McLeod Syndrome via the XK Gene

McLeod Syndrome (MLS) is a progressive multi-system disorder with hematologic, neuromuscular, and central nervous system involvement. MLS is a subtype of neuroacanthocytosis syndrome which is characterized by degeneration of the basal ganglia leading to motor, cognitive, and psychiatric impairment. Acanthocytosis, spike protrusions in erythrocytes, is typically the first indication of MLS and present in asymptomatic individuals. Onset of neurological symptoms such as chorea, involuntary movements, and vocalizations ranges from 25-60 years old with disease duration potentially extending beyond 30 years. Psychiatric manifestations include depression, schizophrenia-like psychosis and obsessive compulsive disorder which typically presents prior to motor and cognitive dysfunction. About 60% of patients develop cardiomyopathy which is the leading cause of death in individuals with MLS (Danek et al. 2001; Jung et al. 2011; Jung et al. 2004). Genetic testing is helpful in the differential diagnosis of MLS from Huntington’s disease and other neuroacanthocytosis syndromes including Chorea-acanthocytosis, Huntington’s disease-like 2 and pantothenate kinase associated neurodegeneration (Jung et al. 2011).

MLS is inherited in an X-linked recessive manner with complete penetrance through mutations in the XK gene. Males are predominantly affected, however, there have been rare instances of heterozygous females presenting with MLS (Ho et al. 1996). Most pathogenic mutations to date are null mutations including nonsense, splice site alterations, small insertions/deletions, and gross deletions which have been reported throughout the XK gene (Danek et al. 2001; Ho et al. 1994; Jung et al. 2004). MLS has also been reported to be part of a contiguous gene syndrome including chronic granulomatous disease (CYBB), Duchenne muscular dystrophy (DMD), and retinitis pigmentosa (RPGR) (Peng et al. 2007). Mutations in the XK gene lead to loss of or truncation of the XK protein Kell binding domain. This interaction is important for surface expression of Kell antigens which are important determinants of blood type (Ho et al. 1994). The exact function of XK is unknown but studies of an analogous C. elegans gene, ced-8, suggest it may be involved in regulating apoptosis (Stanfield et al. 2000).

Mutations in the XK gene are the only reported cause of MLS. In a study of 22 MLS patients, XK mutations were found in each case with one patient exhibiting a deletion of the entire gene (Danek et al. 2001). Analytical sensitivity is >85% for detection of causative mutations in the XK gene. Gross deletions have been reported in a minority of cases (Peng et al. 2007; Danek et al. 2001).

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