The 22q13.3 Deletion Syndrome (Phelan-McDermid Syndrome)

Abstract

The 22q13.3 deletion syndrome, also known as Phelan-McDermid syndrome, is a contiguous gene disorder resulting from deletion of the distal long arm of chromosome 22. In addition to normal growth and a constellation of minor dysmorphic features, this syndrome is characterized by neurological deficits which include global developmental delay, moderate to severe intellectual impairment, absent or severely delayed speech, and neonatal hypotonia. In addition, more than 50% of patients show autism or autistic-like behavior, and therefore it can be classified as a syndromic form of autism spectrum disorders (ASD). The differential diagnosis includes Angelman syndrome, velocardiofacial syndrome, fragile X syndrome, and FG syndrome. Over 600 cases of 22q13.3 deletion syndrome have been documented. Most are terminal deletions of ∼100 kb to >9 Mb, resulting from simple deletions, ring chromosomes, and unbalanced translocations. Almost all of these deletions include the gene SHANK3 which encodes a scaffold protein in the postsynaptic densities of excitatory synapses, connecting membrane-bound receptors to the actin cytoskeleton. Two mouse knockout models and cell culture experiments show that SHANK3 is involved in the structure and function of synapses and support the hypothesis that the majority of 22q13.3 deletion syndrome neurological defects are due to haploinsufficiency of SHANK3, although other genes in the region may also play a role in the syndrome. The molecular connection to ASD suggests that potential future treatments may involve modulation of metabotropic glutamate receptors.

Fig. 1

These patients with 22q13.3 deletion syndrome demonstrate the wide differences in facial phenotype that may make clinical diagnosis difficult. Many children will have facial hypotonia, mild periorbital fullness, long eyelashes, full cheeks, and smoothing of the philtrum.

Fig. 2

Dysplastic toenails. A Small and poorly formed toenails of a 3-year-old child. B Jagged and thick toenails of an 11-year-old girl. Toenails were small and thin during early childhood, then became thicker with a tendency to become ingrown.

Fig. 3

SHANK3 structure and function. A Genomic structure of SHANK3. Alternatively spliced exons are marked with an asterisk. The locations of protein motifs are shown above the gene. The breakpoint hotspot consists of a complex microsatellite (D22S163) and is the location of at least 3 independent deletion breakpoints. ‘Sequence uncertainty’ refers to a small stretch of sequence not included in the Hg19 reference sequence, resulting in the incorrect annotation of an additional exon. B A representation of some of the PSD proteins that bind to SHANK3 which acts as a PSD scaffold. SHANK3 binds to various membrane-bound receptors through Homer, SAPAP, and PSD-95 proteins. SHANK3 connects to the actin cytoskeleton through proteins such as α-Fodrin and Cortactin. Two or more SHANK3 proteins can multimerize through the SAM domains [based on Kreienkamp, 2008].