental delay, intellectual disability, speech delay | Strabismus, doptic atrophy | No | Cryptorchidism | Hypomyotonia | NA | NA | NA |
| P14 | M | 6Y10 M | Coronal | Dysmorphic features, low and flat nose bridge | No | Astigmatism, hyperopia, familial exudative vitreoretinopathy | No | No | Hypertrichiasis, streblomicrodactyly | NA | NA | Yes, 3Y |
| P15 | F | 6 M | NA | Dysmorphic features, congenital narrow posterior nostrils, hydrocephalus | Delayed motor development | No | Ventricular septal defect, atrial septal defect, patent ductus arteriosus | No | Short stature, feeding difficulty, recurrent pneumonia | NA | NA | Yes, 3Y |
| P16 | F | 5Y9M | Coronal, sagittal | Skull malformation, brachycephaly, mildly prominent forehead, mild bilateral ocular protrusion | No | No | No | No | Short stature, scoliosis, flat and bulky right big toe | Abnormal skull morphology, craniosynostosis, discontinuity of the frontal bone and bone adjacent to the left jugular bulb | Abnormal skull morphology, reduced fronto-occipital diameter | No |
| P17 | M | 1Y6M | Coronal, sphenoparietal, sphenofrontal, squamous, occipitomastoid | Microcephaly, flat forehead, ocular ypertelorism, mild external ear dysmorphism | Developmental delay, cognitive impairment, delayed motor development | Astigmatism | Ventricular septal defect, atrial septal defect, patent ductus arteriosus, pulmonary hypertension | No | No | Craniosynostosis | Slightly widened extra-axial spaces in the bilateral frontotemporal regions, with a small amount of subdural effusion in the right frontotemporal region | Yes, 1Y |
| P18 | F | 2Y7M | Sagittal | Scaphocephaly with large head circumference | Developmental delay, delayed motor development, speech delay, autism spectrum disorder | No | No | No | No | Craniosynostosis | Enlarged perivascular spaces | No |
No., number; F, female; M, male; NA, not available; Y, years; M, months; D, days.
Demographic analysis revealed equal gender distribution, with males and females accounting for 50% each, and 12 patients (66.67%) had undergone surgical intervention, with ages at surgery ranging from 2 months to 4 years. As presented in Table 2; Figure 2, among 13 patients with documented suture involvement, coronal suture fusion was most frequent (9/13, 69.23%), followed by sagittal suture fusion (6/13, 46.15%). Multisuture synostosis was observed in 38.46% (5/13) of patients; three sutures were fused in P3, P11 and P17, all involving the coronal suture fused. Five patients had not undergone surgery at the time of analysis, and relevant data were unavailable for one patient.
TABLE 2.
Main phenotypic features of the present cohort.
| Group | Phenotype | Frequency |
|---|---|---|
| CT | Coronal suture fusion involvement | 9/13 (69.23%) |
| Sagittal suture fusion involvement | 6/13 (46.15%) | |
| Multisuture involvement | 5/13 (38.46%) | |
| MRI | Ventriculomegaly | 7/12 (58.33%) |
| White matter signal abnormalities | 6/18 (33.33%) | |
| Chiari malformation | 3/18 (16.67%) | |
| Cranifacial | Facial dysmorphism | 15/18 (83.33%) |
| Microcephaly | 4/18 (22.22%) | |
| Scaphocephaly | 3/18 (16.67%) | |
| Arocephaly | 1/18 (5.56%) | |
| Neurologic | DD | 13/18 (72.22%) |
| Epilepsy | 2/18 (11.11%) | |
| Syringomyelia | 1/18 (5.56%) | |
| Autism spectrum disorder | 1/18 (5.56%) | |
| Ocular abnormalities | Structural abnormalities | 10/18 (55.56%) |
| Strabismus | 4/18 (22.22%) | |
| Astigmatism | 2/18 (11.11%) | |
| Hyperopia | 1/18 (5.56%) | |
| Cardiovascular defects | Atrial septal defect/ventricular septal defec | 5/18 (27.78%) |
| Patent ductus arteriosus | 3/18 (16.67%) | |
| Pulmonary artery stenosis/pulmonary hypertension | 2/18 (11.11%) | |
| Genitourinary anomalies | Cryptorchidism | 3/18 (16.67%) |
| Hypospadias | 1/18 (5.56%) | |
| Renal malformations | 1/18 (5.56%) | |
| Others | Digital/acral anomalies | 4/18 (22.22%) |
| Short stature | 3/18 (16.67%) | |
| Feeding difficulty/malnutrition | 3/18 (16.67%) | |
| Hypomyotonia/hypertonia | 3/18 (16.67%) | |
| Hypertrichiasis | 1/18 (5.56%) | |
| Recurrent pneumonia | 1/18 (5.56%) | |
| Scoliosis | 1/18 (5.56%) | |
| Thin subcutaneous fat | 1/18 (5.56%) | |
| Occipital hemangioma | 1/18 (5.56%) | |
| Neonatal gastrointestinal disorders | 1/18 (5.56%) |
FIGURE 2.
