Bloom's Syndrome via the BLM Gene

Bloom’s syndrome (BS; OMIM 210900) was first described in 1954 as a “congenital” skin disorder in “dwarfs” (Bloom Am J Dis Child 88:754-758, 1954). While patients were found to have additional clinical features, such as immune deficiencies and a propensity for cancer (German et al. Science 148:506-507, 1965; German Am J Hum Genet 21-196-227, 1969), sun-sensitive facial lesions, low birth weight and stunted growth remain the most consistent features of Bloom’s syndrome today. Symptoms of BS are related to increased mutability of proliferating somatic cells, particularly epithelial cells and lymphocytes. When grown in culture and viewed microscopically, cells of BS patients exhibit extensive “chromosome breakage”, including gaps and breaks, structural rearrangements, and telomeric associations (German and Crippa Ann Genet 9143-154, 1966). Chromosome breakage ultimately leads to excessive somatic recombination and high variant rates (Groden and German Hum Genet 90:360-367, 1992). About one-third of individuals with BS die by the age of 30 due to complications of cancer or from chronic lung disease as a result of immune deficiency (German Cancer Genet Cytogenet 93:100-106, 1997).

Bloom’s syndrome is an autosomal recessive disorder, caused by homozygous or compound heterozygous variants in the BLM gene (German et al. Hum Mutat 28:743-753, 2007); more than 60 unique variants have been identified. Most (60%) are single nucleotide changes leading to nonsense, missense, or splicing variants, while the remaining are small insertions or deletions (35%) or large deletions of multiple exons (5%). The BLM gene encodes a DNA helicase of the RecQ family. RecQ proteins are critical for maintaining the efficiency and integrity of DNA replication (Hickson Nat Rev Cancer 3:169-178, 2003); they resolve secondary structures ahead of replication forks, limit recombination to identical sequences, and assist in the replication and maintenance of telomeres (Bennett and Keck Crit Rev Biochem Mol Biol 39:79-97, 2004). In addition to these cellular functions, the BLM protein may also be important for the mismatch repair (MMR) pathway through its interaction with the MLH1 and MSH6 proteins (Langland et al. J Biol Chem 276:30031-30035, 2001; Pedrazzi et al. Biol Chem 384:1155-1164, 2003). Indeed, there is some evidence that heterozygous carriers of a BLM variant have an increased risk for colorectal cancer (Gruber et al. Science 297:2013, 2002), a disease most commonly associated with heterozygous variants in the MMR genes MLH1, MSH2 and MSH6.

In a retrospective study (German et al. Hum Mutat 28(8): 743-53, 2007), 87% of patients diagnosed with Bloom’s syndrome were reported to have two BLM variants. In 6% of the patients, only one variant was found for this recessive disease, indicating the second variant was not detectable by DNA sequencing methods.

Gross deletions of multiple exons account for approximately 5% of BLM cases.

This test provides full coverage of all coding exons of the BLM gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.