Limits...
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

(A) At present, the hands of the proband are notable for malformed digits. (B and C) X-rays of the hands at present. See text for detailed description. (D and E) X-rays of the feet at present. See text for detailed description.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4585449&req=5

fig01: (A) At present, the hands of the proband are notable for malformed digits. (B and C) X-rays of the hands at present. See text for detailed description. (D and E) X-rays of the feet at present. See text for detailed description.

Mentions: The proband is a 46-year-old woman who initially presented to the adult genetics clinic at Brigham and Women’s Hospital in 2005 for evaluation of a personal and family history of congenital hand/foot malformations and peripheral T-cell lymphoma. At 61 in. in height (10th percentile, CDC growth curves), she is shorter than all of her first-degree relatives except one similarly affected sister. She was born with bony abnormalities of the fingers and toes bilaterally, for which she underwent multiple surgical repairs in early childhood. On clinical exam, her fingers demonstrated brachydactyly with disproportionately short index fingers and either valgus or varus deformity at many of the interphalangeal (IP) joints (Fig.1A). Similar findings were observed in the toes. X-ray images were taken of the hands and feet, with multiple notable findings. On the left hand, the index finger displayed a long proximal phalanx, a fused distal phalanx and subluxation of the index metacarpophalangeal (MCP) joint with remodeling of the bony surfaces; the third digit had four phalanges and a horizontal articulation at the base of the proximal phalanx; the fourth and fifth fingers each had long proximal phalanges; and the fifth finger middle phalanx had a curved articulation distally (Fig.1B). The metacarpals appeared more normal with the exception of a hypoplastic index metacarpal. The thumbs and wrist bones appeared normal. Similar findings were observed in radiographs of the right hand (Fig.1C).


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)

(A) At present, the hands of the proband are notable for malformed digits. (B and C) X-rays of the hands at present. See text for detailed description. (D and E) X-rays of the feet at present. See text for detailed description.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig01: (A) At present, the hands of the proband are notable for malformed digits. (B and C) X-rays of the hands at present. See text for detailed description. (D and E) X-rays of the feet at present. See text for detailed description.
Mentions: The proband is a 46-year-old woman who initially presented to the adult genetics clinic at Brigham and Women’s Hospital in 2005 for evaluation of a personal and family history of congenital hand/foot malformations and peripheral T-cell lymphoma. At 61 in. in height (10th percentile, CDC growth curves), she is shorter than all of her first-degree relatives except one similarly affected sister. She was born with bony abnormalities of the fingers and toes bilaterally, for which she underwent multiple surgical repairs in early childhood. On clinical exam, her fingers demonstrated brachydactyly with disproportionately short index fingers and either valgus or varus deformity at many of the interphalangeal (IP) joints (Fig.1A). Similar findings were observed in the toes. X-ray images were taken of the hands and feet, with multiple notable findings. On the left hand, the index finger displayed a long proximal phalanx, a fused distal phalanx and subluxation of the index metacarpophalangeal (MCP) joint with remodeling of the bony surfaces; the third digit had four phalanges and a horizontal articulation at the base of the proximal phalanx; the fourth and fifth fingers each had long proximal phalanges; and the fifth finger middle phalanx had a curved articulation distally (Fig.1B). The metacarpals appeared more normal with the exception of a hypoplastic index metacarpal. The thumbs and wrist bones appeared normal. Similar findings were observed in radiographs of the right hand (Fig.1C).

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