Circular bar plot representing frequencies for phenotypic features in the present cohort; bars are proportional to frequency and 25% intervals indicated by ticks.
Neuroimaging revealed consistent structural abnormalities (Table 2; Figure 2). Craniosynostosis was confirmed by CT in all 12 patients. Abnormal MRI findings were present in all these 12 patients, including ventriculomegaly (7/12, 58.33%), white matter signal abnormalities (4/12, 33.33%), and Chiari malformation (2/12, 16.67%). These imaging futures were closely correlated with neurological manifestations.
Craniofacial dysmorphism was universal (18/18, 100.0%), including facial dysmorphism (15/18, 83.33%), microcephaly (4/18, 22.22%), scaphocephaly (3/18, 16.67%), and arocephaly (1/18, 5.56%). Neurodevelopmental abnormalities were prevalent (13/18, 72.22%), DD (13/18, 72.22%), with additional cases of epilepsy (2/18, 11.11%), syringomyelia (1/18, 5.56%), and autism spectrum disorder (1/18, 5.56%). Ocular structural and functional abnormalities (11/18, 61.11%) included structural abnormalities (10/18, 55.56%), strabismus (4/18, 22.22%), astigmatism (2/18, 11.11%), and hyperopia (1/18, 5.56%). Cardiovascular defects occurred in five patients (27.78%), including atrial septal defect/ventricular septal defect (4/5, 80.0%), patent ductus arteriosus (3/5, 60.0%), and pulmonary artery stenosis/pulmonary hypertension (2/5, 40.0%). Genitourinary anomalies were detected in five patients (27.78%), including cryptorchidism (3/5, 60.0%), hypospadias (1/5, 20.0%), and renal malformations (1/5, 20.0%) (Table 2; Figure 2). Additionally, digital/acral anomalies (4/18, 22.22%), short stature (3/18, 16.67%), and abnormal muscle tone (3/18, 16.67%) were observed.
All 11 patients with ocular abnormalities were found to have concurrent craniofacial dysmorphism (e.g., proptosis, hypertelorism, and ptosis in P1). Cardiovascular defects co-occurred with neuroDD in 80% (4/5) of cases (e.g., DD, speech delay, and cognitive impairment in patient P5). Patient P11, who carried the NOG variant, exhibited hypospadias and fifth finger clinodactyly. Patient P8 manifested severe multisystem involvement, including joint contractures and external genitalia malformation (Table 2; Figure 2).
Genetic findings
A total of 17 distinct pathogenic/likely pathogenic variants and one pathogenic CNV were identified as positive genetic diagnoses (Table 3; Figure 1). Most of these diagnoses (n = 10) involved variants in well-established SCS-related genes and signaling pathways: 4 de novo missense variants in FGFR2, 2 FGFR3 variants (1 maternally inherited), 2 TWIST1 variants (1 paternally inherited and 1 maternally inherited), 1 EFNB1 variant, and 1 ERF variant. Patient P14, who carried the EFNB1 variant, also presented with exudative vitreoretinopathy, which was explained by a de novo FZD4 variant.
TABLE 3.
Genetic causes detected in individuals with craniosynostosis in this study.
| NO. | Gene, transcript and variant/CNV | ACMG class/Criteria | De novo | Have been reported/References |
|---|---|---|---|---|
| P1 | FGFR2, NM_000141.5, c.1021 A>C, p.Thr341Pro | P: PS2+PS3-supporting + PS4-moderate + PM2-supporting + PP3-moderate | Yes | Yes, PMIDs: 7,719,345, 9586546, 16418739, 27028366 |
| P2 | FGFR2, NM_000141.5, c.1025G>C, p.Cys342Ser | P: PS2+PS3-moderate + PS4-moderate + PM1+PM2-supporting + PM5-strong + PP2+PP3-strong | Yes | Yes, PMIDs: 7987400, 8644708, 9586546, 10541159, 12884424, 12884434, 24127277, 25271085, 26362256 |
| P3 | FGFR2, NM_000141.5, c.1040C>G, p.Ser347Cys | P: PS2-very strong + PS4-moderate + PM2-supporting + PP2+PP3 | Yes | Yes, PMIDs: 23754559, 27228464, 7874170, 11781872, 12884424, 20643727, 23348274, 25271085 |
| P4 | FGFR2, NM_000141.5, c.1026C>G, p.Cys342Trp | PS2-very strong + PS4-moderat + PM5+PM2-supporting + PP3-moderate | Yes | Yes, PMIDs: 16418739, 11173845, 11781872, 27803855, 8522336, 8528214, 12186468 |
