See Table A. Genes and Databases for chromosome locus and protein.

See Molecular Genetics for information on allelic variants detected in this gene.

ClinGen-ISCA-3097. Standardized clinical annotation and interpretation for genomic variants from the Clinical Genome Resource (ClinGen) project (formerly the International Standards for Cytogenomic Arrays [ISCA] Consortium)

Chromosomal microarray analysis (CMA) using oligonucleotide arrays or SNP arrays. CMA designs in current clinical use target the 22q13.3 region.

According to the Phelan-McDermid Syndrome Registry, of 232 individuals with microarray results, 181 (79%) have terminal or interstitial deletions, 41 (18%) have unbalanced translocations or other structural abnormalities leading to deletion, and 7 (3%) have SHANK3 pathogenic variants.

Disruption of SHANK3 resulting from a de novo, apparently balanced translocation t(12;22)(q24.1;q13.3) was reported in a male with features of Phelan-McDermid syndrome [Bonaglia et al 2001]. The breakpoints localized to chromosome 22 within exon 21 of SHANK3 and to chromosome 12 within an intron of APPL2.

Although some 22q13 deletions may be visible by karyotype, CMA is recommended to detect large deletions. Karyotype may be necessary to characterize complex rearrangements (e.g., recombinant chromosomes resulting from a parental inversion). Follow-up karyotype of deletions detected by CMA is essential because of the risk for NF2 associated with ring chromosomes (ring chromosomes comprise ~10% of cases).

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

Intragenic SHANK3 deletions have been reported [Bonaglia et al 2011, Pinto et al 2014, Tucker et al 2014].

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.