Table 3.

Molecular Genetic Testing Used in Disorders of Intracellular Cobalamin Metabolism

Gene 1Complementation Group / DisorderProportion of Disorders of Intracellular Cobalamin Metabolism Attributed to Pathogenic Variants in GeneProportion of Pathogenic Variants 2 Detected by Method
Sequence analysis 3Gene-targeted deletion/duplication analysis 4
MMACHC cblC 80%96%-98% 5, 6, 7Unknown 8, 9
MMADHC cblD-combined; cblD-homocystinuria<5%22/22 10Unknown 8
MTRR cblE <5%21/22 11Unknown 8
LMBRD1 cblF <5%23/24 12One reported 13
MTR cblG <5%64/74 11Unknown 8
ABCD4 cblJ <<1%12/12 14Unknown 8
HCFC1 cblX <1%14/17 15Unknown 8
THAP11 Not yet defined-cblX-like<1%Single case report 16Unknown 8
ZNF143 Not yet defined-cblX-like<1%Single case report 17Unknown 8

Genes are listed in order of complementation group number.

1.
2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

5.
6.
7.

A rare complex variant of MMACHC and adjacent genes has been described [Guéant et al 2018].

8.

No data on detection rate of gene-targeted deletion/duplication analysis are available.

9.

One consanguineous individual has been found to have biallelic MMACHC whole-gene deletions [Author, unpublished observation].

10.
11.
12.
13.

A deletion spanning exon 2 was reported by Miousse et al [2011].

14.
15.
16.
17.

From: Disorders of Intracellular Cobalamin Metabolism

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