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  • Test code: 06184
  • Turnaround time:
    10–21 calendar days (14 days on average)
  • Preferred specimen:
    3mL whole blood in a purple-top tube
  • Alternate specimens:
    DNA or saliva/assisted saliva
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Invitae Mucolipidosis Panel

Test description

The Invitae Mucolipidosis panel analyzes 4 genes associated with the mucolipidoses. This panel may be appropriate for individuals with clinical symptoms of any of the mucolipidoses including non-immune fetal hydrops, skeletal abnormalities, psychomotor delay, progressive vision loss and/or coarse facial features. This panel may be appropriate for those in whom a mucolipidosis is suspected due abnormal enzyme or biochemical studies, or in whom a mucopolysaccharidosis is suspected but biochemical testing has not been informative. Genetic testing of these genes may confirm a diagnosis, help guide management decisions and provide adequate genetic counseling.

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Primary panel (4 genes)
  • mucolipidosis I (ML I), (sialidosis)
  • mucolipidosis II (ML II) (I-cell disease)
  • mucolipidosis III alpha/beta (ML IIIa/b)(pseudo-Hurler polydystrophy)
  • mucolipidosis III gamma (ML IIIG), (Variant Pseudo Hurler Polydystrophy)
  • mucolipidosis IV (ML IV)

The mucolipidoses (MLs) are a diverse group of lysosomal storage diseases with disparate etiologies. There are four known types of mucolipidosis: Type 1 (also called sialidosis), Type II (I-cell and Type III a/b), Type IIIg and Type IV. Each type of ML is caused by a different enzyme deficiency and affected individuals have biallelic, pathogenic variants in the same gene.

Mucolipidosis Type I is due to the inability to remove sialic acid molecules (a form of sugar) from sugar-protein complexes in the lysosome. This causes the progressive accumulation of these complexes within lysosome and cellular dysfunction. Affected individuals present with a broad phenotypic spectrum that includes prenatal through adult-onset presentations, and severity is inversely related to the amount of residual enzyme activity. The most severe end of the spectrum manifests prenatally with ascites and/or non-immune hydrops fetalis. Infantile onset cases are normal at birth but progressively manifest symptoms similar to those observed in MPS I (Hurler syndrome) such as coarse facial features, dysostosis multiplex, short stature, hepatosplenomegaly and developmental disability. Later-onset forms may present in late childhood through the second to third decade of life with gait abnormalities, progressive vision loss, cherry-red spot on ophthalmologic evaluation and myoclonus.

Mucolipidosis II and ML III alpha/beta represent opposite ends of the spectrum of the same disease. Both conditions are due to pathogenic variants in the GNPTAB gene and symptom severity is inversely related to the amount of residual enzyme activity. GNPTAB encodes the alpha and beta subunits of an enzyme involved in the first step of synthesis of the essential mannose-6-phosphate tag. This tag targets newly synthesized enzymes to the lysosome (the gamma subunit is encoded by GNPTG). Failure to traffic these enzymes to the lysosome causes them to be released into the extracellular space and consequently substrates that would normally be degraded within the lysosome progressively accumulate inside it. Biochemical features of ML II and ML III alpha/beta include extremely elevated lysosomal hydrolases in plasma and other fluids (compared to controls) due to impaired targeting to the lysosome. Urinary oligosaccharides are elevated while glycosaminoglycans are normal.

Mucolipidosis II (commonly known as I cell disease) is a severe multisystemic condition with prenatal onset and early death. The clinical features closely resemble those observed in the mucopolysaccharidoses (MPSs), but presentation occurs significantly earlier. Features include diminished growth, joint contractures, coarse facial features, recurrent otitis media, respiratory compromise, cardiac valve thickening, psychomotor delay and cognitive impairment. Skeletal findings are present at birth and in some cases, may also be visible by prenatal ultrasound.

ML III alpha/beta is a slowly progressive condition primarily affecting the skeletal system while also causing mildly coarse facial features and mild cognitive impairment. Birth parameters are typically normal and growth deceleration is typically noticed around three years of age. Final height rarely exceeds the 10th percentile and contractures become a significant complication. Connective tissue is significantly affected and leads to joint stiffness, reduced range of motion, respiratory compromise and cardiac complications such as thickening of cardiac valves. Coarse facial features may appear gradually, but are not as pronounced as in other storage disorders.

Mucolipidosis III gamma is a progressive lysosomal storage disorder caused by pathogenic variants in the gene GNPTG. GNPTG encodes the gamma subunits of an enzyme involved in the first step of synthesis of the essential mannose-6-phosphate tag. This tag targets newly synthesized enzymes to the lysosome (the alpha and beta subunits are encoded by GNPTAB). Failure to traffic these enzymes to the lysosome causes them to be released into the extracellular space and consequently substrates that would normally be degraded within the lysosome progressively accumulate causing cellular dysfunction. Phenotypic features characteristically involve skeletal and connective tissues, although milder cognitive involvement has also been reported. Affected individuals generally have normal birth parameters but present with a diminished growth rate in early childhood. Growth generally doesn’t progress beyond the 10th percentile and is complicated by progressive contractures. Connective tissue is significantly affected and leads to joint stiffness, reduced range of motion, respiratory compromise and cardiac complications such as thickening of cardiac valves. Cognitive function is typically normal. Biochemical features include extremely elevated lysosomal hydrolases in plasma and other fluids, compared to controls, due to impaired targeting to the lysosome. Urinary oligosaccharides are elevated while glycosaminoglycans are normal.

