Megalencephalic Leukoencephalopathy with Subcortical Cysts Panel

Megalencephalic leukoencephalopathy with subcortical cysts (MLC), also known as Van der Knaap disease, is a slowly progressive myelinopathy characterized by macrocephaly, delay in walking, early-onset ataxia, seizure, and spasticity. Motor dysfunction, mild mental retardation, and behavioral problems may occur later in life. Additional late-onset symptoms include cerebellar ataxia, hypertonia, dysarthria, and dysphagia. Hallmark magnetic resonance imaging (MRI) findings include subcortical cysts in the tips of the temporal lobes and in frontoparietal subcortical areas and swollen cerebral white matter. Onset of symptoms usually occurs during the first year of life (Van der Knaap et al. 1995). MLC is clinically heterogeneous with regards to age of onset, degree of macrocelphaly, mental impairment, severity and disease progression. MLC is a rare disease that affects patients worldwide. Incidence is higher than expected within consanguineous populations (Topcu et al. 1998).

Defects in one of two genes, MLC1 and HEPACAM, have been reported in the majority of patients with a clinical diagnosis and MRI findings suggestive of MLC (Leegwater et al. 2001; López-Hernández et al. 2011).

Recessive pathogenic variants in MLC1 account for more to 75% of patients (Boor et al. 2005). Over 100 different pathogenic variants have been reported to date. About half of the variants are missense; while the other half are truncating and include several large deletions (Cao et al. 2016). Recently, a c.-42C>T variant that is predicted to create an alternate start codon in the MLC1 mRNA has been reported in one patient of Iranian origin (Kariminejad et al. 2015). MLC1 pathogenic variants have been reported in patients from various ethnic populations. Several variants are prevalent in specific populations. These include two missense variants, p.Gly59Glu and p.Ser93Leu, that are common in the Libyan Jewish and Japanese populations, respectively (Ben-Zeev et al. 2002; Leegwater et al. 2001). A founder mutation, c.135insC (p.Cys46LeufsX34), has been documented in East-Indian populations from the Agrawal community (Leegwater et al. 2002; Gorospe et al. 2004). However, no genotype-phenotype correlations have been established because of the clinical variability among patients with the same MLC1 pathogenic variant.

Pathogenic variants in the HEPCAM gene have been reported in about 20% of patients (López-Hernández et al. 2011; Cao et al. 2016). In about half of these patients, the disease is inherited in an autosomal dominant manner and patients are heterozygous for one pathogenic variant. In this group of patients the clinical symptoms and MRI findings recover significantly over time, while the macrocephaly is maintained. The remaining patients present with a typical MLC phenotype, and the disease is inherited in an autosomal recessive manner. This group of patients have two recessive HEPACAM pathogenic variants; while their asymptomatic parents are heterozygous for the variants. To date, 22 different pathogenic HEPACAM variants have been reported. Although the majority are missense, several truncating variants, including two large deletions have been reported (Yamamoto et al. 2015).

The MLC1 protein is expressed mainly in the brain and leukocytes and has a putative transport function (Boor et al. 2005; Lanciotti et al. 2012). The HEPACAM gene encodes GlialCAM, an IgG-like cell adhesion molecule that binds directly to the MLC1 protein (López-Hernández et al. 2011).

This test will detect pathogenic variants in about 95% of individuals with a clinical diagnosis of MLC (Ilja Boor et al. 2006; López-Hernández et al. 2011; Cao et al. 2016).

Pathogenic large deletions in the MLC1 gene account for about 5% of patients (Cao et al. 2016). Large pathogenic deletions in the HEPACAM gene appear to be rare. To date, such deletions have been reported in two patients only (Yamamoto et al. 2015).

This panel provides 100% coverage of all coding exons of the genes listed, plus ~10 bases of flanking noncoding DNA. We define coverage as ≥20X NGS reads or Sanger sequencing.