| P5 | FGFR3, NM_000142.5, c.749C>G, p.Pro250Arg | PS2+PS4+PS3+PM2-supporting | Yes | Yes, PMIDs: 15241680, 8841188, 9042914 |
| P6 | TWIST1, NM_000474.4, c.415C>T, p.Pro139Ser | LP: PS4-moderate + PM2-supporting + PM5+PP3 | From mother | Yes, PMID: 9585583 |
| P7 | ERF, NM_006494.4, c.787C>T, p.Gln263Ter | LP: PVS1-strong + PS2-moderate + PM2-supporting | Yes | NO |
| P8 | del (11) (q23.3q25) (chr11:119627366–134,946,516) | P: 3C (0.9)+4 A (0.45) | Na | Yes, PMID: 8880580 |
| P9 | SON, NM_138,927.4, c.5753_c.5756del, p.Val1918 GlufsTer87 | P: PVS1+PS2-very strong + PS4+PM2-supporting | Yes | Yes, PMIDs: 27545680, 27545676, 27256762 |
| P10 | HUWE1,NM_031407.7, c.12067C>T, p.Arg4023Cys | LP: PS4+PM2-supporting + PP3 | From mother | Yes, PMIDs: 29180823, 36353900 |
| P11 | NOG, NM_005450.6, c.562G>T, p.Glu188Ter | LP: PVS1-strong + PS2-supporting + PM2-supporting | Yes | NO |
| P12 | SRCAP, NM_006662.3, c.7330C>T, p.Arg2444Ter | P: PVS1-strong + PS2-very strong + PS4+PM2-supporting | Yes | Yes, PMIDs: 25433523, 23621943, 22265015, 22965468 |
| P13 | KRAS, NM_004985.5, c.40G>A, p.Val14Ile | P: PS2+PS3-moderate + PS4+PM1+PM2-supporting + PP2+PP3 | From mother | Yes, PMIDs: 16474405, 17704260, 18958496, 19020799, 20949621 |
| P14 | EFNB1, NM_004429.5, c.708dup, p.Lys237 GlnfsTer82 FZD4, NM_012193.4, c.1511G>A, p.Trp504Ter |
LP: PVS1-strong + PS2-moderate + PM2-supporting LP: PVS1-moderate + PS2+PM2-supporting + PP4 |
Yes; Yes | NO; NO |
| P15 | FGFR3, NM_000142.5, c.1172C>A, p.Ala391GLu | P: PS2-very strong + PS3-supporting + PS4-moderate + PM2-supporting + PP3 | From mother | Yes, PMIDs: 7493034, 8880573, 11426459, 20199409 |
| P16 | TWIST1, NM_000474.4, c.396_416dup, p.Lys133pro139dup | P: PS4+PM2-supporting + PM4+P P1-strong |
From father | Yes, PMID: 20643727 |
| P17 | PQBP1, NM_001,032,382.2, c.459_462del, p.Arg153 SerfsTer41 | P: PVS1+PS4+PM2-supporting | From mother | Yes, PMIDs: 20950397, 30500859, 31316545 |
| P18 | PTEN, NM_000314.8, c.72C>G, p.Asp24GLu | LP:PS4-supporting + PM2-supporting + PM5 +PP2+PP3 | From mother | NO |
No., number; Na, not available; P, pathogenic; LP, likely pathogenic.
Additionally, KRAS, HUWE1, SON, and an 11q23.3q25 microdeletion (previously reported to be associated with craniosynostosis) were identified in patients P9, P10, P13, and P8, respectively, with detailed clinical and genetic data provided in Tables 1, 3.
Three pathogenic variants in PTEN, PQBP1, and SRCAP were detected in patients P12, P17, and P18, respectively. All three probands presented with craniosynostosis along with other clinical manifestations; while megalocephaly, microcephaly, and skeletal anomalies are well-documented features of syndromes related to these genes, craniosynostosis represents a novel phenotypic feature.
Furthermore, a heterozygous de novo nonsense variant (c.562G>T, p. Glu188Ter) in NOG (NM_005450.6) was identified in patient P11 (Figure 3A), who presented with scaphocephaly, craniosynostosis, skeletal abnormalities, and hypospadias (Figures 3B–D). Pathogenic NOG variants are typically associated with syndromes characterized by limb synostoses and hearing loss, with no previous reports linking them to cranial suture synostosis, thus supporting NOG as a novel candidate gene for SCS.
FIGURE 3.
Clinical and genetic features of the proband (P11) harboring the NOG variant (c.562G>T, p. Glu188Ter). (A) Sanger sequencing confirming the de novo variant. (B) Head CT scan (3D reconstruction, bone window) showing scaphocephaly (elongated anterior-posterior axis), bilateral depression of the cranial vault, and premature fusion of the metopic suture, superior sagittal suture, and right coronal suture. (C) Clinical photograph of the hands demonstrating restricted flexion at the distal interphalangeal joints of the fifth fingers and absence of flexion creases. Clinical photograph of the feet showing upward deviation of the middle toes and absence of creases on toes 2–5. (D) Hand and foot radiographs showing no evidence of bony fusion or synostosis.
