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Inherited CHST11/MIR3922 deletion is associated with a novel recessive syndrome presenting with skeletal malformation and malignant lymphoproliferative disease.

Chopra SS, Leshchiner I, Duzkale H, McLaughlin H, Giovanni M, Zhang C, Stitziel N, Fingeroth J, Joyce RM, Lebo M, Rehm H, Vuzman D, Maas R, Sunyaev SR, Murray M, Cassa CA - Mol Genet Genomic Med (2015)

Bottom Line: The deletion was homozygous in the proband but not in each of three unaffected siblings.Genotyping data from the 1000 Genomes Project suggest that deletions inclusive of both CHST11 and MIR3922 are rare events.Given that CHST11 deficiency causes severe chondrodysplasia in mice that is similar to human limb malformation, these results underscore the importance of chondroitin modification in normal skeletal development.

View Article: PubMed Central - PubMed

Affiliation: Dana Farber Cancer Institute, Brigham and Women's Hospital Boston, Massachusetts.

ABSTRACT
Glycosaminoglycans (GAGs) such as chondroitin are ubiquitous disaccharide carbohydrate chains that contribute to the formation and function of proteoglycans at the cell membrane and in the extracellular matrix. Although GAG-modifying enzymes are required for diverse cellular functions, the role of these proteins in human development and disease is less well understood. Here, we describe two sisters out of seven siblings affected by congenital limb malformation and malignant lymphoproliferative disease. Using Whole-Genome Sequencing (WGS), we identified in the proband deletion of a 55 kb region within chromosome 12q23 that encompasses part of CHST11 (encoding chondroitin-4-sulfotransferase 1) and an embedded microRNA (MIR3922). The deletion was homozygous in the proband but not in each of three unaffected siblings. Genotyping data from the 1000 Genomes Project suggest that deletions inclusive of both CHST11 and MIR3922 are rare events. Given that CHST11 deficiency causes severe chondrodysplasia in mice that is similar to human limb malformation, these results underscore the importance of chondroitin modification in normal skeletal development. Our findings also potentially reveal an unexpected role for CHST11 and/or MIR3922 as tumor suppressors whose disruption may contribute to malignant lymphoproliferative disease.

No MeSH data available.


Related in: MedlinePlus

There are very few observed sequence reads in the region between chr12:104,948,000-105,005,000, providing much more precise resolution on the boundaries of the deletion.
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fig04: There are very few observed sequence reads in the region between chr12:104,948,000-105,005,000, providing much more precise resolution on the boundaries of the deletion.

Mentions: The population frequency of these homozygous deletions was determined using genotyping data generated by Genome STRiP in the 1KG cohort (Fig.3). The two deletions on chromosome 19 have many individuals with deletions in the 1KG samples (>1%), while the deletion on chromosome 12 that includes CHST11 and MIR3922 appears to be a rare variant, with no deletions observed in the 1KG project. The parents of the proband were born in the same region in Ireland, suggesting that the rare homozygous deletion could be a part of a region where there is identity by descent (IBD). Indeed, a potential IBD region of approximately 180 kb overlaps the entire deletion, spanning chr12:104,920,000-105,100,000 (Fig.4).


Inherited CHST11/MIR3922 deletion is associated with a novel recessive syndrome presenting with skeletal malformation and malignant lymphoproliferative disease.

Chopra SS, Leshchiner I, Duzkale H, McLaughlin H, Giovanni M, Zhang C, Stitziel N, Fingeroth J, Joyce RM, Lebo M, Rehm H, Vuzman D, Maas R, Sunyaev SR, Murray M, Cassa CA - Mol Genet Genomic Med (2015)

There are very few observed sequence reads in the region between chr12:104,948,000-105,005,000, providing much more precise resolution on the boundaries of the deletion.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4585449&req=5

fig04: There are very few observed sequence reads in the region between chr12:104,948,000-105,005,000, providing much more precise resolution on the boundaries of the deletion.
Mentions: The population frequency of these homozygous deletions was determined using genotyping data generated by Genome STRiP in the 1KG cohort (Fig.3). The two deletions on chromosome 19 have many individuals with deletions in the 1KG samples (>1%), while the deletion on chromosome 12 that includes CHST11 and MIR3922 appears to be a rare variant, with no deletions observed in the 1KG project. The parents of the proband were born in the same region in Ireland, suggesting that the rare homozygous deletion could be a part of a region where there is identity by descent (IBD). Indeed, a potential IBD region of approximately 180 kb overlaps the entire deletion, spanning chr12:104,920,000-105,100,000 (Fig.4).

Bottom Line: The deletion was homozygous in the proband but not in each of three unaffected siblings.Genotyping data from the 1000 Genomes Project suggest that deletions inclusive of both CHST11 and MIR3922 are rare events.Given that CHST11 deficiency causes severe chondrodysplasia in mice that is similar to human limb malformation, these results underscore the importance of chondroitin modification in normal skeletal development.

View Article: PubMed Central - PubMed

Affiliation: Dana Farber Cancer Institute, Brigham and Women's Hospital Boston, Massachusetts.

ABSTRACT
Glycosaminoglycans (GAGs) such as chondroitin are ubiquitous disaccharide carbohydrate chains that contribute to the formation and function of proteoglycans at the cell membrane and in the extracellular matrix. Although GAG-modifying enzymes are required for diverse cellular functions, the role of these proteins in human development and disease is less well understood. Here, we describe two sisters out of seven siblings affected by congenital limb malformation and malignant lymphoproliferative disease. Using Whole-Genome Sequencing (WGS), we identified in the proband deletion of a 55 kb region within chromosome 12q23 that encompasses part of CHST11 (encoding chondroitin-4-sulfotransferase 1) and an embedded microRNA (MIR3922). The deletion was homozygous in the proband but not in each of three unaffected siblings. Genotyping data from the 1000 Genomes Project suggest that deletions inclusive of both CHST11 and MIR3922 are rare events. Given that CHST11 deficiency causes severe chondrodysplasia in mice that is similar to human limb malformation, these results underscore the importance of chondroitin modification in normal skeletal development. Our findings also potentially reveal an unexpected role for CHST11 and/or MIR3922 as tumor suppressors whose disruption may contribute to malignant lymphoproliferative disease.

No MeSH data available.


Related in: MedlinePlus