Research Information System
Genetics in Medicine Open, vol.4, pp.92, 2026 (Scopus)
Introduction: Phelan-McDermid syndrome (PMS; MIM 606232) is a rare neurodevelopmental disorder mainly caused by terminal 22q13 deletions and pathogenic SHANK3 variants. However, a subset of cases presents atypical 22q13 rearrangements with intact SHANK3, broadening the molecular and clinical spectrum of the disorder. Advanced structural variant detection technologies such as optical genome mapping (OGM) have enabled comprehensive characterization of complex genomic events. Here, we report a case with a de novo complex 22q13 rearrangement involving multiple inversions and copy number variations (CNV), elucidated through OGM, and classified as SHANK3-unrelated PMS, emphasizing the diagnostic value of integrated genomic analyses. Case Presentation: A 7-month-old male, the first child of non-consanguineous healthy parents, was referred for evaluation of hypotonia and dysmorphic features. Antenatal ultrasonography revealed polyhydramnios, hydronephrosis, and ureteropelvic junction (UPJ) obstruction. He was born at term by cesarean section with normal anthropometric parameters. The neonatal period was notable for hypotonia and jaundice requiring phototherapy. During infancy, the case experienced recurrent urinary tract infections secondary to UPJ obstruction and vesicoureteral reflux. Persistent hypotonia, macrocephaly, and developmental delay prompted referral for genetic evaluation. Dysmorphic features included frontal bossing, downslanting palpebral fissures, smooth philtrum, thin upper lip, and low-set ears. Neurologically, marked axial hypotonia was noted. At one year, brain magnetic resonance imaging showed white-matter abnormalities, and later febrile focal seizures with a left temporal focus emerged. Motor milestones were delayed, and speech delay persisted despite preserved social interaction. The case also had bilateral pes planus and renal pelviectasis under surgical follow-up. Diagnostic Workup: Conventional karyotyping revealed an atypical banding pattern on chromosome 22, suggestive of a structural rearrangement. Parental karyotypes were normal, indicating a de novo event. Fluorescence in situ hybridization demonstrated a pericentric inversion involving 22p12-q11.2, described as [46,XY,der(22).ish inv(22)(p12q11.2?)(N25+, SHANK3+, EWSR1+) dn]. Exome sequencing with CNV analysis revealed several CNV within the 22q13 region, including three deletions (1.1-3.7 Mb) and multiple small duplications (0.06-0.6 Mb). Chromosomal microarray analysis (CMA) validated three terminal deletions spanning 22q13.2-q13.33, while the SHANK3 gene remained intact. OGM revealing a complex 22q13 architecture composed of three interspersed deletions, four duplications, and four distinct inversions. This intricate de novo rearrangement extensively reorganized the distal 22q13 region but spared SHANK3, consistent with a diagnosis of SHANK3-unrelated PMS. Treatment and Management: Management has been multidisciplinary, including antiepileptic therapy with carbamazepine, physiotherapy four times weekly, and early developmental interventions. The case is under regular nephrology follow-up for VUR and pelviectasis (on prophylactic trimethoprim/sulfamethoxazole) and orthopedic care for pes planus. Outcome and Follow-Up: At 2 years, the case demonstrates gradual motor improvement but persistent global developmental delay and hypotonia. Seizures are partially controlled with antiepileptic therapy. Comprehensive supportive rehabilitation and scheduled renal and orthopedic surgeries are ongoing under multidisciplinary follow-up. Discussion: The present report highlights the expanding molecular heterogeneity of PMS and emphasizes the critical role of structural variant analysis in 22q13 abnormalities. Although most PMS cases involve SHANK3 deletions, some with intact SHANK3 gen show overlapping phenotypes, suggesting that neighboring genes or complex rearrangements might disrupt SHANK3 expression or other regulatory mechanism. Our findings support this concept by demonstrating extensive genomic reorganization of 22q13 without SHANK3 loss. OGM delineate this architecture, demonstrating its unique ability to unravel complex genomic events beyond the capacity of CMA or exome-based CNV analysis. These results highlight the diagnostic superiority of OGM in uncovering atypical genomic architectures. Conclusion: This case demonstrates that complex 22q13 structural abnormalities can cause a PMS phenotype even without SHANK3 disruption. OGM successfully localizes these rearrangements, highlighting the critical role of high-resolution cytogenomic methods in comprehensive molecular diagnosis. Such advanced structural variant analysis enhances our understanding of SHANK3-unrelated PMS and may reveal novel genotype-phenotype correlations in that neurodevelopmental disease.