Among the 17 variants, four were novel, 10 occurred de novo, six were maternally inherited, and 1 was paternally inherited. Maternal carriers (patients P6, P10, P13, P15, P17, and P18) exhibited variable phenotypes, with some being clinically asymptomatic. In contrast, patient P16, who harbored a paternally inherited TWIST1 variant, and his elder twin sister presented with identical symptoms, while their father only showed mild hypertelorism—findings indicative of high clinical heterogeneity even among individuals carrying the same variant.
Functional analysis of key modules
To explore the functional interaction of key genes identified in our study, we performed PPI network analysis using STRING database. As illustrated in Figures 4A,B, NOG was clustered with BMP4, which was further connected to well-established driver genes, including FGFR2, FGFR3, TWIST1, RUNX2, and MSX2.
FIGURE 4.
Gene regulatory network, functional enrichment network, and integrated Sankey-bubble analysis of key craniosynostosis genes. (A,B) Gene regulatory network of craniosynostosis-associated factors, through BMP4, NOG is linked to a set of well-characterized genes implicated in craniosynostosis pathogenesis (colored nodes: query proteins/first-shell interactors; white nodes: second-shell interactors; edges = protein-protein associations, cyan and magenta edges: known interactions; green, red, and blue edges: predicted interactions; light green, black and light blue edges: textmining, co-expression, and protein homology). (C) Metascape-generated enrichment network of significantly enriched GO biological processes (nodes = terms; edges = shared genes; colors = functional clusters). (D) Integrated Sankey diagram and bubble plot showing relationships between candidate genes, enriched biological processes, gene counts, and enrichment significance (bubble size = gene count; color intensity = significance), highlighting core pathways in abnormal osteoblast/mesenchymal differentiation and suture development in which NOG involved.
Subsequently, to elucidate the biological functions underlying these PPI-derived core genes, we conducted functional enrichment analysis of all 12 core genes using the Metascape database. This analysis identified several significantly enriched and highly interconnected GO biological processes (Figures 4C,D; Table 4), which were closely associated with skull development, osteogenic differentiation, and tissue growth regulation—core biological events governing cranial suture patency and fusion.
TABLE 4.
Enriched Gene Ontology biological process terms for the 12 genes.
| Category | Term | Count | % | List total | P Value | Genes | Fold enrichment |
|---|---|---|---|---|---|---|---|
| GOTERM_BP_DIRECT | Mesenchymal cell differentiation | 4 | 33.33 | 12 | 5.54E-07 | EFNB1, FGFR2, TWIST1, NOG | 148.1863 |
| GOTERM_BP_DIRECT | Negative regulation of developmental growth | 3 | 25 | 12 | 6.69E-06 | FGFR3, PTEN, NOG | 78.72396 |
| GOTERM_BP_DIRECT | Organ growth | 3 | 25 | 12 | 6.28E-06 | FGFR3, FGFR2, KRAS | 80.39894 |
| GOTERM_BP_DIRECT | Regulation of osteoblast differentiation | 4 | 33.33 | 12 | 3.62E-07 | FGFR2, PTEN, TWIST1, NOG | 137.4091 |
| GOTERM_BP_DIRECT | Rhythmic process | 3 | 25 | 12 | 0.000141 | PTEN, TWIST1, HUWE1 | 28.30524 |
An integrated Sankey diagram combined with a bubble plot (Figure 4D; Table 4) further systematically depicted the correspondence between key hub genes and the enriched biological processes. The enriched gene set mainly included NOG, FGFR2, FGFR3, TWIST1, PTEN, KRAS, EFNB1, and HUWE1, among which FGFR2, FGFR3, and TWIST1 are well-characterized causative genes of craniosynostosis. Notably, NOG was significantly enriched in pathways regulating both osteoblast differentiation and mesenchymal cell differentiation, which strongly supports its functional relevance to cranial suture development.
Discussion
Craniosynostosis is characterized by substantial genetic heterogeneity, which complicates molecular diagnosis due to incomplete penetrance, variable expressivity, and weak genotype-phenotype correlations. The core genetic finding of this study is the identification of pathogenic/likely pathogenic variants in 12 genes (FGFR2, FGFR3, TWIST1, EFNB1, ERF, SON, HUWE1, KRAS, PTEN, PQBP1, SRCAP, and NOG) and one 11q23.3q25 microdeletion in 18 SCS patients. Notably, FGFR2 contributed the highest diagnostic yield (22.22%), followed by FGFR3 and TWIST1 (13.33% each), while the remaining nine genes were each associated with a single patient. Most importantly, our study is the first to report an association between PTEN, PQBP1, SRCAP, and NOG and craniosynostosis, which significantly expands the genetic spectrum of this disorder.
