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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

The pedigree demonstrates a large sibship with two affected individuals, one deceased. The table below the pedigree indicates the genotyping results for the proband and the three siblings who underwent testing. The data include number of CHST11 deletion alleles (homozygous , heterozygous, or homozygous wild type) as well as results of droplet digital PCR (exon 2, intron 1), including mean and standard deviation. STR genotyping results (for chimerism) are also indicated.
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fig02: The pedigree demonstrates a large sibship with two affected individuals, one deceased. The table below the pedigree indicates the genotyping results for the proband and the three siblings who underwent testing. The data include number of CHST11 deletion alleles (homozygous , heterozygous, or homozygous wild type) as well as results of droplet digital PCR (exon 2, intron 1), including mean and standard deviation. STR genotyping results (for chimerism) are also indicated.

Mentions: The proband and her deceased sister have five unaffected living siblings (Fig.2). No other individuals in the extended family are reported to have congenital abnormalities of the hands or feet. With the exception of the proband’s father, who was diagnosed with chronic lymphocytic leukemia (CLL) at age 59 and died at age 64, no other individuals have developed any lymphoproliferative disorders. The proband’s parents were both immigrants to the US from the same region of Ireland, so the possibility of distant consanguinity cannot be ruled out. The family history is most consistent with a rare monogenic disorder of autosomal recessive inheritance.


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)

The pedigree demonstrates a large sibship with two affected individuals, one deceased. The table below the pedigree indicates the genotyping results for the proband and the three siblings who underwent testing. The data include number of CHST11 deletion alleles (homozygous , heterozygous, or homozygous wild type) as well as results of droplet digital PCR (exon 2, intron 1), including mean and standard deviation. STR genotyping results (for chimerism) are also indicated.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig02: The pedigree demonstrates a large sibship with two affected individuals, one deceased. The table below the pedigree indicates the genotyping results for the proband and the three siblings who underwent testing. The data include number of CHST11 deletion alleles (homozygous , heterozygous, or homozygous wild type) as well as results of droplet digital PCR (exon 2, intron 1), including mean and standard deviation. STR genotyping results (for chimerism) are also indicated.
Mentions: The proband and her deceased sister have five unaffected living siblings (Fig.2). No other individuals in the extended family are reported to have congenital abnormalities of the hands or feet. With the exception of the proband’s father, who was diagnosed with chronic lymphocytic leukemia (CLL) at age 59 and died at age 64, no other individuals have developed any lymphoproliferative disorders. The proband’s parents were both immigrants to the US from the same region of Ireland, so the possibility of distant consanguinity cannot be ruled out. The family history is most consistent with a rare monogenic disorder of autosomal recessive inheritance.

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