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

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).

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).

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).

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. 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).