Clinically, craniofacial dysmorphism was the most prevalent symptom (100%), followed by neurodevelopmental impairment (72.22%) and ocular defects (61.11%). We observed significant expansion of systemic involvement, including congenital heart defects (27.78%, primarily atrial septal defect/patent ductus arteriosus), genitourinary defects (27.78%, e.g., cryptorchidism/hypospadias), and digital/acral anomalies (22.22%). These findings support the hypothesis of multi-germ layer (ectodermal/mesodermal) disruption in SCS pathogenesis. Additionally, trans-system phenotypic associations (e.g., eye-craniofacial, neuro-cardiovascular) further corroborate multi-germ layer involvement. Practically, these observations highlight the need for universal neurodevelopmental and ophthalmological assessments, cardiovascular screening for SCS patients, prioritization of genetic testing combined with neuroimaging for precision diagnosis and management, and leveraging specific phenotypic combinations (e.g., SCS + hypospadias + digital/acral anomalies) to facilitate novel gene discovery.
Consistent with established literature (Yapijakis et al., 2023; Timberlake et al., 2023), disruptions in FGF-FGFR, TGF-β/BMP, Wnt, and ephrin signaling—mediated by variants in FGFR1-3, TWIST1, MSX2, EFNB1, ERF, RUNX2, and TCF12—are major causes of craniosynostosis (Wu and Gu, 2019; Yapijakis et al., 2023). In our cohort, variants in FGFR2, FGFR3, TWIST1, ERF, and EFNB1 accounted for over half of genetically resolved cases, reinforcing the predominance of FGF/TWIST and BMP/MSX2 pathway dysregulation in SCS (Yapijakis et al., 2023). These genes are linked to well-defined syndromes: FGFR1-3 variants cause Pfeiffer, Crouzon, Apert, and Muenke syndromes; TWIST1 variants underlie Saethre-Chotzen syndrome and Craniosynostosis type 1; ERF variants (encoding an ETS2 repressor factor in FGF/TWIST pathways (Yapijakis et al., 2023; Armand et al., 2019), typically cause Craniosynostosis 4 (OMIM#600775). ERF truncating variants impair nuclear-cytoplasmic shuttling (via disrupted ERK interaction/C-terminal domains) and abrogate osteoblast proliferation repression, a mechanism likely underlying craniofacial abnormalities (Goto et al., 2025). Our novel ERF nonsense variant (P7, p. Gln263Ter) is predicted to exert a similar loss-of-function effect.
Trio sequencing yielded a critical finding: a high de novo variant rate (10/18, 55.56%), which underscores its high clinical utility for SCS molecular diagnosis. Additionally, we observed maternal inheritance in 27.78% of cases (FGFR3, KRAS, TWIST1, HUWE1, PTEN, PQBP1), highlighting notable inheritance risks—particularly in cases with mild maternal phenotypes (e.g., midface hyperplasia in P15’s mother, valvulopathy in P13’s mother, slightly enlarged head circumference in P17’s mother). This finding emphasizes the importance of family-based genetic analysis to inform accurate genetic counseling and risk assessment for SCS families.
Four probands (P13, P9, P10, P8) harbored pathogenic variants/CNV associated with known craniosynostosis-related syndromes: KRAS (Noonan syndrome 3, OMIM #609942), SON (ZTTK syndrome, OMIM 617140), HUWE1 (Turner type, OMIM 309590), and 11q23.3q25 microdeletion (Jacobsen syndrome, OMIM 147791). KRAS (RAS/MAPK pathway) may disrupt skull development via constitutive activation when mutated (Ueda et al., 2017). SON (RNA splicing cofactor) and HUWE1 are craniosynostosis risk genes, highly expressed in cranial neural crest cells and converging on regulatory networks controlling osteoblast differentiation (Timberlake et al., 2023; Moortgat et al., 2018). While craniosynostosis is a known feature of Jacobsen syndrome (Linares et al., 2016), the mechanism linking 11q23.3q25 microdeletion to suture fusion remains unclear and requires further investigation.
One of the most important novel findings of this study is the identification of craniosynostosis in patients harboring variants in PTEN (P18), PQBP1 (P17), and SRCAP (P12)—a phenotype never previously reported for these genes. For PTEN, functional enrichment analysis (Figure 4D) confirms its involvement in osteoblast differentiation regulation and developmental growth suppression, and we propose it may contribute to craniosynostosis by inhibiting PI3K/AKT signaling to regulate neural crest development and craniofacial morphogenesis (Yang et al., 2018). For PQBP1, its knockdown in developing mesoderm (bone/cartilage precursor) inhibits FGF-induced target gene expression and Fgf4 levels (Yang et al., 2020), suggesting it may contribute to SCS pathogenesis via regulating FGF/FGFR signaling—a hypothesis requiring further validation. For SRCAP, its role in histone H2A.Z deposition (Johal et al., 2025) implicates epigenetic dysregulation in suture biology, potentially converging with mechanisms involving other chromatin modifiers (e.g., HUWE1) (Beacon et al., 2021).
