Massively Parallel Sequencing/Exonic Oligonucleotide-based CGH Microarray
For tests to consider before ordering genetic testing, see Related Tests.
Disorders of cobalamin (vitamin B12)/propionate/homocysteine metabolism result from defects in the vitamin B12 metabolic pathway. Age of disease onset ranges from the perinatal period to adulthood. Multiple organ systems are affected. Molecular testing is used to confirm suspected cobalamin/propionate/homocysteine metabolism-related disorder in individuals with clinical symptoms and/or biochemical findings.
Disease Overview
Findings
- Cardiovascular
- Gastrointestinal
- Hematological
- Immunological
- Neurological
- Neuromuscular/skeletal
- Ocular
- Renal
- Respiratory
- Dysmorphic features
- Failure to thrive
- Metabolic decompensation
Etiology
- Defects of absorption, transport, and intracellular metabolism of cobalamin/propionate/homocysteine lead to accumulation of methylmalonic acid, methionine, and/or homocysteine in blood and urine.
- Elevated propionylcarnitine level and/or propionyl/acetylcarnitine ratio are usually detected in plasma, and increased methylmalonic acid is detected in blood, despite normal or elevated vitamin B12 levels.
Prevalence
- Methylmalonic aciduria from all causes – 1/48,000-61,000 in North America
- Isolated methylmalonic acidemia – 1/50,000-100,000
- Combined malonic/methylmalonic aciduria – ~1/30,000
- Methylmalonic aciduria, vitamin B12-responsive, cblA type – 1/50,000-100,000
- Methylmalonic aciduria, vitamin B12-responsive, cblB type – 1/50,000-100,000
- Methylmalonic aciduria and homocystinuria, cblC type – up to 1/67,000
- Methylmalonic aciduria, and homocystinuria, cblD type – 1/50,000-100,000
- Methylmalonic aciduria, mut (0) type – 1/50,000-100,000
- Methylmalonyl-CoA epimerase deficiency – 1/50,000-100,000
- Homocystinuria due to cystathionine beta-synthase deficiency – 1/1,800 in Qatar; 1/6,400 in Norway; 1/17,800 in Germany
- Methionine adenosyltransferase deficiency – 1/22,000 in Spain; 1/26,000 in Portugal
- Homocystinuria, B6-responsive and nonresponsive types, combined – 1/58,000-1,000,000
- Propionic acidemia – 1/50,000-100,000; 1/1,000-2,000 in Inuit in Greenland; 1/5,000 in Saudi Arabia
- Rare for other disorders included in the panel
Inheritance
Autosomal recessive for all genes tested, except for HCFC1 (X-linked) and MAT1A (autosomal dominant or autosomal recessive)
Genotype-Phenotype Correlation
- Variants in multiple genes cause overlapping and highly variable phenotypes.
- Other genetic and/or biochemical/dietary factors may influence severity of clinical phenotype.
- Clinical features and age of onset are highly variable.
Test Description
See Genes Tested table for genes included in the panel.
Clinical Sensitivity
Variable, dependent on condition
Limitations
- A negative result does not exclude a heritable form of cobalamin metabolism disorders.
- Diagnostic errors can occur due to rare sequence variations.
- Interpretation of this test result may be impacted if the individual has had an allogeneic stem cell transplantation.
- The following will not be evaluated:
- Variants outside the coding regions and intron-exon boundaries of the targeted genes
- Regulatory region variants and deep intronic variants
- Breakpoints of large deletions/duplications
- Deletions/duplications in the ADK, AHCY, and GNMT genes
- Non-coding transcripts
- The following may not be detected:
- Deletions/duplications/insertions of any size by massively parallel sequencing
- Deletions/duplications less than 1 kb in the targeted genes by array
- Some variants due to technical limitations in the presence of pseudogenes, repetitive, or homologous regions
- Low-level somatic variants
- Single exon deletions/duplications in the following exons:
- ABCD4 (NM_005050) 1; HCFC1 (NM_005334) 26; MTHFR (NM_001330358) 1; PCCB (NM_001178014) 4; SUCLA2 (NM_003850) 11
Analytical Sensitivity
For massively parallel sequencing:
Variant Class | Analytical Sensitivity (PPA) Estimatea (%) | Analytical Sensitivity (PPA) 95% Credibility Regiona (%) |
---|---|---|
SNVs |
99.2 |
96.9-99.4 |
Deletions 1-10 bp |
93.8 |
84.3-98.2 |
Deletions 11-44 bp |
100 |
87.8-100 |
Insertions 1-10 bp |
94.8 |
86.8-98.5 |
Insertions 11-23 bp |
100 |
62.1-100 |
aGenes included on this test are a subset of a larger methods-based validation from which the PPA values are derived. bp, base pairs; PPA, positive percent agreement; SNVs, single nucleotide variants |
Genes Tested
Gene | Alias Symbol(s) | MIM Number | Disorder | Inheritance |
---|---|---|---|---|
ABCD4 |
PXMP1L, PMP69, P70R, EST352188 |
603214 |
Methylmalonic aciduria and homocystinuria, cblJ type |
AR |
ACSF3 |
614245 |
Combined malonic and methylmalonic aciduria |
AR |
|
ADK |
AK |
102750 |
Hypermethioninemia due to adenosine kinase deficiency |
AR |
AHCY |
SAHH |
180960 |
