Invitae Homocystinuria Panel


Test description

The Invitae Homocystinuria Panel analyzes four 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. Depending on the underlying genetic condition, plasma methionine may be low or elevated. Age of diagnosis and subsequent metabolic management are some of the greatest determinants of long-term outcome.

Order test

Primary panel (4 genes)


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

  • Homocystinuria
  • Cobalamin C deficiency
  • Cobalamin D deficiency
  • Cobalamin E deficiency

The homocystinurias are a diverse group of conditions that are a result of a disruption of homocysteine homeostasis. Disruption 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
MMACHC Cobalamin activation Cobalamin C deficiency
MMADHC Cobalamin activation Cobalamin D deficiency
MTRR Cobalamin activation Cobalamin E deficiency

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.

Homocystinuria due to cobalamin deficiencies
Cobalamin C (cblC) deficiency is due to biallelic pathogenic variants in MMACHC and is the most common disorder of intracellular cobalamin metabolism. This step occurs along the common arm of the cobalamin modification pathway, and affected individuals have significantly elevated methylmalonic acid and homocysteine levels. CblC displays wide clinical heterogeneity, with age of onset from prenatal to adulthood, but the infantile presentation is the most widely recognized. Infants often present with failure to thrive, macrocytic anemia, hypotonia, and developmental delay; some develop hemolytic uremic syndrome or acute metabolic encephalopathy that can be lethal if untreated. Long-term complications are primarily neurologic and also include progressive retinopathy without lens dislocation. Adolescent and adult presentations manifest predominantly with neurologic (cognitive decline) and neuropsychiatric symptoms. Treatment consists of normalizing abnormal methylmalonic acid and homocysteine levels with pharmacologic doses of hydroxocobalamin (also known as hydroxycobalamin), homocysteine-lowering medications, and aggressive intervention during metabolic crisis. Use of dietary amino acid restriction remains controversial.

Cobalamin D (cblD) deficiency is due to biallelic pathogenic variants in MMADHC. CblD functions at the cobalamin modification pathway branch point and can lead to the decreased function of methylmalonyl-CoA mutase, methionine synthase, or both. Genotype can determine which enzyme(s) is/are affected. Depending on the enzyme(s) affected, patients can present with isolated methylmalonic aciduria, isolated homocystinuria, or a combined methylmalonic aciduria and homocystinuria. Affected individuals most commonly present with infantile and early-childhood neurologic and hematologic problems, including progressive encephalopathy, seizures, hypotonia, developmental delay, feeding difficulties, megaloblastic anemia, and cytopenias. An infant presenting with acute neonatal hyperammonemia has also been reported.

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.

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.

  • MMACHC—An estimated 80% of both combined adenosylcobalamin and methylcobalamin deficiency and isolated methylcobalamin deficiency is caused by biallelic pathogenic variants identified in MMACHC.
  • MMADHC—An estimated <5% of combined adenosylcobalamin and methylcobalamin deficiency is caused by biallelic pathogenic variants identified in MMADHC; inheritance is autosomal recessive. Isolated methylmalonic acidemia and isolated homocystinuria are both inherited in an autosomal recessive manner; they occur rarely and the clinical sensitivity of this panel is unknown.
  • MTRR—An estimated <5% of intracellular cobalamin metabolism conditions are attributed to MTRR.

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. The overall incidence of cobalamin C deficiency has been estimated at 1 in 200,000, but US newborn screening programs have suggested that the incidence is approximately 1 in 100,000 in New York state and 1 in 37,000 among the California Hispanic population. Fewer than 20 cases cobalamin D deficiency have been described. Fewer than 40 cases 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: 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. The online metabolic and molecular bases of inherited disease. New York: McGraw-Hill; retrieved January 2016. Chapter 155, Inherited disorders of folate and cobalamin transport and metabolism.
  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
CBS NM_000071.2
MMACHC NM_015506.2
MMADHC NM_015702.2
MTRR* NM_002454.2

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