The most striking finding of our study is the identification of a de novo NOG nonsense variant (p.Glu188Ter) in SCS patient P11. NOG encodes noggin, a potent BMP antagonist critical for cranial suture patency and skull vault development, and dysregulated BMP signaling is a well-recognized cause of craniosynostosis (Warren et al., 2003; Maxson and Ishii, 2008; Whitton et al., 2016; Komatsu et al., 2013). Reduced noggin expression is consistently documented in fused human sutures and craniosynostosis models, while noggin application prevents pathological fusion in animals (Wu and Gu, 2019; Cooper et al., 2007; Shen et al., 2009; Gabbay et al., 2006; Hel et al., 2007; Al-Rekabi et al., 2017; Jacob et al., 2007; Sanchez-Lara et al., 2010; Wang et al., 2019). Studies on Nog−/− lacZ mice have further estabolished noggin as a BMP antagonist that governs dorsoventral patterning of the neural tube, somite differentiation, as well as limb cartilage and joint formation, with loss of Noggin resulting in multiple axial and appendicular skeletal malformations (McMahon et al., 1998; Brunet et al., 1998). Moreover, Noggin had been shown to regulate cranial suture fusion in postnatal mice (Warren et al., 2003). Cnosistently, the Mouse Genome Informatics (MGI) database (https://www.informatics.jax.org) documents that Nog mutant mice exhibit craniosynostosis accompanied a spectrum of craniofacial defects—including frontal bossing, brachyturricephaly, dolichocephaly, wide anterior fontanel, micrognathia, maxillary hypoplasia, shallow orbits, microcephaly, prominent forehead, and palatal abnormalities—as well as skeletal involvement across the basicranium, vertebrae, cartilage, joints, and bone mineralization. Collectively, these MGI-derived phenotypes provide in vivo evidence reinforcing the essential role of NOG in cranial suture patency and skeletal development, further supporting the pathogenicity of the p. Glu188Ter variant identified in our patient. Our functional analyses provide direct support for this novel association: PPI network analysis showed NOG directly interacts with BMP4, which connects to established craniosynostosis-related genes (FGFR1-3, MSX2, RUNX2, TWIST1), implicating NOG in key pathogenic signaling pathways; functional enrichment analysis confirmed NOG is significantly enriched in osteoblast and mesenchymal cell differentiation regulation. This is the first human genetic evidence linking NOG dysfunction to craniosynostosis, expanding its phenotypic spectrum and identifying dysregulated BMP antagonism as a novel pathogenic mechanism. Further functional studies are needed to elucidate NOG’s precise role in suture biology.
Conclusion
In conclusion, our genetic analysis identified causative variants and one CNV in 18 Chinese craniosynostosis probands, including four novel variants and novel gene associations. Acknowledging limitations, retrospective design and small sample size, our findings reinforce craniosynostosis’ genetic heterogeneity, including established pathways (e.g., FGF/TWIST) and diverse syndromic genes. Critically, we implicate PTEN, PQBP1, and SRCAP in a novel craniosynostosis phenotype and identify NOG as a new candidate gene for craniosynostosis. These findings expand the genotypic and phenotypic spectrum of craniosynostosis and provide new avenues for pathogenesis research.
Funding Statement
The author(s) declared that financial support was received for this work and/or its publication. This study was supported by Wuhan Municipal Health Commission Young Talents “Chen Xing” Project (2023); the Construction Project of Clinical Medical Research Center for Neurodevelopmental Disorders in Children in Hubei Province (HST 2020-19); and the Construction Project of Clinical Medical Research Center for Birth Defect Prevention and Treatment in Wuhan (WK (2023)123-4).
Footnotes
Edited by: Shruthi Kumar Bharadwaj, Ahalia Hospital (Abu Dhabi), United Arab Emirates
Reviewed by: Xueqian Wang, Children’s Hospital of Soochow University, China
Omid Jazayeri, University of Mazandaran, Iran
Data availability statement
The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.
Ethics statement
The studies involving humans were approved by Ethics Committee of Wuhan Children’s Hospital (Approval NO: 2020R006-E05). The studies were conducted in accordance with the local legislation and institutional requirements. Written informed consent for participation in this study was provided by the participants’ legal guardians/next of kin. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.
Author contributions
YfH: Writing – original draft. LnH: Writing – original draft. LlH: Writing – original draft. LT: Writing – original draft. PZ: Writing – original draft. SL: Writing – original draft. TY: Writing – original draft. YnH: Writing – original draft. YaH: Writing – review and editing. HD: Writing – review and editing. XH: Writing – review and editing.
Conflict of interest
The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Generative AI statement
The author(s) declared that generative AI was not used in the creation of this manuscript.
Any alternative text (alt text) provided alongside figures in this article has been generated by Frontiers with the support of artificial intelligence and reasonable efforts have been made to ensure accuracy, including review by the authors wherever possible. If you identify any issues, please contact us.