Hypermethioninemia with S-adenosylhomocysteine hydrolase deficiency |
AR |
AMN |
amnionless |
605799 |
Megaloblastic anemia 1, Norwegian type |
AR |
CBLIF (GIF) |
TCN3, IF, IFMH, INF |
609342 |
Intrinsic factor deficiency |
AR |
CBS |
HIP4 |
613381 |
Homocystinuria due to cystathionine beta-synthase deficiency |
AR |
CD320 |
8D6, 8D6A |
606475 |
Methylmalonic aciduria, transient, due to transcobalamin receptor defect |
AR |
CUBN |
MGA1, IFCR, gp280 |
602997 |
Megaloblastic anemia 1, Finnish type |
AR |
GNMT |
606628 |
Glycine N-methyltransferase deficiency |
AR |
|
HCFC1 |
HFC1, MRX3, HCF-1, HCF1, CFF, VCAF, MGC70925, PPP1R89 |
300019 |
Methylmalonic acidemia and homocysteinemia, cblX type; intellectual disability, X-linked 3 |
XL |
LMBRD1 |
C6orf209, FLJ11240, bA810I22.1, cblF |
612625 |
Methylmalonic aciduria and homocystinuria, cblF type |
AR |
MAT1A |
MAT, SAMS, MATA1, SAMS1 |
610550 |
Methionine adenosyltransferase I/III deficiency |
AD and AR |
MCEE |
GLOD2 |
608419 |
Methylmalonyl-CoA epimerase deficiency |
AR |
MMAA |
cblA |
607481 |
Methylmalonic aciduria, B12 responsive, cblA type |
AR |
MMAB |
cblB, CFAP23 |
607568 |
Methylmalonic aciduria, cblB type |
AR |
MMACHC |
DKFZP564I122, cblC |
609831 |
Methylmalonic aciduria and homocystinuria, cblC type |
AR |
MMADHC |
C2orf25, CL25022, cblD |
611935 |
Mmethylmalonic aciduria and homocystinuria, cblD type |
AR |
MMUT (MUT) |
MCM |
609058 |
Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency, mut (0) type |
AR |
MTHFR |
607093 |
Homocystinuria due to deficiency of N(5,10)-methylenetetrahydrofolate |
AR |
|
MTR |
cblG |
156570 |
Homocystinuria-megaloblastic anemia, cblG complementation type |
AR |
MTRR |
cblE |
602568 |
Homocystinuria-megaloblastic anemia, cblE complementation type |
AR |
PCCA |
232000 |
Propionic acidemia |
AR |
|
PCCB |
232050 |
Propionic acidemia |
AR |
|
SUCLA2 |
603921 |
Mitochondrial DNA depletion syndrome 5 (encephalomyopathic with or without methylmalonic aciduria) |
AR |
|
SUCLG1 |
611224 |
Mitochondrial dna depletion syndrome 9 (encephalomyopathic type with methylmalonic aciduria) |
AR |
|
TCN1 |
TCI, TC1 |
189905 |
Transcobalamin I deficiency |
AR |
TCN2 |
D22S676, D22S750, TC2 |
613441 |
Transcobalamin II deficiency |
AR |
AD, autosomal dominant; AR, autosomal recessive; XL, X-linked |
25205257
Baumgartner MR, Hörster F, Dionisi-Vici C, et al. Proposed guidelines for the diagnosis and management of methylmalonic and propionic acidemia. Orphanet J Rare Dis. 2014;9:130.
Cobalamin C disease identified by newborn screening
Cusmano-Ozog K, Levine S, Martin M, et al. Cobalamin C disease identified by newborn screening: the California experience. In: Program and abstracts for the SIMD annual meeting. Mol Genet Metab. 2007:227-65. [ Accessed: Apr 2022]
GeneReviews - Isolated Methylmalonic Acidemia
Manoli I, Sloan JL, Venditti CP. Isolated methylmalonic acidemia. In: Adam MP, Ardinger HH, Pagon RA, et al, editors. GeneReviews, University of Washington; 1993-2020. [Last Revision: Dec 2016; Accessed: Apr 2022]
23430947
Martins E, Marcăo A, et al. Methionine adenosyltransferase I/III deficiency in Portugal: high fFrequency of a dominantly inherited form in a small area of Douro High Lands. JIMD Rep. 2012;6:107-112.
Methylmalonic acidemia without homocystinuria
Rosenblatt D, Watkins D. Methylmalonic acidemia without homocystinuria. Orphanet. [Last update: Mar 2012; Accessed: Apr 2022]
GeneReviews - Homocystinuria Caused by Cystathionine Beta-Synthase Deficiency
Sacharow SJ, Picker JD, Levy HL. Homocystinuria caused by cystathionine beta-synthase deficiency. In: Adam MP, Ardinger HH, Pagon RA, et al, editors. GeneReviews, University of Washington; 1993-202s. [Last Update: May 2017; Accessed: Apr 2022]
19819175
Skovby F, Gaustadnes M, Mudd SH. A revisit to the natural history of homocystinuria due to cystathionine beta-synthase deficiency. Mol Genet Metab. 2010;99(1):1-3.
GeneReviews - Disorders of Intracellular Cobalamin Metabolism
Sloan JL, Carrillo N, Adams D, et al. Disorders of intracellular cobalamin metabolism. In: Adam MP, Ardinger HH, Pagon RA, et al, editors. GeneReviews, University of Washington; 1993-2020. [Last Update: Sep 2018; Accessed: Apr 2022]
21841779
Sloan JL, Johnston JJ, Manoli I, et al. Exome sequencing identifies ACSF3 as a cause of combined malonic and methylmalonic aciduria. Nat Genet. 2011;43(9):883-6.
19836982
Weisfeld-Adams JD, Morrissey MA, Kirmse BM, et al. Newborn screening and early biochemical follow-up in combined methylmalonic aciduria and homocystinuria, cblC type, and utility of methionine as a secondary screening analyte. Mol Genet Metab. 2010;99(2):116-123.
Confirm suspected cobalamin (vitamin B12)/propionate/homocysteine metabolism-related disorder in individuals with clinical symptoms and/or biochemical findings. Should not be ordered to assess vitamin B12 level.