De Novo SYNCRIP Variant in a Korean Child with Developmental Delay, Epilepsy, and Blepharophimosis, Ptosis, and Epicanthus Inversus Syndrome-Like Craniofacial Dysmorphism
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Variants in synaptotagmin binding cytoplasmic RNA interacting protein (SYNCRIP) (also known as HNRNPQ) have recently been implicated in neurodevelopmental disorders (NDDs). SYNCRIP encodes a heterogeneous nuclear ribonucleoprotein that plays a key role in mRNA splicing, transport, and turnover, which are processes essential for neuronal development [1-3]. In addition to its primary role in RNA metabolism, SYNCRIP has also been associated with autophagosome biogenesis [4]. In 2021, Semino et al. [5] reported three unrelated patients with de novo SYNCRIP variants who exhibited developmental delay, epilepsy, autism spectrum disorder, and craniofacial dysmorphism. A recent prenatal case involving a mosaic SYNCRIP variant has further expanded the phenotypic spectrum [6]. To the best of our knowledge, based on a literature review updated to October 2025, this is the first reported case of a de novo SYNCRIP variant in a Korean patient.
This case was reviewed and approved by the Institutional Review Board (IRB) of Keimyung University Dongsan Hospital (IRB No. 2025-10-010). The IRB waived the requirement for informed consent.
The patient was a girl born in December 2021 to healthy, non-consanguineous Korean parents following an uneventful full-term pregnancy. Her birth weight was 3.2 kg, length 49 cm, and head circumference 34 cm, all within normal ranges. She exhibited global developmental delay, achieving head control at 6 months and independent sitting at 12 months, but she had not begun walking independently by 24 months. By age 3, her expressive language was limited to a few single words. At 2 years of age, she experienced recurrent generalized tonic-clonic seizures. Electroencephalography revealed multifocal epileptiform discharges. Treatment with valproate and levetiracetam provided only partial seizure control.
On examination, she displayed features consistent with blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES), along with facial asymmetry, plagiocephaly, torticollis, and malalignment of the right toes (Fig. 1). Despite these findings, her growth parameters remained within the normal range. Trio whole-exome sequencing identified a heterozygous missense variant in the SYNCRIP gene (NM_006372.5:c.1121C>A; p.Ala374Glu), which was absent in both parents, indicating a de novo origin. The de novo status of the SYNCRIP variant was further confirmed by Sanger sequencing. This variant was not present in the Genome Aggregation Database (gnomAD) or other population databases and was predicted to be deleterious by multiple in silico tools. According to the American College of Medical Genetics and Genomics/Association for Molecular Pathology criteria [7], it was classified as a variant of uncertain significance (VUS) (pathogenic strong 2 [PS2], pathogenic moderate 2 [PM2], pathogenic supporting 3 [PP3], and pathogenic supporting 4 [PP4]). Additionally, a heterozygous collagen type XI alpha 1 chain (COL11A1) variant (maternal, c.580C>T; p.Thr187Met) was identified but deemed unrelated to the phenotype.
Frontal facial photographs at 4 months of age, showing blepharophimosis, ptosis, epicanthus inversus, and facial asymmetry.
Our patient exhibits the core features commonly seen in previously reported SYNCRIP-related cases, including global developmental delay and seizures [5]. A comparison with previously reported patients is summarized in Table 1. However, she also presents with more pronounced craniofacial anomalies resembling BPES. While earlier cases occasionally mentioned ptosis or facial asymmetry, the specific combination of blepharophimosis, ptosis, and epicanthus inversus has not been emphasized. The negative forkhead box L2 (FOXL2) testing suggests that the SYNCRIP variant may provide an alternative explanation for the BPES-like morphology [8]. Although the identified variant is currently classified as a VUS, several factors support its clinical relevance: it arose de novo, is absent from population databases, is predicted to be deleterious, and aligns with the observed phenotype. Documenting such cases is crucial for future reclassification of variants as additional evidence accumulates [5,6,9]. Recent reports indicate that pathogenic SYNCRIP variants tend to cluster within RNA-binding domains. However, the potential influence of variants outside these canonical domains, such as p.Ala374Glu, on the clinical phenotype remains uncertain. Additional case reports with consistent phenotypes will be essential for defining genotype–phenotype correlations.
Comparison of clinical features between previously reported patients with SYNCRIP variants and the present case.
This case also underscores the broader significance of exome sequencing in identifying ultra-rare NDDs within pediatric neurology. Even when individual variants are classified as of uncertain significance, systematic documentation of clinically well-characterized patients allows data aggregation that facilitates future reclassification and supports genetic counseling. From a pediatric neurology perspective, this case highlights the importance of early genetic testing in children with unexplained developmental delay and epilepsy. Exome sequencing is now recommended as a first-tier diagnostic test for NDDs [10]. Although the present variant is classified as a VUS, meeting PS2, PM2, PP3, and partial PP4 criteria, reporting such cases is vital for accumulating evidence that may enable future reclassification.
Notes
Conflicts of interest
No potential conflict of interest relevant to this article was reported.
Author contribution
Conceptualization: JCB. Data curation: JCB. Formal analysis: JCB. Methodology: JCB. Project administration: JCB. Visualization: JCB. Writing - original draft: JCB. Writing - review & editing: JCB.