Publisher’s note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
References
- Al-Rekabi Z., Cunningham M. L., Sniadecki N. J. (2017). Cell mechanics of craniosynostosis. ACS Biomater. Sci. Eng. 3 (11), 2733–2743. 10.1021/acsbiomaterials.6b00557 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Armand T., Schaefer E., Di Rocco F., Edery P., Collet C., Rossi M. (2019). Genetic bases of craniosynostoses: an update. Neurochirurgie 65 (5), 196–201. 10.1016/j.neuchi.2019.10.003 [DOI] [PubMed] [Google Scholar]
- Beacon T. H., Delcuve G. P., Lopez C., Nardocci G., Kovalchuk I., van Wijnen A. J., et al. (2021). The dynamic broad epigenetic (H3K4me3, H3K27ac) domain as a mark of essential genes. Clin. Epigenetics 13 (1), 138. 10.1186/s13148-021-01126-1 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Brunet L. J., McMahon J. A., McMahon A. P., Harland R. M. (1998). Noggin, cartilage morphogenesis, and joint formation in the Mammalian skeleton. Science 280 (5368), 1455–1457. 10.1126/science.280.5368.1455 [DOI] [PubMed] [Google Scholar]
- Cooper G. M., Curry C., Barbano T. E., Burrows A. M., Vecchione L., Caccamese J. F., et al. (2007). Noggin inhibits postoperative resynostosis in craniosynostotic rabbits. J. Bone Min. Res. 22 (7), 1046–1054. 10.1359/jbmr.070410 [DOI] [PubMed] [Google Scholar]
- Gabbay J. S., Heller J., Spoon D. B., Mooney M., Acarturk O., Askari M., et al. (2006). Noggin underexpression and runx-2 overexpression in a craniosynostosis rabbit model. Ann. Plast. Surg. 56 (3), 306–311. 10.1097/01.sap.0000197740.75563.4f [DOI] [PubMed] [Google Scholar]
- Goto Y., Niihori T., Mizuno S., Okamoto N., Ogata T., Kurosawa K., et al. (2025). Missense and truncated variants in ERF in individuals with a Noonan-like phenotype without craniosynostosis. Sci. Rep. 15 (1), 15179. 10.1038/s41598-025-89719-1 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Heller J. B., Gabbay J. S., Wasson K., Mitchell S., Heller M. M., Zuk P., et al. (2007). Cranial suture response to stress: expression patterns of noggin and Runx2. Plast. Reconstr. Surg. 119 (7), 2037–2045. 10.1097/01.prs.0000260589.75706.19 [DOI] [PubMed] [Google Scholar]
- Huang Y., Deng W., Huang H., Zhang X., Chen X., Ye J., et al. (2024). Detection of inversion with breakpoints in ARSB causing MPS VI by whole-genome sequencing: lessons learned and best practices. Front. Genet. 15, 1452498. 10.3389/fgene.2024.1452498 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Jacob S., Wu C., Freeman T. A., Koyama E., Kirschner R. E. (2007). Expression of Indian hedgehog, BMP-4 and noggin in craniosynostosis induced by fetal constraint. Ann. Plast. Surg. 58 (2), 215–221. 10.1097/01.sap.0000232833.41739.a5 [DOI] [PubMed] [Google Scholar]
- Johal K., Youssef S., Ibrahim S., Dizon-Mapula L., Galluzzo I., Stefanelli G. (2025). Srcap loss alters H2A.Z-dependent and neuronal differentiation-related gene expression in N2A cells. Biochem. Cell Biol. 103, 1–12. 10.1139/bcb-2024-0294 [DOI] [PubMed] [Google Scholar]
- Kalia S. S., Adelman K., Bale S. J., Chung W. K., Eng C., Evans J. P., et al. (2017). Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2016 update (ACMG SF v2.0): a policy statement of the American college of medical genetics and genomics. Genet. Med. 19 (2), 249–255. 10.1038/gim.2016.190 [DOI] [PubMed] [Google Scholar]
- Komatsu Y., Yu P. B., Kamiya N., Pan H., Fukuda T., Scott G. J., et al. (2013). Augmentation of Smad-dependent BMP signaling in neural crest cells causes craniosynostosis in mice. J. Bone Min. Res. 28 (6), 1422–1433. 10.1002/jbmr.1857 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kutkowska-Kazmierczak A., Gos M., Obersztyn E. (2018). Craniosynostosis as a clinical and diagnostic problem: molecular pathology and genetic counseling. J. Appl. Genet. 59 (2), 133–147. 10.1007/s13353-017-0423-4 [DOI] [PubMed] [Google Scholar]
- Linares C. E. P., Toral Lopez J., Valdes Miranda J. M., Gonzalez H. L. M., Perez Cabrera A., Del Refugio Rivera Vega M., et al. (2016). Jacobsen syndrome: surgical complications due to unsuspected diagnosis, the importance of molecular studies in patients with craniosynostosis. Mol. Syndromol. 6 (5), 229–235. 10.1159/000442477 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Luo S., Chen L., Wei W., Tan L., Zhang M., Duan Z., et al. (2021). Prenatal genetic diagnosis in three fetuses with left heart hypoplasia (LHH) from three unrelated families. Front. Cardiovasc Med. 8, 631374. 10.3389/fcvm.2021.631374 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Maxson R., Ishii M. (2008). The bmp pathway in skull vault development. Front. Oral Biol. 12, 197–208. 10.1159/000115042 [DOI] [PubMed] [Google Scholar]
