Walker-Warburg Syndrome via the CRPPA/ISPD Gene

Walker-Warburg syndrome (WWS, OMIM 236670) is a genetically heterogeneous congenital muscular dystrophy for which six causative genes have been previously identified. These genes are POMT1, POMT2, POMGNT1, FKTN, FKRP, 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 the six 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 six genes referenced above account for only approximately half of all cases of WWS. A newly discovered gene, CRPPA/ISPD, has been shown to lead to ADG hypoglycoslyation and a clinical presentation of WWS (Willer et al. Nat Genet 44:575-580, 2012 and Roscioli et al. Nat Genet 44:581-587, 2012).

Loss of function variants in the CRPPA gene are the seventh documented cause of Walker-Warburg syndrome (Willer et al. 2012 and Roscioli et al. 2012). CRPPA encodes a protein that may be involved in lipid precursor synthesis (Willer et al. 2012), thus representing a novel pathophysiological mechanism for ADG hypoglycosylation and WWS. CRPPA-related WWS is inherited in an autosomal recessive manner. CRPPA variants reported thus far include splice site variants, nonsense variants, a small deletion, gross deletions, and a variant that extends the amino acid reference sequence.

The isoprenoid synthase domain containing gene is encoded by exons 1- 10 of the CRPPA gene located on chromosome 7p21.2.

In a cohort of 11 WWS cases in which variants in POMT1, POMT2, POMGNT1, FKTN, FKRP, and LARGE had been ruled-out, Willer et al. (2012) found 7 patients (6 unrelated cases) with loss of function CRPPA gene variants. Based on this finding, CRPPA may be the most common cause of WWS. The occurrence of CRPPA variants in other forms of dystroglycanopathy is unknown at present (Willer et al. 2012).

This test provides full coverage of all coding exons of the CRPPA gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.