Legius Syndrome via the SPRED1 Gene

Legius Syndrome, previously known as neurofibromatosis type 1-like syndrome (NFLS, OMIM 611431), has been recently described at both the clinical and molecular genetics level (Brems et al. Nat Genet 39:1120-1126, 2007). The most common clinical features of Legius syndrome are multiple café-au-lait spots. Additional features may include a Noonan-like dysmorphy (NS, OMIM 163950), axillary freckling, macrocephaly, psychomotor developmental delay, behavioral problems and learning difficulties. Although Legius syndrome resembles the Neurofibromatosis Type 1 phenotype (NF1, OMIM 162200), some typical features of NF1, such as Lisch nodules in the iris, neurofibromas, central nervous system tumors and long bone dysplasias are absent (Brems et al. Nat Genet 39:1120-1126, 2007).

Autosomal dominant inheritance was documented in most reported cases , while family medical history was not available for several patients. It is therefore not clear whether these cases are familial or sporadic. Mutations in the SPRED1 gene cause Legius syndrome. Over 50 heterozygous SPRED1 causative mutations have been reported to date. The mutations are distributed throughout the gene and are mostly truncating. Only seven missense mutations were documented. The SPRED1 protein negatively regulates MAP kinase signaling within the RAS-MAPK pathway, similar to neurofibromin, the defective protein in patients with NF1.

SPRED1 mutations account for ~ 8 % of patients with Legius Syndrome (Brems et al. Nat Genet 39:1120-1126, 2007).

This test provides full coverage of all coding exons of the SPRED1 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).

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).