Diagnosis

The diagnosis of PMS is made through one of the two different types of genetic tests described below.

Chromosomal Microarray Analysis (CMA):

Individuals with autism or developmental delay should be referred for a chromosomal microarray (CMA).  The test involves providing a small amount of blood.

If a deletion of 22q13 is detected through microarray, additional steps should be undertaken:

  • Because there can be special health concerns for individuals with a ring chromosome, in which the ends of the chromosome stick together at deletion breakpoints, chromosome analysis (also known as karyotype) should be performed to determine if the individual has Ring 22.

If the CMA shows a terminal deletion of chromosome 22q and a terminal duplication in another chromosome, the individual may have an unbalanced translocation, and Fluorescence in situ hybridization (FISH) and/or karyotype studies are warranted.

PMS-related deletions arise from parental balanced rearrangements in about 20% of cases. Parents who carry a balanced rearrangement, although healthy, have an increased risk of having another affected child.

Parents should undergo metaphase FISH and/or karyotype testing to determine if the child’s deletion is de novo (spontaneous) or if it resulted from a parental chromosomal rearrangement, such as a balanced translocation or inversion, or if one of the parents themselves has the same deletion.

Whole Exome Sequencing:

If Chromosomal Microarray Analysis (CMA) has been done, but a pathogenic deletion is not identified, the next step is Whole Exome Sequencing (WES).

  • WES detects genetic spelling errors, called variants, in genetic sequence.
    • Some variants are benign (they do not cause disease).
    • Some variants have uncertain effects (they are called variants of unknown significance).
    • Other variants are known to cause disease (they are called pathogenic mutations).
  • Pathogenic mutations of SHANK3 are associated with Phelan-McDermid syndrome.

If a likely pathogenic variant of SHANK3 is detected, the parents should also undergo WES to determine if one of the parents carries the same variant. If the variant is present in a healthy parent, it is unlikely to be pathogenic. Indeed, pathogenic mutations in SHANK3 are de novo in the vast majority of cases (this is, they are present in the child and absent in the parents).

PMSF | Phelan-McDermid Syndrome Foundation