General information: The SALSA MLPA Probemix P369 Smith-Magenis syndrome is a research use only (RUO) assay for the detection of deletions or duplications in the 17p11.2 chromosomal region, including RAI1. Deletion of this region is associated with Smith-Magenis syndrome (SMS), whereas duplication of this region is associated with Potocki-Lupski syndrome (PTLS). Furthermore, two probes targeting the 2q37.3 region are included, among which one probe for the HDAC4 gene. Haploinsufficiency (either by a mutation or deletion) of the HDAC4 gene causes Brachydactyly-mental retardation syndrome, which has an overlapping phenotype with SMS. Furthermore, deletion or mutation of the HDAC4 gene results in reduced expression of RAI1 (Williams et al. 2010).

SMS is a developmental disorder characterised by craniofacial anomalies, and several neurological and behavioural abnormalities. It is primarily caused by an interstitial deletion on chromosome 17p11.2 which comprises multiple genes, including RAI1. In most cases (~70%), SMS is due to a ~3.7 Mb deletion, but atypical (smaller or larger) deletions, as well as RAI1 mutations have also been found in patients. Haploinsufficiency of RAI1 is therefore thought to play a major role in SMS (Elsea & Girirajan 2008).

Duplication of the same ~3.7 Mb region is associated with PTLS, which shows some phenotypical overlap with SMS, yet the clinical features of each syndrome are somewhat distinct. As in SMS, size of the duplication can vary between patients. The prevalence for SMS and PTLS is approximately 1 in 25,000 (Neira-Fresneda & Potocki 2015).

More information is available at: https://www.ncbi.nlm.nih.gov/books/NBK1310/ (SMS) & https://www.ncbi.nlm.nih.gov/books/NBK447920/ (PTLS).

Probemix content: The SALSA MLPA Probemix P369-A2 Smith-Magenis syndrome contains 35 MLPA probes with amplification products between 133 and 429 nt. This includes 23 probes for the 17p11.2 chromosomal region, of which eight target the RAI1 gene. Furthermore, two probes for the 2q37.3 chromosomal region are also present. In addition, ten reference probes are included and detect ten different autosomal chromosomal locations. Complete probe sequences and the identity of the genes detected by the reference probes is available online (www.mlpa.com).

This Probemix contains nine quality control fragments generating amplification products between 64 and 121 nt: four DNA Quantity Fragments (Q-fragments), two DNA Denaturation Fragments (D-fragments), one Benchmark Fragment, and one chromosome X and one chromosome Y-specific fragment. More information on how to interpret observations on these control fragments can be found in the MLPA General Protocol and online at www.mlpa.com.