Walker-Warburg Syndrome via the RXYLT1/TMEM5 Gene

Walker-Warburg syndrome (WWS, OMIM 236670) is a genetically heterogeneous congenital muscular dystrophy in which many causative genes have been previously identified. These genes include POMT1, POMT2, POMGNT1, FKTN, FKRP, ISPD, and LARGE, each of which is believed to be involved in post translational modification of the sarcolemma-spanning protein alpha dystroglycan (ADG). Loss of function of any of these genes results in hypoglycosylation of ADG and reduced binding of ADG to the basal lamina through laminin (Barresi and Campbell. J Cell Sci 119:199-207, 2006). WWS is the most severe form of ADG-related congenital muscular dystrophy, presenting with profound hypotonia, defective neuronal migration and associated structural brain and eye abnormalities. CNS findings include cobblestone lissencephaly, cerebellar malformations, microophthalmia and cataracts. Patients have profound mental retardation and typically die in the first year of life. Muscle biopsies demonstrate a dystrophic process and markedly reduced or absent staining with antibodies to the glycolepitope of ADG. The genes referenced above account for only approximately half of all cases of WWS. A newly discovered gene, RXYLT1/TMEM5, has been shown to lead to severe cobblestone lissencephaly and a clinical presentation consistent with WWS (OMIM 615041; Vuillaumier-Barrot et al. Am J Hum Genet 91:1135-1143, 2012).

Mutations of the RXYLT1 gene are a documented cause of autosomal recessive severe cobblestone lissencephaly and other findings consistent with Walker-Warburg syndrome (Vuillaumier-Barrot et al. Am J Hum Genet 91:1135-1143, 2012). RXYLT1 (OMIM 605862) encodes a transmembrane protein that has a glycosyltransferase domain, although enzymatic activity has not yet been demonstrated. Mutations in RXYLT1 reported to date include small deletions and insertions and amino acid substitutions (http://www.LOVD.nl/TMEM5).

Among fifty-eight families with severe cobblestone lissencephaly, Vuillaumier-Barrot et al. (Am J Hum Genet 91:1135-1143, 2012), found RXYLT1 mutations in five, or 9%. Among this same cohort, the relative frequency of genetically diagnosed cases is: POMT1 (42%), POMT2 (17%), POMGNT1 (17%), RXYLT1 (9%), ISPD (9%), LARGE (3%), and FKRP (3%). Sequence analysis of genomic DNA for RXYLT1 should have high analytical sensitivity because all RXYLT1 mutations identified to date are detectable by this method.

This test provides full coverage of all coding exons of the RXYLT1 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).