Megalencephalic Leukoencephalopathy with Subcortical Cysts Panel

Summary and Pricing

Test Method

Sequencing and CNV Detection via NextGen Sequencing using PG-Select Capture Probes
Test Code Test Copy Genes Gene CPT Codes Copy CPT Codes
3423 HEPACAM 81479,81479 Order Options and Pricing
MLC1 81479,81479
Test Code Test Copy Genes Panel CPT Code Gene CPT Codes Copy CPT Code Base Price
3423Genes x (2)81479 81479 $640 Order Options and Pricing

Pricing Comments

This test is also offered via our exome backbone with CNV detection (click here). The exome-based test may be higher priced, but permits reflex to the entire exome or to any other set of clinically relevant genes.

An additional 25% charge will be applied to STAT orders. STAT orders are prioritized throughout the testing process.

Turnaround Time

18 days on average for standard orders or 14 days on average for STAT orders.

Once a specimen has started the testing process in our lab, the most accurate prediction of TAT will be displayed in the myPrevent portal as an Estimated Report Date (ERD) range. We calculate the ERD for each specimen as testing progresses; therefore the ERD range may differ from our published average TAT. View more about turnaround times here.

Targeted Testing

For ordering sequencing of targeted known variants, go to our Targeted Variants page.

EMAIL CONTACTS

Genetic Counselors

Geneticist

Clinical Features and Genetics

Clinical Features

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).

Genetics

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).

Clinical Sensitivity - Sequencing with CNV PG-Select

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).

Testing Strategy

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.

Indications for Test

Patients with clinical diagnosis and MRI findings suggestive of MLC, with or without mental retardation and with autosomal recessive or dominant inheritance. Potential heterozygous carriers are also candidates for this panel.

Genes

Official Gene Symbol OMIM ID
HEPACAM 611642
MLC1 605908
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Related Test

Name
PGxome®

Citations

  • Ben-Zeev B. et al. 2002. Human Genetics. 111: 214-8. PubMed ID: 12189496
  • Boor P.K. et al. 2005. Journal of Neuropathology and Experimental Neurology. 64: 412-9. PubMed ID: 15892299
  • Cao B. et al. 2016. Plos One. 11: e0157258. PubMed ID: 27322623
  • Gorospe J.R. et al. 2004. Neurology. 62: 878-82. PubMed ID: 15037685
  • Ilja Boor P.K. et al. 2006. Human Mutation. 27: 505-12. PubMed ID: 16652334
  • Kariminejad A. et al. 2015. European Journal of Medical Genetics. 58: 71-4. PubMed ID: 25497041
  • Lanciotti A. et al. 2012. Human Molecular Genetics. 21: 2166-80. PubMed ID: 22328087
  • Leegwater P.A. et al. 2001. American Journal of Human Genetics. 68: 831-8. PubMed ID: 11254442
  • Leegwater P.A. et al. 2002. Human Genetics. 110: 279-83. PubMed ID: 11935341
  • López-Hernández T. et al. 2011. American Journal of Human Genetics. 88: 422-32. PubMed ID: 21419380
  • Topcu M. et al. 1998. Brain & Development. 20: 142-53. PubMed ID: 9628190
  • Van der Knaap M.S. et al. 1995. Annals of Neurology. 37: 324–34. PubMed ID: 7695231
  • Yamamoto T. et al. 2015. European Journal of Medical Genetics. 58: 492-6. PubMed ID: 26193381

Ordering/Specimens

Ordering Options

We offer several options when ordering sequencing tests. For more information on these options, see our Ordering Instructions page. To view available options, click on the Order Options button within the test description.

myPrevent - Online Ordering

  • The test can be added to your online orders in the Summary and Pricing section.
  • Once the test has been added log in to myPrevent to fill out an online requisition form.

Requisition Form

  • A completed requisition form must accompany all specimens.
  • Billing information along with specimen and shipping instructions are within the requisition form.
  • All testing must be ordered by a qualified healthcare provider.

For Requisition Forms, visit our Forms page


Specimen Types

Specimen Requirements and Shipping Details

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ORDER OPTIONS

View Ordering Instructions

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2) Select Additional Test Options

STAT and Prenatal Test Options are not available with Patient Plus.

No Additional Test Options are available for this test.

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