Variability in Phelan-McDermid Syndrome in a Cohort of 210 Individuals

Abstract

Phelan-McDermid syndrome (PMS, OMIM# 606232) results from either different rearrangements at the distal region of the long arm of chromosome 22 (22q13.3) or pathogenic sequence variants in the SHANK3 gene. SHANK3 codes for a structural protein that plays a central role in the formation of the postsynaptic terminals and the maintenance of synaptic structures. Clinically, patients with PMS often present with global developmental delay, absent or severely delayed speech, neonatal hypotonia, minor dysmorphic features, and autism spectrum disorders (ASD), among other findings. Here, we describe a cohort of 210 patients with genetically confirmed PMS. We observed multiple variant types, including a significant number of small deletions (<0.5 Mb, 64/189) and SHANK3 sequence variants (21 cases). We also detected multiple types of rearrangements among microdeletion cases, including a significant number with post-zygotic mosaicism (9.0%, 17/189), ring chromosome 22 (10.6%, 20/189), unbalanced translocations (de novo or inherited, 6.4%), and additional rearrangements at 22q13 (6.3%, 12/189) as well as other copy number variations in other chromosomes, unrelated to 22q deletions (14.8%, 28/189). We compared the clinical and genetic characteristics among patients with different sizes of deletions and with SHANK3 variants. Our findings suggest that SHANK3 plays an important role in this syndrome but is probably not uniquely responsible for all the spectrum features in PMS. We emphasize that only an adequate combination of different molecular and cytogenetic approaches allows an accurate genetic diagnosis in PMS patients. Thus, a diagnostic algorithm is proposed.

Keywords: 22q13 deletion syndrome; Phelan-McDermid syndrome (PMS); SHANK3; autistic behavior; intellectual disabilities (ID); subtelomeric deletion syndrome.

FIGURE 1

Facial views of individuals with PMS with 22q13.3 deletions or SHANK3 sequence variants.

FIGURE 2

Examples of statistically significant correlations (p < 0.001) between intercategorical variables in individuals with 22q13.3 deletions (top) or SHANK3 variants (bottom). Statistical analyses were performed using Kendal tau_b correlation coefficient. In bold, positive correlations and in gray negative correlations.

FIGURE 3

Reasons for referral for genetic evaluation stratified according to the type of genetic defect. Analyses were performed by one-way ANOVA. DD, developmental delay; ASD, autism spectrum disorder; DF, dysmorphic features; ID, intellectual disability; Hy, hypotonia; Lang., language.

FIGURE 4

Examples of molecular characterization of two individuals with PMS. Different molecular approaches were used, including CGH-array, SNP array, and MLPA.

FIGURE 5

Detection of post-zygotic mosaicism in PMS by using microarrays and MLPA. (A) examples of mosaicism detected by CGH-array; (B) examples of mosaicism detected by MLPA.

FIGURE 6

Distribution of continuous variables according to the type of genetic defect. (A) GFAP, global function assessment of the patient (arbitrary values); (B) Size of the deletions (Mb); (C) Age at diagnosis (months); (D) Age at evaluation (years). *ASD diagnosis according to the psychiatrists of the referring institutions.

FIGURE 7

Laboratory algorithm for management of samples suspected of PMS. ID, intellectual disability; ASD, autism spectrum disorder; CM, congenital malformations; PMS, Phelan-McDermid syndrome; CMA, chromosome microarray analysis; MLPA, multiplex ligation-dependent probe amplification; STR, short tandem repeat; CNV, copy number variation; r(22), ring chromosome 22.