Neurodevelopmental delay and intellectual disability associated with a novel FRYL variant: a Pan-Chung-Bellen syndrome case report
Year: 2026
Type: conference-abstract
Abstract: Case Presentation: A male patient with global developmental delay (GDD) was diagnosed with Level 3 ASD at age 2. Physical examination revealed hypotonia, arachnodactyly, and left congenital talipes equinovarus, in addition to craniofacial features including macrotia, trichomegaly, short palpebral fissures, a depressed nasal bridge, and a short philtrum. At age 8, the patient developed onset of focal seizures, which were successfully managed with sodium valproate. Neuropsychological assessment was consistent with profound intellectual disability (ID). Diagnostic investigations, initially comprising brain MRI and brainstem auditory evoked response (BAER), yielded unremarkable results. Subsequent genetic investigation was pursued; Array-CGH (aCGH) revealed no copy number variations (CNVs), and FMR1 testing for Fragile X syndrome was negative. At age 6, whole exome sequencing (WES) identified a maternally inherited heterozygous variant of uncertain significance (VUS) in the KMT2A gene. At age 10, a new exome sequencing identified a likely pathogenic FRYL variant (c.2997-2A>G). This variant affects the canonical splice site and likely results in loss of gene function (LoF), establishing the diagnosis of Pan-Chung-Bellen Syndrome (OMIM #621049; 4p11). Discussion: Pan-Chung-Bellen syndrome is a recently delineated clinical entity in the medical literature, with its most prevalent hallmarks including global developmental delay (GDD), intellectual disability (ID), ASD, ADHD, and epilepsy. Furthermore, the condition encompasses distinctive physical features such as craniofacial dysmorphisms and multisystemic congenital malformations involving the central nervous, cardiovascular, gastrointestinal, genitourinary, and skeletal systems. The FRYL gene exhibits evidence of haploinsufficiency in humans and is expressed across a wide range of tissues, notably within the neurons of the central nervous system. Consequently, loss-of-function (LoF) variants, such as the one identified in this case, are pathogenic and provide a definitive explanation for the patient 's neurological phenotype. Final Comments: This report underscores the importance of genetic investigation in patients presenting with syndromic phenotypes of uncertain etiology and unresolved diagnoses. Given the exponential growth in the number of genes associated with neurodevelopmental disorders, the re-analysis of previously negative whole-exome sequencing (WES) results after several years may uncover variants that were not previously identified or classified. Achieving diagnostic resolution brings the diagnostic odyssey to a close, facilitates the early identification of comorbidities, enables tailored management, and refines prognostic assessment, while providing essential data for familial genetic counseling.
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: gold
OpenAlex ID: W7225056117