Methylmalonic Aciduria and Homocystinuria, cblF type, via the LMBRD1 Gene

Summary and Pricing

Test Method

Exome Sequencing with CNV Detection
Test Code Test Copy GenesPrice Test CPT CodeGene CPT Codes Copy CPT Codes STAT Prenatal
11837 LMBRD1$890 8147981479,81479 Add to Order

Pricing Comments

Our favored testing approach is exome based NextGen sequencing with CNV analysis. This will allow cost effective reflexing to PGxome or other exome based tests. However, if full gene Sanger sequencing is desired for STAT turnaround time, insurance, or other reasons, please see link below for Test Code, pricing, and turnaround time information. If the Sanger option is selected, CNV detection may be ordered through Test #600.

A 25% additional charge will be applied to STAT orders. View STAT turnaround times here.

For Reflex to PGxome pricing click here.

The Sanger Sequencing method for this test is NY State approved.

For Sanger Sequencing click here.

Targeted Testing

For ordering sequencing of targeted known variants, go to our Targeted Variants page.

Turnaround Time

18 days on average

EMAIL CONTACTS

Genetic Counselors

Geneticist

Clinical Features and Genetics

Clinical Features

Cobalamin (Cbl or vitamin B12) is an important cofactor in homocysteine metabolism and in branched-chain amino acid and odd-chain fatty acid catabolism. A series of inherited inborn errors of cobalamin metabolism have been identified, designated cblA through cblG. In CblF deficiency, cobalamin accumulates in lysosomes and cannot be used to synthesize the cofactors adenosylcobalamin (AdoCbl) and methylcobalamin (MeCbl). As a result, methylmalonyl CoA mutase cannot convert L-methylmalonyl-CoA to succinyl CoA, and methionine synthase cannot convert homocysteine to methionine. Patients have elevated homocysteine and methylmalonic acid concentrations in blood and urine, and some patients with increased propionylcarnitine concentrations are identified through newborn screening (Rutsch et al. 2009; Carrillo-Carrasco et al. 2013; Watkins and Rosenblatt 2014). Clinical presentation is variable, but includes being small for gestational age, poor feeding, failure to thrive, developmental delay, and persistent stomatitis (Gailus et al. 2010; Rutsch et al. 2009). Hematological abnormalities are common and include macrocytic anemia, neutropenia, thrombocytopenia, and pancytopenia. Two patients have been reported to have minor craniofacial abnormalities (including pegged teeth and bifid incisors), and four patients have been described with congenital heart defects (Rutsch et al. 2009).

Genetics

The cblF disorder is inherited in an autosomal recessive manner, and is caused by pathogenic variants in the LMBRD1 gene. The LMBRD1 gene consists of 16 coding exons and encodes the 540 amino acid LMBD1 protein that localizes to lysosomal membranes. This protein shares some homology with the lipocalin-1 interacting membrane receptor (LIMR), and while the exact function of LMBD1 protein remains unknown, it has been hypothesized to act as a lysosomal exporter for cobalamin (Rutsch et al. 2009; Watkins and Rosenblatt 2014). The great majority of LMBRD1 pathogenic variants identified to date include small frameshift deletions detectable by sequencing. Furthermore, there appears to be a common European founder mutation, c.1056delG (p.L352fsX18) in exon 11. In one recent study of 12 unrelated patients with cblF defect, 18 of 24 alleles carried this particular mutation (Rutsch et al. 2009).

Testing Strategy

This test provides full coverage of all coding exons of the LMBRD1 gene 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 full coverage as >20X NGS reads or Sanger sequencing.

Since this test is performed using exome capture probes, a reflex to any of our exome based tests is available (PGxome, PGxome Custom Panels).

Clinical Sensitivity - Sequencing with CNV

In the largest published study of patients with cblF deficiency, all 12 affected patients were found to have LMBRD1 pathogenic variants in either a compound heterozygous or homozygous state (Rutsch et al. 2009).

The sensitivity of duplication/deletion testing for this rare disorder appears to be low. Only one pathogenic gross deletion spanning more than 6.7 kb and encompassing exon 2 has been reported (Miousse et al. 2011).

Indications for Test

Candidates for this test are patients with biochemical findings and/or clinical symptoms consistent with cblF deficiency, including infants with a positive newborn screen. Testing is also indicated for family members of patients with known LMBRD1 mutations. We will also sequence the LMBRD1 gene to determine carrier status.

Gene

Official Gene Symbol OMIM ID
LMBRD1 612625
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Disease

Name Inheritance OMIM ID
Methylmalonic Aciduria and Homocystinuria, cblF Type AR 277380

Citations

  • Carrillo-Carrasco N. et al. 2013. Disorders of Intracellular Cobalamin Metabolism. In: Pagon RA, Adam MP, Ardinger HH, Bird TD, Dolan CR, Fong C-T, Smith RJ, and Stephens K, editors. GeneReviews(®), Seattle (WA): University of Washington, Seattle. PubMed ID: 20301503
  • Gailus et al. 2010. PubMed ID: 20127417
  • Miousse et al. 2011. PubMed ID: 21303734
  • Rutsch et al. 2009. PubMed ID: 19136951
  • Watkins and Rosenblatt. 2014. Inherited Disorders of Folate and Cobalamin Transport and Metabolism. In: Valle D, Beaudet A.L., Vogelstein B, et al., editors. New York, NY: McGraw-Hill. OMMBID.

Ordering/Specimens

Ordering Options

myPrevent - Online Ordering

  • The test can be added to your online orders in the Summary and Pricing section.
  • Once the test has been added log in to myPrevent to fill out an online requisition form.

Requisition Form

  • A completed requisition form must accompany all specimens.
  • Billing information along with specimen and shipping instructions are within the requisition form.
  • All testing must be ordered by a qualified healthcare provider.

For Requisition Forms, visit our Forms page


Specimen Types

Specimen Requirements and Shipping Details

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