OBJECTIVE: To explore the clinical phenotype and genetic characteristics of four patients with Phelan-McDermid syndrome (PMS) due to variants of SHANK3 gene. METHODS: Four patients diagnosed with PMS at Guangzhou Women and Children's Medical Center Liuzhou Hospital from January 2020 to January 2025 were selected as the study subjects. Clinical data of the patients were collected. Peripheral venous blood samples were collected from each patient for the extraction of genomic DNA, followed by whole-exome sequencing (WES) and validation by Sanger sequencing. Pathogenicity of candidate variants was rated based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), and multiple bioinformatic tools were used to assess the pathogenic effects of the variants. The study was approved by the Ethics Committee of the Hospital (Ethics No. 2025-007). RESULTS: All four patients had exhibited language delay and intellectual disability (IQ 35 ~ 65). Some also presented with autism spectrum disorder and schizophrenia, albeit with significant phenotypic heterogeneity. All patients were found to harbor deletions of 22q13.33 region, ranging from 55.46 Kb to 112.64 Kb, primarily involving the SHANK3 gene. CONCLUSION PMS is typically caused by deletions or mutations of the SHANK3 gene. The clinical manifestations are diverse, with developmental delay and intellectual disability being the most common. Accurate diagnosis requires integration of genetic testing and standardized clinical assessment. Genetic screening for suspected patients and at-risk pregnant women is recommended to facilitate their genetic counseling.
Child ; Humans ; Chromosome Deletion ; Chromosome Disorders/genetics* ; Chromosomes, Human, Pair 22/genetics* ; Exome Sequencing ; Nerve Tissue Proteins/genetics* ; Phenotype

Objective To explore the clinical phenotype and genetic variation of familial short stature. Method The clinical data of a familial short stature pedigree in Guangxi Zhuang autonomous region were retrospectively analyzed. The disease-causing gene was identified using targeted high-throughput sequencing combined with Sanger sequencing in May 2017. The related literature were searched and the relationship between the clinical phenotype and genotype of the ACAN gene mutation were summarized. Results The two patients were brothers, one was 9-year and 10-month old boy and the other was 7-year-old boy. Both of them had short stature. Their parents were non-consanguineous marriage and both were 150 cm in height, with. Their uncle and grandpa are also short stature. Gene sequencing revealed a novel heterozygous variation c.6193delC (p.Gln2065Serfs*27) in exon 12 of ACAN gene in both brothers, which were inherited from their father. No report of this mutation was found by searching literature and databases. A total of 11 related articles in English were retrieved. Totally (including our study) 32 patients in 41 families were reported to have the pathogenic variants of ACAN gene, including 4 variants from Chinese children, but no such reports were found in Chinese literatures. The most common clinical manifestation is idiopathic short stature, which is mostly familial but could also be sporadic. Some children also suffered from osteoarthritis, disc herniation or degeneration. Most of the children had advanced bone age, but some of them were normal or even lagged. Treatment of postponing puberty by growth hormone combined with gonadotropin-releasing hormone analogues can effectively improve final height. Conclusion Heterozygous mutation of ACAN gene can cause short stature in children and has significant familial genetic characteristics, and the clinical characteristics have no relationship with genotypes.