BLM – Bloom Syndrome

Bloom syndrome is a rare autosomal recessive disorder caused by biallelic pathogenic variants in the BLM gene, encoding a RecQ family DNA helicase. Clinically, affected individuals present with prenatal and postnatal growth deficiency, characteristic sun-sensitive telangiectatic erythema of the face, immunodeficiency, infertility, and a greatly increased risk of early‐onset malignancies, particularly hematological and gastrointestinal cancers. Cytogenetically, a hallmark is an approximately tenfold increase in sister chromatid exchanges (SCEs) in patient lymphocytes and fibroblasts, which is virtually diagnostic for the syndrome.

Clinical Validity

The BLM–Bloom syndrome association is Definitive. Over 125 unrelated patients have been documented with biallelic loss-of-function variants and consistent autosomal recessive segregation in multiple pedigrees (PMID:17407155). Segregation analysis in families shows concordant transmission of pathogenic alleles with phenotype in siblings and cousins, and no evidence of phenotypic overlap in heterozygous carriers beyond mild SCE elevation.

Genetic Evidence

Inheritance is autosomal recessive, with pathogenic variants spanning nonsense, frameshift, splice, and missense classes. Segregation has been demonstrated in over 102 affected relatives across more than 30 families (PMID:17407155). Case series report 134 registry subjects with 64 distinct causative alleles, 54 truncating and 10 missense (PMID:17407155). A common Ashkenazi Jewish founder frameshift (c.2281_2291delinsTAGATTC) occurs at ~1:100 carrier frequency (PMID:10464606).

Variant Spectrum

Reported allele types include:

• Nonsense: c.1642C>T (p.Gln548Ter) ([PMID:28611551])
• Frameshift: c.1624delG (p.Asp542ThrfsTer2) ([PMID:24932421])
• Splice: c.2074+2T>C (p.?) ([PMID:38113221])
• Missense: rare pathogenic substitutions in helicase motifs (e.g., p.Cys901Tyr, p.Gly891Glu) ([PMID:17878217]).

Functional Evidence

BLM deficiency abolishes helicase and ATPase activities, leading to hyper-recombination and chromosomal instability in cellular and yeast models (PMID:17878217). Patient‐derived induced pluripotent stem cells recapitulate SCE elevation and impaired genome maintenance (PMID:31918214). Structural modelling and mutagenesis map critical helicase core residues, corroborating the loss-of-function mechanism (PMID:10965492).

Conflicting Evidence

Heterozygous carriers exhibit elevated SCEs but no overt Bloom syndrome phenotype, and population studies find no significant cancer risk for single‐allele carriers outside the autosomal recessive context (PMID:12702560).

Conclusion

Biallelic BLM inactivation leads to Bloom syndrome via loss of helicase‐mediated genome stability, with robust genetic and experimental concordance. The clinical identification of pathogenic BLM variants informs reproductive counseling, cancer surveillance, and tailored management of photosensitivity and infection risk. Key take‐home: Genetic confirmation of BLM loss-of-function alleles provides definitive diagnosis and directs early intervention to mitigate cancer and immunodeficiency complications.

References

• Human mutation • 2007 • Syndrome-causing mutations of the BLM gene in persons in the Bloom's Syndrome Registry PMID:17407155
• Genetic testing • 1998 • High frequency of a common Bloom syndrome Ashkenazi mutation among Jews of Polish origin PMID:10464606
• Expert review of molecular diagnostics • 2004 • Clinical features of Bloom syndrome and function of the causative gene, BLM helicase PMID:15137905
• Nucleic acids research • 2007 • Structural and functional analyses of disease-causing missense mutations in Bloom syndrome protein PMID:17878217
• Molecular syndromology • 2017 • First Two Cases of Bloom Syndrome in Russia: Lack of Skin Manifestations in a BLM c.1642C>T (p.Q548X) Homozygote as a Likely Cause of Underdiagnosis PMID:28611551
• Stem cell research • 2020 • iPSC line derived from a Bloom syndrome patient retains an increased disease-specific sister-chromatid exchange activity PMID:31918214
• Clinical genetics • 2021 • Missing heritability in Bloom syndrome: First report of a deep intronic variant leading to pseudo-exon activation in the BLM gene PMID:33073370

Evidence Based Scoring (AI generated)

Gene–Disease Association Definitive Biallelic BLM mutations in >125 unrelated BS patients, consistent autosomal recessive segregation and hallmark cytogenetic findings ([PMID:17407155]) Genetic Evidence Strong Over 134 registry cases with 64 distinct pathogenic variants, segregation in multiple families, and founder alleles in Ashkenazi Jews ([PMID:17407155]; [PMID:10464606]) Functional Evidence Moderate Knock-in and patient-derived cell models show loss of helicase/ATPase activity, high SCEs, and rescue studies confirm mechanism ([PMID:17878217]; [PMID:31918214])