Phelan-Mcdermid Syndrome, 22q13 Deletion Syndrome, or Autism Spectrum Disorder via the SHANK3 Gene

Phelan-McDermid syndrome is a rare form of intellectual disability. 84% of patients with Phelan-McDermid syndrome meet the criteria for Autism Spectrum Disorder (Betancur and Buxbaum 2013). Major features of Phelan-McDermid syndrome include neonatal hypotonia, global developmental delay, moderate to severe intellectual disability, gait disturbance, increased tolerance to pain, absent or severely delayed speech, and autistic-like behavior with reduced social interaction and poor eye contact (Phelan and McDermid 2012). Notably, overall growth is normal. Dysmorphic features commonly displayed by patients include flat midface with a wide brow, long eyelashes, bulbous nose, sacral dimple, dysplastic ears, toenails and large hands. Brain MRI commonly reveals abnormalities including thinning of the corpus callosum, white matter changes and ventricular dilation (Soorya et al. 2013).

Phelan-McDermid syndrome is inherited in an autosomal dominant manner and is caused by either deletion of 22q13.33 or SHANK3 pathogenic variants. SHANK3 is contained within reported 22q13 deletion intervals and is believed to account for the core features of Phelan-Mcdermid syndrome. The causative pathogenic variants include missense and nonsense variants, splicing variants, small deletions and insertions, large deletions encompassing the SHANK3 gene, as well as chromosomal re-arrangements. About ~80% of SHANK3 chromosomal abnormalities are interstitial or terminal q22 deletions. Most cases of Phelan-McDermid syndrome are sporadic resulting from de novo pathogenic variants in the SHANK3 locus.

SHANK3 encodes a scaffold protein that is primarily expressed in the brain, particularly in the cerebral cortex and cerebellum. The SHANK3 protein localizes to the core of postsynaptic glutamatergic synapses. SHANK3 contains multiple protein binding domains which allow it to interact and organize a series of other proteins. SHANK3 also interacts with neuroligins in the postsynatpic membrane, which is required for proper synapse formation (Phelan and McDermid 2012; Cochoy et al 2015).

The majority of reported pathogenic variants in SHANK3 are large deletions (Human Gene Mutation Database), therefore the clinical sensitivity of SHANK3 sequencing with CNV detection is expected to be significantly higher than a sequencing only test.

Reported 22q13 deletions range in size from 100kb to 4Mb. In a recent study of Phelan-McDermid syndrome patients, ~72% (30/44) had simple 22q13 terminal deletions, 14% had deletions that resulted in the formation of ring chromosomes, 9% had interstitial deletions which included SHANK3 and 7% contained unbalanced translocations (Bonaglia et al. 2011). Balanced translocations in which the breakpoint disrupts SHANK3 have been reported, but their frequency is unknown.

This test provides full coverage of all coding exons of the SHANK3 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Exon 11 of SHANK3 is not sequenced due to DNA structural difficulties and inconsistency in the reference sequence. No pathogenic variants have been reported in this exon.

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).