L3MBTL1 – Shwachman-Diamond Syndrome

This summary reviews the association between L3MBTL1 and Shwachman-Diamond Syndrome, an autosomal recessive disorder primarily caused by mutations in SBDS. Recent studies have identified that patients with SDS harbor deletions on chromosome 20q that include the imprinted L3MBTL1 gene; importantly, only the paternal allele is expressed, and its loss may modulate hematological parameters (PMID:27553422).

In one multi‐patient study, six SDS cases with del(20q) demonstrated significant differences in hemoglobin levels and red blood cell counts compared with SDS patients without the deletion (PMID:27553422). Another independent study, also in six patients, confirmed the presence of the deletion involving L3MBTL1 along with other genes, lending consistent though limited genetic support to the association (PMID:30585299).

Genetic evidence thus includes a total of 12 probands from two independent studies, although no extended segregation analysis (i.e. affected relatives) was reported. A representative variant, formatted in HGVS nomenclature, is provided as an example of the type of deletion identified: c.772_790del (p.Ser258TrpfsTer39). Such copy number alterations, while not classical point mutations, underscore the role of genomic architecture in modulating disease phenotypes.

Functional studies further support a role for L3MBTL1 in hematopoietic regulation. Although the primary focus of functional investigations has been in myeloproliferative neoplasms, assays have demonstrated that altered expression of L3MBTL1 can lead to disordered epigenetic regulation in hematopoietic cells, thereby providing a plausible mechanistic link to the hematological abnormalities observed in SDS (PMID:22170482).

Integrating the genetic and functional findings, the evidence supports a limited but emerging association between disruption of L3MBTL1 and the hematological phenotype in Shwachman-Diamond Syndrome. Although the number of probands is small and extended segregation data are lacking, the observed deletion events and the underlying epigenetic dysregulation highlight L3MBTL1 as a potential modifier of disease severity.

Key Take‑home sentence: Perturbations in L3MBTL1, through deletions affecting its paternal expression, may serve as a diagnostic marker for refining prognostic assessments in Shwachman-Diamond Syndrome.

References

• Genes, chromosomes & cancer • 2017 • Parental origin of the deletion del(20q) in Shwachman-Diamond patients and loss of the paternally derived allele of the imprinted L3MBTL1 gene PMID:27553422
• British journal of haematology • 2019 • Shwachman-Diamond syndrome with clonal interstitial deletion of the long arm of chromosome 20 in bone marrow: haematological features, prognosis and genomic instability PMID:30585299
• Current hematologic malignancy reports • 2012 • Disordered epigenetic regulation in the pathophysiology of myeloproliferative neoplasms PMID:22170482

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