Invitae Homocystinuria Panel

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  • Test code: 06144
  • 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
  • Sample requirements
  • Request a sample kit
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Test description

The Invitae Homocystinuria Panel analyzes up to 19 genes that are known to cause increased plasma homocysteine.

This panel is intended for any individual with elevated methionine on newborn screening (NBS), elevated total plasma homocysteine (free and bound homocysteine), or a suspected diagnosis of a homocystinuria that is based on clinical presentation. Additionally, in a clinically affected individual, plasma methionine may be low or elevated, depending on the underlying genetic condition. Age of diagnosis and subsequent metabolic management are some of the greatest determinants of long-term outcome.

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Primary panel (4 genes)

CBS MTHFR MTR MTRR

MTRR: Analysis includes the intronic variant NM_002454.2:c.903+469T>C.

Add-on Combined Methylmalonic Acidemia and Homocystinuria Genes (11 genes)

Disorders of cobalamin absorption and transport and well as some disorders of intracellular cobalamin metabolism can cause combined methylmalonic acidemia and homocystinuria. Given the biochemical overlap between these disorders and disorders that cause isolated homocystinuria, these genes can be included at no additional charge.

ABCD4 AMN CD320 CUBN GIF HCFC1 LMBRD1 MMACHC MMADHC TCN1 TCN2

CUBN: Analysis includes the intronic variant NM_001081.3: c.3330-439C>G.

Add-on Elevated Methionine Genes (4 genes)

Methionine transmethylation defects may present increased homocysteine or homocysteine levels. Given the biochemical overlap between these disorders and disorders that cause isolated homocystinuria, these genes can be included at no additional charge.

AHCY CBS GNMT MAT1A

  • homocystinuria due to cystathionine beta-synthase deficiency
  • cobalamin E deficiency
  • cobalamin G deficiency
  • MTHFR deficiency

The homocystinurias are a diverse group of conditions due to a disruption of homocysteine homeostasis. This can occur due to impaired catabolism of the amino acid homocysteine by the enzyme cystathionine beta-synthase (CBS), or as a result of defects in intracellular metabolism of the enzymatic co-factor cobalamin (Cbl).

An affected individual is homozygous or compound heterozygous for pathogenic variants in the same gene. Biallelic variants in any of the four genes can cause homocystinuria.

Gene Function Clinical condition
CBS Homocysteine catabolism Classic homocystinuria
MTR Cobalamin activation Cobalamin G deficiency
MTRR Cobalamin activation Cobalamin E deficiency
MTHFR Methionine remethylation MTHFR deficiency *see reporting limitations below

Classic homocystinuria
The most commonly recognized cause of homocystinura is a deficiency of the enzyme cystathionine beta-synthase (CBS), which causes “classic homocystinuria.” This enzyme catalyzes the condensation of homocysteine and serine to create cystathionine, and it is the first step of the irreversible catabolic transsulfuration pathway. Reduction in CBS enzymatic activity leads to a metabolic block with the accumulation of excess homocysteine and methionine. CBS is a pyridoxine-dependent (vitamin B6) enzyme, and specific variants may be responsive or non-responsive to pyridoxine supplementation.

CBS deficiency has wide clinical heterogeneity and is characterized by involvement of the eye, skeletal system, vascular system, and central nervous system (CNS). Affected individuals may be impacted in all four areas or just in one. Clinical presentations can occur from infancy through adulthood. Classic symptoms include developmental delay, mental retardation, psychiatric problems, childhood myopia with or without ectopia lentis (ocular lens dislocation), excessive height and limb length with a thin appearance resulting in a Marfanoid habitus, osteoporosis, and vascular abnormalities with thromboembolism. Thromboembolism is the most significant cause of morbidity and mortality, with cerebrovascular events occurring as early as infancy (though they most typically occur in young adulthood). Individuals with the pyridoxine-responsive form of CBS-deficient homocystinuria are typically more mildly affected.

CBS-deficient homocystinuria is treatable with dietary protein restriction commensurate to the amount of residual CBS activity. Some forms of CBS are responsive to oral pyridixine (B6) supplementation, which may allow for liberalization of the dietary restriction. Any dietary interventions should be managed by a metabolic nutritionist to avoid any nutritional deficiencies.

Cobalamin E (cblE) deficiency results in diminished activity of the enzyme methionine synthase reductase. This deficiency results in homocystinuria without elevated methylmalonic acid. The exact function of cblE in this reaction is not completely understood. Affected individuals usually present within the first twelve months of life with vomiting, feeding difficulties, lethargy, and significant neurologic dysfunction, including hypotonia, seizures, and developmental delay. Megaloblastic anemia is also usually present. Milder presentations with persistent megaloblastic anemia and minimally elevated homocysteine have also been reported.

The features of cobalamin G (cblG) deficiency are due to a defect in the methionine synthase enzyme. Affected individuals typically present in the first year of life with neurologic manifestations and megaloblastic anemia; however, this highly variable condition may present anywhere from infancy to adulthood. Manifestations of cblG may include weakness, hypotonia, seizures, neurocognitive changes, optic nerve atrophy, and leukoencephalopathy developing in adulthood. Megaloblastic anemia, neuropsychiatric symptoms, and progressive weakness may be observed in adult-onset cases.

