Prenatal and Postnatal Identification of Phelan–McDermid Syndrome in a Tertiary Referral Center: A 15-Case Series and Literature Review

Objectives: To characterize the clinical and genetic features of Phelan–McDermid syndrome (PMS) in a Chinese prenatal and postnatal cohort, explore genotype–phenotype correlations, and provide evidence to support prenatal genetic counseling. Methods: G-banded karyotyping, single-nucleotide polymorphism arrays (SNP arrays), copy number variation sequencing, and trio whole-exome sequencing were used for genetic diagnosis. Fifteen patients with PMS (11 prenatal and 4 postnatal) were retrospectively enrolled. Genomic visualization, protein structural prediction, and phenotypic heatmap analyses were conducted to analyze genotype–phenotype associations. Results: The prenatal and postnatal detection rates of PMS were 0.061% and 0.49%, respectively. Only 13.3% of cases were detected by karyotyping, whereas 14 cases were confirmed by SNP array analysis. All 22q13 deletions (69.4 kb–8.5 Mb) involved SHANK3, and all copy number variants were de novo. A novel SHANK3 frameshift variant, c.3513_3514delCC, was identified and predicted to result in protein truncation leading to intellectual disability. Prenatal cases mainly presented non-specific ultrasound anomalies (63.6%, 7/11), with fetal growth restriction, renal malformations, and cardiovascular defects being the most frequent findings. A notable 36.4% (4/11) of prenatal cases were complicated by missed abortion, whereas postnatal patients showed predominant neurodevelopmental impairments. In our cohort, larger deletions were observed in cases presenting with more extensive multisystem involvement, a pattern that mirrors findings from recent large-cohort studies. central nervous system abnormalities were predominantly linked to SHANK3 haploinsufficiency, while multi-system malformations seemed to correlate with the cumulative loss of multiple genes across the 22q13 region, in keeping with current hypotheses on contiguous gene effects. Conclusions: PMS presents obvious prenatal–postnatal phenotypic heterogeneity. SHANK3 is the core pathogenic gene, and deletion may influence the extent of multisystem involvement. Combined genetic testing can improve the accuracy of prenatal diagnosis and counseling for PMS.