Prenatal and postnatal diagnosis of Phelan-McDermid syndrome: A report of 21 cases from a medical center and review of the literature

Abstract

Background: Phelan-McDermid syndrome (PMS), caused by deletions at 22q13.3 and pathogenic variants in the SHANK3 gene, is a rare developmental disorder characterized by hypotonia, developmental delay (DD), intellectual disability (ID), autism spectrum disorder (ASD), dysmorphic features, absence of or delayed language, and other features. Methods: Conventional karyotyping, chromosomal microarray analysis (CMA), and whole exome sequencing (WES) have been used to detect genetic defects causing PMS. We summarized the genetic and clinical findings from prenatal to postnatal stages of detected cases of PMS and mapped potential candidate haploinsufficient genes for deletions of 22q13. This study aimed to summarize the laboratory findings, genetic defects, and genotype-phenotype correlations for Chinese patients with PMS. Results: Seven prenatal cases and fourteen postnatal cases were diagnosed with PMS in our center. Thirteen cases had a deletion ranging in size from 69 to 9.06 Mb at 22q13.2-q13.33, and five cases had a pathogenic variant or an intragenic deletion in the SHANK3 gene. Three familial cases with a parental carrier of a balanced translocation were noted. A review of the literature noted another case series of 29 cases and a report of five cases of PMS in China. Genotype-phenotype correlations confirmed haploinsufficiency of the SHANK3 gene for PMS and suggested other candidate haploinsufficient genes TNFRSFI3C and NFAM1 genes for immunological features and TCF20, SULT4A1, PARVB, SCO2, and UPK3A genes for intellectual impairment and behavioral abnormality, neurological features, macrocephaly/hypotonia, oculopathy, and renal adysplasia, respectively. Conclusion: Indications for prenatal diagnosis of PMS are not specific, and approximately 85% prenatally diagnosed PMS elected termination of pregnancies after genetic counseling. For postnatal cases, 62.5% were caused by a deletion at 22q13 and 37.5% were caused by a pathogenic variant or an intragenic deletion in the SHANK3 gene. Approximately 6.7% of cases with a deletion were familial, and almost all pathogenic variants were de novo. Combined karyotype, CMA, and WES should be performed to increase the diagnostic yield. The identification of other candidate haploinsufficient genes in deletions of 22q13.2-q13.33 could relate to more severe dysmorphic features, neurologic defects, and immune deficiency. These results provided evidence for diagnostic interpretation, genetic counseling, and clinical management for the Chinese cases of PMS.

Keywords: 22q13.3 deletion syndrome; Phelan–McDermid syndrome (PMS); SHANK3 gene; genotype–phenotype correlations; prenatal diagnosis.

FIGURE 1

Cytogenomic mapping and genotype–phenotype correlations for candidate genes of 22q13.2-q13.33. A cytogenomic map for sizes of deletions and candidate genes of 22q13.2-q13.33. The upper panel shows chromosome 22 with the band location information. The region of 22q13.2-q13.33 is boxed in red. The middle panel shows the size and location of the 41 deletions: 17 cases in our study, 20patients in the literature of Xu et al. (2020), and four samples in the literature of Gong et al. (2012). The lower panel shows OMIM genes in 22q13.2-q13.33. The HI genes are circled in red and six other genes associated with the PMS phenotype are circled in black.

FIGURE 2

The pedigree of three cases from three families. (A) Family 1; (B) family 2; and (C) family 3.

FIGURE 3

Images of patients with PMS. (A) Case 9, 2 years old; (B) case 3, 4 years old; (C) case 14, 6 years old; (D) case 16, 7 years old; (E) case 15, 8 years old; (F) case 13, 9 years old; (G) case 12, 10 years old; (H) case 20, 11 years old; (I) case 10, 13 years old; and (J) case 21, 13 years old. (H,J) Patients with pathogenic variants of the SHANK gene; others: the patients with 22q13 deletion encompass the SHANK3 gene or an intragenic deletion of this gene.