Methylenetetrahydrofolate reductase (MTHFR) deficiency
MTHFR deficiency is a common inborn error of folate metabolism. This condition is caused by a defect in the folate-dependent methylation pathways, resulting in diminished conversion of homocysteine to methionine. Biochemical lab values are characterized by moderate homocystinuria and reduced-to-normal plasma methionine. Clinical features of pathogenic variants, while highly variable, may include intellectual disability, progressive neurologic impairment, and white-matter disease.

* The NM_005957.4:c.665C>T (p.Ala222Val) (aka 677C>T) and c.1286A>C (p.Glu429Ala) (aka 1298A>C) variants are not reported in our Primary report as they are classified as Benign. If present, these variants would be listed in our Supplemental report, which is available upon request. Additionally, the following medical organizations recommend against testing for these common variants:

  • American College of Medical Genetics PMID: 23288205
  • American Congress of Obstetricians and Gynecologists PMID: 23963422
  • The British Committee for Standards in Haematology and the British Society for Haematology PMID: 20128794

CBS—96%–100% of patients with a suspected diagnosis of CBS deficiency due to clinical or biochemical findings (elevated methionine and total plasma homocysteine) are expected to have biallelic pathogenic variants in the CBS gene.

  • MTRR—An estimated <5% of intracellular cobalamin metabolism conditions are attributed to MTRR.
  • MTR—An estimated <5% of intracellular cobalamin metabolism conditions are attributed to MTR.

Homocystinuria and the other metabolic defects causing elevated homocystine levels are inherited in an autosomal recessive manner.

Worldwide prevalence of classic homocystinuria due to CBS deficiency is estimated at 1 in 200,00–335,000, but this is likely an underestimate. Prevalence has been reported as high as 1 in 1800 in Qatar, 1 in 6400 in Norway, and 1 in 17,800 in Germany.

The overall prevalence of cobalamin metabolism disorders is not known and the conditions remain under-diagnosed. Fewer than 40 cases of cobalamin E deficiency have been described.

  1. Blom, HJ, Smulders, Y. Overview of homocysteine and folate metabolism. With special references to cardiovascular disease and neural tube defects. J. Inherit. Metab. Dis. 2011; 34(1):75-81. PMID: 20814827
  2. Carrillo-Carrasco, N, et al. Disorders of Intracellular Cobalamin Metabolism. 2008 Feb 25. In: Pagon, RA, et al, editors. GeneReviews(®) (Internet). University of Washington, Seattle. PMID: 20301503
  3. Fischer, S, et al. Clinical presentation and outcome in a series of 88 patients with the cblC defect. J. Inherit. Metab. Dis. 2014; 37(5):831-40. PMID: 24599607
  4. Lerner-Ellis, JP, et al. Spectrum of mutations in MMACHC, allelic expression, and evidence for genotype-phenotype correlations. Hum. Mutat. 2009; 30(7):1072-81. PMID: 19370762
  5. Picker, JD, Levy, HL. Homocystinuria Caused by Cystathionine Beta-Synthase Deficiency. 2004 Jan 15. In: Pagon, RA, et al, editors. GeneReviews (Internet). University of Washington, Seattle; Available from: http://www.ncbi.nlm.nih.gov/books/NBK1524/ PMID: 20301697
  6. Rosenblatt, DS, et al. Clinical heterogeneity and prognosis in combined methylmalonic aciduria and homocystinuria (cblC). J. Inherit. Metab. Dis. 1997; 20(4):528-38. PMID: 9266389
  7. Vilaseca, MA, et al. CblE type of homocystinuria: mild clinical phenotype in two patients homozygous for a novel mutation in the MTRR gene. J. Inherit. Metab. Dis. 2003; 26(4):361-9. PMID: 12971424
  8. Watkins D, Rosenblatt DS, Fowler B. Inborn metabolic diseases: diagnosis and treatment. 5th ed. Heidelberg: Springer; 2012. Chapter 28, Disorders of Cobalamin and Folate Transport and Metabolism; p. 385-402.
  9. Yap, S. Classical homocystinuria: vascular risk and its prevention. J. Inherit. Metab. Dis. 2003; 26(2-3):259-65. PMID: 12889665

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, and select noncoding variants. Our assay provides a Q30 quality-adjusted mean coverage depth of 350x (50x minimum, or supplemented with additional analysis). Variants classified as pathogenic or likely pathogenic are confirmed with orthogonal methods, except individual variants that have high quality scores and previously validated in at least ten unrelated samples.

Our analysis detects most intragenic deletions and duplications at single exon resolution. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. If you are requesting the detection of a specific single-exon copy number variation, please contact Client Services before placing your order.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
ABCD4 NM_005050.3
AHCY NM_000687.3
AMN NM_030943.3
CBS NM_000071.2
CD320 NM_016579.3
CUBN* NM_001081.3
GIF NM_005142.2
GNMT NM_018960.5
HCFC1 NM_005334.2
LMBRD1 NM_018368.3
MAT1A NM_000429.2
MMACHC NM_015506.2
MMADHC NM_015702.2
MTHFR NM_005957.4
MTR NM_000254.2
MTRR* NM_002454.2
TCN1 NM_001062.3
TCN2 NM_000355.3

CUBN: Analysis includes the intronic variant NM_001081.3: c.3330-439C>G.
MTRR: Analysis includes the intronic variant NM_002454.2:c.903+469T>C.