Fraser Syndrome Panel

Fraser syndrome (FS) is rare and is clinically characterized by classical features of bilateral congenital cryptophthalmos (hidden rudimentary eye), cutaneous syndactyly, ambiguous genitalia, laryngeal and genitourinary malformations, craniofacial dysmorphism oral clefting, musculoskeletal anomalies and mental retardation (Kabra et al. 2000; Slavotinek et al. 2006).

Fraser syndrome is inherited in an autosomal recessive manner. Pathogenic variants in FRAS1, FREM1, FREM2 and GRIP1 are reported to be causative for FS (Ozemri Sag et al. 2015). The encoded proteins Fras1, Frem1 and Frem2 all localize underneath the lamina densa of epithelial basement membranes. Frem1 and Frem2 belong to the protein complex of the extracellular matrix. All these proteins, including GRIP1 encoded scaffolding protein, are involved in the structural adhesion of skin epithelium to its underlying mesenchyme by forming a macromolecular ternary complex (Petrou et al. 2008). Dysfunction of any of these proteins due to pathogenic variants in these genes results in the collapse of the protein assembly, which explains the characteristic features of FS such as cryptophthalmos and cutaneous syndactyly.

So far, over 30 pathogenic variants in FRAS1 (nonsense, missense, splicing, small and gross deletions and insertions), ~20 pathogenic variants in FREM1 (nonsense, missense, splicing, small and gross deletions and complex genomic rearrangements), ~5 pathogenic variants in FREM2 (missense, splicing and small deletions) and ~10 pathogenic variants in GRIP1 (missense, nonsense, splicing, small and gross deletions) have been reported that are causative for Fraser syndrome (Human Gene Mutation Database).

See individual gene test descriptions for more information on molecular biology of gene products.

A molecular analysis of 48 FS patients (48 consanguineous and 15 nonconsanguineous families) identified pathogenic variants in FRAS1 and FREM2 in 43% of the cases (van Haelst et al. 2008). Due to genotypic heterogeneity and limited number of cases, clinical sensitivity of the FREM1 and GRIP1 genes is currently unknown.

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel provides 100% coverage of all coding exons of the genes 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 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).