Dystroglycanopathy via the FKTN Gene

Variants in the FKTN gene (OMIM 607440) cause muscular dystrophies in the dystroglycanopathy spectrum, the most severe of which is Walker-Warburg syndrome (WWS, OMIM 236670; Beltran-Valero de Bernabe et al. J Med Genet 40:845-848, 2003). Patients with WWS typically die at birth or shortly thereafter due to complications from severe CNS structural abnormalities. Fukuyama congenital muscular dystrophy (FCMD, OMIM 253800) is a less severe phenotype and is the second most common muscular dystrophy among Japanese people (Kobayashi et al. Nature 394:388-392, 1998). In the vast majority of cases the causative variant is an inserted 3 kb retrotransposon at the 3’ UTR of the FKTN gene. Patients who are compound heterozygous for the Japanese founder variant, and an FKTN coding variant may have more severe WWS-like features than homozygous founder variant patients (Kondo-Iida, et al. Hum Molec Genet 8:2303-2309, 1999). A third reported variant is limb girdle muscular dystrophy due to FKTN variants (LGMD2M, OMIM 611588; Godfrey et al. Ann Neurol 60:603-610, 2006). These patients are responsive to steroid treatment and, unlike WWS and FCMD patients, are able to ambulate and have normal intelligence and normal brain structure (Godfrey et al. Brain 130:2725-2735, 2007; Puckett et al. Neuromusc Disord 19:352-356, 2009). Although apparently rare, severe cardiomyopathy in the absence of significant skeletal muscle weakness or intellectual impairment has been reported in patients with FKTN variants (Murakami et al. Ann Neurol 60:597-602, 2006).

The FKTN-related disorders are inherited in an autosomal recessive manner. Although the Japanese retrotransposon insertion variant is the most commonly reported pathogenic variant, variants of other forms are found throughout the gene (www.dmd.nl). Additional founder variants include the c.1167dupA variant in exon 9 in Ashkenazi Jewish individuals (Chang et al. Prenatal Diagnosis 29:560-569, 2009) and a deep intronic variant (c.647+2084G>T) that activates a pseudoexon within intron 5 among Koreans (Lim et al. Neuromuscul Disord 20:524-530, 2010). Variants in FKTN lead to reduced glycosylation of alphadystroglycan (ADG), a component of the dystrophin-glycoprotein complex (Ervasti et al. Nature 345:315-319, 1990). Evaluation of a patient’s muscle biopsy by immunofluorescence can detect abnormal glycosylation of ADG and can, therefore, help direct a diagnostic evaluation. It should be noted that at least six other genes (POMT1, POMT2, ISPD, POMGNT1, FKRP, and LARGE) encode proteins required for processing of ADG, and that overlap exists between clinical phenotypes resulting from variants in these genes.

This test will not detect the Japanese founder variant underlying the Fukuyama congenital muscular dystrophy phenotype. If FCMD is suspected in a person of Japanese heritage, a separate test (#354) should be performed to rule-out presence of the ancestral variant. Because LGMD and CMD demonstrate extensive locus and allelic heterogeneity, a negative FKTN sequence result does not rule-out a diagnosis of these disorders when classic clinical findings are present. If a muscle biopsy is available, immunostaining may also be an appropriate diagnostic approach.

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

Additionally, this test includes the region of intron 5 including and surrounding the Korean c.647+2084G>T variant.