Disorders Related to Metabolism of Cobalamin, Folate and Homocysteine Panel

The disorders caused by defects in the genes in this sequencing panel are all inborn errors of metabolism related to the transport and metabolism of cobalamin, propionic acid, methylmalonyl-CoA, folate and methionine. Clinical features vary with the different disorders, but can include symptoms such as feeding difficulties, vomiting, failure to thrive, lethargy, hypotonia and myopathy along with increased creatine kinase (CK) levels. Liver abnormalities, such as hepatomegaly and elevation of serum transaminases, are also common. Neurologic abnormalities often occur, and may include intellectual impairment, cerebral atrophy and developmental delay, seizures, microcephaly, increased tendon reflexes, ataxia, dystonia, and nystagmus. Hematological abnormalities are also common, and may include megaloblastic anemia, neutropenia and/or coagulopathy. Visual defects such as ectopia lentis, strabismus, severe myopia or blindness may occur. Less common features may include skeletal abnormalities, vascular disease, behavioral issues, and dysmorphic features. Biochemically, patients may have hypoglycemia, ketosis, metabolic acidosis, hyperammonemia, and abnormally low or high levels of serum and/or urine homocysteine, methylmalonic acid, methionine, and/or propionic acid; the specific biochemical profile will vary with each of the different disorders. Onset for the majority of patients is early in life, though later-onset cases do occur. See Sloan et al. 2018. (PubMed ID: 20301503) for a review of a number of these disorders.

The disorders included in this panel are very rare in most populations, with a frequency of ~1/50,000 or less, depending on the disorder (Sloan et al. 2018. PubMed ID: 20301503).

Obtaining an accurate molecular diagnosis may help in determining the patient’s prognosis, planning for the best treatment and/or management of symptoms, and allow for reproductive planning. For details on specific disorders, please visit the individual gene summary page.

This sequencing panel currently includes genes that have been associated with inborn errors of cobalamin, propionic acid, methylmalonyl-CoA, folate and methionine metabolism. The majority of the disorders associated with these genes are inherited in an autosomal recessive manner, with the exception of methionine adenosyltransferase I/III deficiency, which primarily autosomal recessive but is sometimes associated with autosomal dominant inheritance, and cblX type methylmalonic aciduria and homocystinuria, which is an X-linked disorder caused by pathogenic variants in the HCFC1 gene. Of note, female carriers of HCFC1 genes are generally unaffected (Sloan et al. 2018. PubMed ID: 20301503). Pathogenic de novo variants have occasionally been reported in HCFC1. To our knowledge, de novo variants are not a common cause of disease for the remaining genes in this panel.

It has been recently reported that patients compound heterozygous for a pathogenic variant in MMACHC and a variant that disrupts the intron 5 splice acceptor site of the PRDX1 gene (which is adjacent to the MMACHC gene) present with cblC type methylmalonic aciduria and homocystinuria. Disruption of the splice site at the junction of intron 5 and exon 6 of PRDX1 was shown to lead to PRDX1 exon 6 skipping, transcription of antisense MMACHC RNA, and resultant hypermethylation of the MMACHC promoter and exon 1. This lead to silencing of MMACHC gene expression (Guéant et al. 2018. PubMed ID: 29302025).

See individual gene summaries for information about molecular biology of gene products and spectra of pathogenic variants.

The clinical sensitivity of this specific grouping of genes is difficult to estimate as we are unaware of any reports in the literature in which all of these genes have been sequenced together in a patient cohort. One study of 131 patients with elevated methylmalonic acid in the blood or urine but no molecular diagnosis based on initial testing has been published. A 24 gene sequencing panel, of which 22 genes overlap with our test, was run for each of these patients to attempt to obtain a diagnosis. Eight patients (6%) were reported with pathogenic variants consistent with their diagnosis (Pupavac et al. 2016. PubMed ID: 26827111).

The clinical sensitivity of sequencing the individual genes in this test is high in patient groups with biochemical and/or enzymatic diagnoses of the relevant disorders; details are available on the individual gene summary pages. Analytical sensitivity is expected to be high as nearly all variants reported in these genes are detectable via direct sequencing.

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel typically provides 99.7% coverage of all coding exons of the genes plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define coverage as ≥20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).