Mucolipidosis IV is a neurodevelopmental lysosomal storage disease and hallmark clinical features include severe psychomotor impairment and vision abnormalities. Symptoms typically manifest by end of the first year of life with marked motor delays, visual impairment (corneal clouding, retinal degeneration, optic atrophy, strabismus) and an asymptomatic achlorhydria (low or absent stomach secretions). Small stature and reduced head circumference are also commonly observed. Cognitive development generally doesn’t progress beyond the 12-15 month level. Once these initial disease manifestations are evident, the disease often remains stable for two to three decades, although approximately 15% individuals will have neurodegeneration. Most develop severe visual impairment due to retinal degeneration. Dysmorphic facial features and organomegaly is not commonly observed in ML IV. Affected individuals usually survive to adulthood, but overall life expectancy is reduced. Biochemical findings include normal activity of the lysosomal hydrolases.

  • ML I: the clinical sensitivity is not known
  • ML II: >95% of individuals with a diagnosis of ML II will have pathogenic variants in GNPTAB
  • ML III a/b: >95% of individuals with a diagnosis of ML IIIG will have pathogenic variants in GNPTAB
  • ML IIIG: >95% of individuals with a diagnosis of ML IIIG will have pathogenic variants in GNPTG
  • ML IV: In individuals with a clinical diagnosis of ML IV, approximately 77-81% of those of Ashkenazi Jewish heritage and 99% of those of non-Ashkenazi heritage will have pathogenic variant in MCOLN1. Approximately 18% of Ashkenazi patients will have a deletion in MCOLN1.

The mucolipidoses follow autosomal recessive inheritance.

ML I, ML II, ML IIIa/b, ML IIIG are very rare conditions and the exact prevalence is not known, but incidence of each condition has been reported at <1:100,000 live births.

ML IV is a panethnic condition, but >70% of of reported patients are of Ashkenazi Jewish ancestry. Two pathogenic variants in MCOLN1, c.406-2A>G and a 6.4-kb deletion beginning in the 5’UTR and extending into exon 6, account for 95% of the pathogenic variants in the Ashkenazi Jewish population. Carrier frequency for these variants in the Ashkenazi Jewish population is 1:100-127.

For a broader analysis of the genetics of lysosomal storage disorders

  1. Wraith, JE. Mucopolysaccharidoses and mucolipidoses. Handb Clin Neurol. 2013; 113:1723-9. PMID: 23622395
  2. Coutinho, MF, et al. Mannose-6-phosphate pathway: a review on its role in lysosomal function and dysfunction. Mol. Genet. Metab. 2012; 105(4):542-50. PMID: 22266136
  3. Wakabayashi, K, et al. Mucolipidosis type IV: an update. Mol. Genet. Metab. 2011; 104(3):206-13. PMID: 21763169
  4. Seyrantepe, V, et al. Molecular pathology of NEU1 gene in sialidosis. Hum. Mutat. 2003; 22(5):343-52. PMID: 14517945
  5. Cathey, SS, et al. Phenotype and genotype in mucolipidoses II and III alpha/beta: a study of 61 probands. J. Med. Genet. 2010; 47(1):38-48. PMID: 19617216
  6. Franceschetti, S, Canafoglia, L. Sialidoses. Epileptic Disord. 2016; 18(S2):89-93. PMID: 27621198
  7. Schiffmann, R, et al. Mucolipidosis IV. 2005 Jan 28. In: Pagon, RA, et al, editors. GeneReviews(®) (Internet). University of Washington, Seattle. PMID: 20301393
  8. Raas-Rothschild, A, Spiegel, R. Mucolipidosis III Gamma. 2010 Jan 28. In: Pagon, RA, et al, editors. GeneReviews(®) (Internet). University of Washington, Seattle. PMID: 20301784
  9. Leroy, JG, et al. Mucolipidosis III Alpha/Beta. 2008 Aug 26. In: Pagon, RA, et al, editors. GeneReviews(®) (Internet). University of Washington, Seattle. PMID: 20301730
  10. Leroy, JG, et al. Mucolipidosis II. 2008 Aug 26. In: Pagon, RA, et al, editors. GeneReviews(®) (Internet). University of Washington, Seattle. PMID: 20301728
  11. Poupetová, H, et al. The birth prevalence of lysosomal storage disorders in the Czech Republic: comparison with data in different populations. J. Inherit. Metab. Dis. 2010; 33(4):387-96. PMID: 20490927

Assay and technical information

Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).

Our sequence analysis covers clinically important regions of each gene, including coding exons, +/- 10 base pairs of adjacent intronic sequence in the transcript listed below. In addition, analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any specific limitations in the analysis of these genes are also listed in the table below.

Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions <15bp in length, and exon-level deletions and duplications. Invitae's methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. Invitae’s deletion/duplication analysis determines copy number at a single exon resolution at virtually all targeted exons. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases, (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion) the analyzed DNA may not represent the patient's constitutional genome.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
GNPTAB NM_024312.4
GNPTG NM_032520.4
MCOLN1 NM_020533.2
NEU1 NM_000434.3