- McMahon J. A., Takada S., Zimmerman L. B., Fan C. M., Harland R. M., McMahon A. P. (1998). Noggin-mediated antagonism of BMP signaling is required for growth and patterning of the neural tube and somite. Genes Dev. 12 (10), 1438–1452. 10.1101/gad.12.10.1438 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Moortgat S., Berland S., Aukrust I., Maystadt I., Baker L., Benoit V., et al. (2018). HUWE1 variants cause dominant X-linked intellectual disability: a clinical study of 21 patients. Eur. J. Hum. Genet. 26 (1), 64–74. 10.1038/s41431-017-0038-6 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Nowaczyk M. J. M., Nikkel S. M., White S. M. (1993). “SRCAP-related floating-harbor syndrome,” in Genereviews((R)). Editors Adam M. P., Feldman J., Mirzaa G. M., Pagon R. A., Wallace S. E., Amemiya A. (Seattle (WA)). [PubMed] [Google Scholar]
- Sanchez-Lara P. A., Carmichael S. L., Graham J. M., Jr, Lammer E. J., Shaw G. M., Ma C., et al. (2010). National birth defects Prevention S: fetal constraint as a potential risk factor for craniosynostosis. Am. J. Med. Genet. A 152A (2), 394–400. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Shen K., Krakora S. M., Cunningham M., Singh M., Wang X., Hu F. Z., et al. (2009). Medical treatment of craniosynostosis: recombinant Noggin inhibits coronal suture closure in the rat craniosynostosis model. Orthod. Craniofac Res. 12 (3), 254–262. 10.1111/j.1601-6343.2009.01460.x [DOI] [PMC free article] [PubMed] [Google Scholar]
- Tan L., Li Y., Liu F., Huang Y., Luo S., Zhao P., et al. (2021). A 9-month-old Chinese patient with Gabriele-de Vries syndrome due to novel germline mutation in the YY1 gene. Mol. Genet. Genomic Med. 9 (2), e1582. 10.1002/mgg3.1582 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Timberlake A. T., McGee S., Allington G., Kiziltug E., Wolfe E. M., Stiegler A. L., et al. (2023). De novo variants implicate chromatin modification, transcriptional regulation, and retinoic acid signaling in syndromic craniosynostosis. Am. J. Hum. Genet. 110 (5), 846–862. 10.1016/j.ajhg.2023.03.017 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ueda K., Yaoita M., Niihori T., Aoki Y., Okamoto N. (2017). Craniosynostosis in patients with RASopathies: accumulating clinical evidence for expanding the phenotype. Am. J. Med. Genet. A 173 (9), 2346–2352. 10.1002/ajmg.a.38337 [DOI] [PubMed] [Google Scholar]
- Wang W., Zhou C., Feng Z., Li H., Zhang Y., Bao B., et al. (2019). PLGA-based control release of noggin blocks the premature fusion of cranial sutures caused by retinoic acid. Appl. Microbiol. Biotechnol. 103 (1), 291–301. 10.1007/s00253-018-9457-8 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Warren S. M., Brunet L. J., Harland R. M., Economides A. N., Longaker M. T. (2003). The BMP antagonist noggin regulates cranial suture fusion. Nature 422 (6932), 625–629. 10.1038/nature01545 [DOI] [PubMed] [Google Scholar]
- Whitton A., Hyzy S. L., Britt C., Williams J. K., Boyan B. D., Olivares-Navarrete R. (2016). Differential spatial regulation of BMP molecules is associated with single-suture craniosynostosis. J. Neurosurg. Pediatr. 18 (1), 83–91. 10.3171/2015.12.PEDS15414 [DOI] [PubMed] [Google Scholar]
- Wu X., Gu Y. (2019). Signaling mechanisms underlying genetic pathophysiology of craniosynostosis. Int. J. Biol. Sci. 15 (2), 298–311. 10.7150/ijbs.29183 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Yang T., Moore M., He F. (2018). Pten regulates neural crest proliferation and differentiation during mouse craniofacial development. Dev. Dyn. 247 (2), 304–314. 10.1002/dvdy.24605 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Yang S. S., Ishida T., Fujita K., Nakai Y., Ono T., Okazawa H. (2020). PQBP1, an intellectual disability causative gene, affects bone development and growth. Biochem. Biophys. Res. Commun. 523 (4), 894–899. 10.1016/j.bbrc.2019.12.097 [DOI] [PubMed] [Google Scholar]
- Yapijakis C., Pachis N., Sotiriadou T., Vaila C., Michopoulou V., Vassiliou S. (2023). Molecular mechanisms involved in craniosynostosis. Vivo 37 (1), 36–46. 10.21873/invivo.13052 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Zhou Y., Zhou B., Pache L., Chang M., Khodabakhshi A. H., Tanaseichuk O., et al. (2019). Metascape provides a biologist-oriented resource for the analysis of systems-level datasets. Nat. Commun. 10 (1), 1523. 10.1038/s41467-019-09234-6 [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.