[1] The Developmental Synaptopathies Consortium defines PMS as being caused by SHANK3 mutations, a definition that appears to exclude terminal deletions.

The availability of DNA microarray technology for revealing multiple genetic problems simultaneously has been the diagnostic tool of choice.

Although early researchers sought a monogenic (single gene genetic disorder) explanation, recent studies have not supported that hypothesis (see Etiology).

[4][5][6][7] Patients are consistently characterized by global developmental delay, intellectual disability, speech abnormalities, ASD-like behaviors, hypotonia and mild dysmorphic features.

In the de novo form, the size of the terminal deletion is variable and can go from 130 Kb (130,000 base pairs) to 9 Mb.

SHANK3 is also adjacent to a gene cluster (ARSA and MAPK8IP2)[33] that has a high probability of contributing to ASD,[34] suggesting the effects of SHANK3 deletion may be indistinguishable from other genetic losses.

A landmark study of induced pluripotent stem cell neurons cultured from patients with 22q13 deletion syndrome shows that restoration of the SHANK3 protein produces a significant, but incomplete rescue of membrane receptors, supporting both a substantial role for SHANK3 and an additional role for other genes in the distal 1 Mb of chromosome 22.

[40] A group of genes (MPPED1,[41] CYB5R3,[42] FBLN1,[43] NUP50,[44] C22ORF9,[45] KIAA1644,[46] PARVB,[39] TRMU,[47] WNT7B[48] and ATXN10[49]), as well as microRNAs may all contribute to loss of language, a feature that varies notably with deletion size.

Table of protein coding genes involved in 22q13 deletion syndrome (based on Human Genome Browser – hg38 assembly [51]).

Biological parents should be tested with fluorescence in situ hybridization (FISH) to rule out balanced translocations or inversions.

[61] Clinical genetic evaluations and dysmorphology exams should be done to evaluate growth, pubertal development, dysmorphic features (table 1) and screen for organ defects (table 2) All patients should undergo comprehensive developmental, cognitive and behavioral assessments by clinicians with experience in developmental disorders.

Individuals with PMS should be followed by a pediatric neurologist regularly to monitor motor development, coordination, and gait, as well as conditions that might be associated with hypotonia.

[5] All patients should have a baseline renal and bladder ultrasonography and a voiding cystourethrogram should be considered to rule out structural and functional abnormalities.

The most common CHD include tricuspid valve regurgitation, atrial septal defects and patent ductus arteriosus.

[66][67] The first case of PMS was described in 1985 by Watt et al., who described a 14-year-old boy with severe intellectual disability, mild dysmorphic features and absent speech, which was associated with terminal loss of the distal arm of chromosome 22.