Position effects due to chromosome breakpoints that map ∼900 Kb upstream and ∼1.3 Mb downstream of SOX9 in two patients with campomelic dysplasia

Gopalrao V N Velagaleti, Gabriel A. Bien-Willner, Jill K. Northup, Lillian Lockhart, Judy C. Hawkins, Syed M. Jalal, Marjorie Withers, James R. Lupski, Pawel Stankiewicz

Research output: Contribution to journalArticle

134 Citations (Scopus)

Abstract

Campomelic dysplasia (CD) is a semilethal skeletal malformation syndrome with or without XY sex reversal. In addition to the multiple mutations found within the sex-determining region Y-related high-mobility group box gene (SOX9) on 17q24.3, several chromosome anomalies (translocations, inversions, and deletions) with breakpoints scattered over 1 Mb upstream of SOX9 have been described. Here, we present a balanced translocation, t(4;17)(q28.3;q24.3), segregating in a family with a mild acampomelic CD with Robin sequence. Both chromosome breakpoints have been identified by fluorescence in situ hybridization and have been sequenced using a somatic cell hybrid. The 17q24.3 breakpoint maps ∼900 kb upstream of SOX9, which is within the same bacterial artificial chromosome clone as the breakpoints of two other reported patients with mild CD. We also report a prenatal identification of acampomelic CD with male-to-female sex reversal in a fetus with a de novo balanced complex karyotype, 46,XY,t(4;7;8;17)(4qter→4p15.1::17q25. 1→17qter;7qter→7p15.3::4p15.1→4pter;8pter→8q12.1:: 7p15.3→7pter;17pter→17q25.1::8q12.1→8qter). Surprisingly, the 17q breakpoint maps ∼1.3 Mb downstream of SOX9, making this the longest-range position effect found in the field of human genetics and the first report of a patient with CD with the chromosome breakpoint mapping 3′ of SOX9. By using the Regulatory Potential score in conjunction with analysis of the rearrangement breakpoints, we identified a candidate upstream cis-regulatory element, SOX9cre1. We provide evidence that this 1.1-kb evolutionarily conserved element and the downstream breakpoint region colocalize with SOX9 in the interphase nucleus, despite being located 1.1 Mb upstream and 1.3 Mb downstream of it, respectively. The potential molecular mechanism responsible for the position effect is discussed.

Original languageEnglish (US)
Pages (from-to)652-662
Number of pages11
JournalAmerican Journal of Human Genetics
Volume76
Issue number4
DOIs
StatePublished - Apr 2005

Fingerprint

Campomelic Dysplasia
Chromosome Breakpoints
Pierre Robin Syndrome
Bacterial Artificial Chromosomes
Hybrid Cells
Chromosome Mapping
Interphase
Medical Genetics
Fluorescence In Situ Hybridization
Karyotype
Fetus
Clone Cells
Chromosomes
Mutation
Genes

ASJC Scopus subject areas

  • Genetics

Cite this

Position effects due to chromosome breakpoints that map ∼900 Kb upstream and ∼1.3 Mb downstream of SOX9 in two patients with campomelic dysplasia. / Velagaleti, Gopalrao V N; Bien-Willner, Gabriel A.; Northup, Jill K.; Lockhart, Lillian; Hawkins, Judy C.; Jalal, Syed M.; Withers, Marjorie; Lupski, James R.; Stankiewicz, Pawel.

In: American Journal of Human Genetics, Vol. 76, No. 4, 04.2005, p. 652-662.

Research output: Contribution to journalArticle

Velagaleti, GVN, Bien-Willner, GA, Northup, JK, Lockhart, L, Hawkins, JC, Jalal, SM, Withers, M, Lupski, JR & Stankiewicz, P 2005, 'Position effects due to chromosome breakpoints that map ∼900 Kb upstream and ∼1.3 Mb downstream of SOX9 in two patients with campomelic dysplasia', American Journal of Human Genetics, vol. 76, no. 4, pp. 652-662. https://doi.org/10.1086/429252
Velagaleti, Gopalrao V N ; Bien-Willner, Gabriel A. ; Northup, Jill K. ; Lockhart, Lillian ; Hawkins, Judy C. ; Jalal, Syed M. ; Withers, Marjorie ; Lupski, James R. ; Stankiewicz, Pawel. / Position effects due to chromosome breakpoints that map ∼900 Kb upstream and ∼1.3 Mb downstream of SOX9 in two patients with campomelic dysplasia. In: American Journal of Human Genetics. 2005 ; Vol. 76, No. 4. pp. 652-662.
@article{9973495524a34bc599d11ead4b89ebb0,
title = "Position effects due to chromosome breakpoints that map ∼900 Kb upstream and ∼1.3 Mb downstream of SOX9 in two patients with campomelic dysplasia",
abstract = "Campomelic dysplasia (CD) is a semilethal skeletal malformation syndrome with or without XY sex reversal. In addition to the multiple mutations found within the sex-determining region Y-related high-mobility group box gene (SOX9) on 17q24.3, several chromosome anomalies (translocations, inversions, and deletions) with breakpoints scattered over 1 Mb upstream of SOX9 have been described. Here, we present a balanced translocation, t(4;17)(q28.3;q24.3), segregating in a family with a mild acampomelic CD with Robin sequence. Both chromosome breakpoints have been identified by fluorescence in situ hybridization and have been sequenced using a somatic cell hybrid. The 17q24.3 breakpoint maps ∼900 kb upstream of SOX9, which is within the same bacterial artificial chromosome clone as the breakpoints of two other reported patients with mild CD. We also report a prenatal identification of acampomelic CD with male-to-female sex reversal in a fetus with a de novo balanced complex karyotype, 46,XY,t(4;7;8;17)(4qter→4p15.1::17q25. 1→17qter;7qter→7p15.3::4p15.1→4pter;8pter→8q12.1:: 7p15.3→7pter;17pter→17q25.1::8q12.1→8qter). Surprisingly, the 17q breakpoint maps ∼1.3 Mb downstream of SOX9, making this the longest-range position effect found in the field of human genetics and the first report of a patient with CD with the chromosome breakpoint mapping 3′ of SOX9. By using the Regulatory Potential score in conjunction with analysis of the rearrangement breakpoints, we identified a candidate upstream cis-regulatory element, SOX9cre1. We provide evidence that this 1.1-kb evolutionarily conserved element and the downstream breakpoint region colocalize with SOX9 in the interphase nucleus, despite being located 1.1 Mb upstream and 1.3 Mb downstream of it, respectively. The potential molecular mechanism responsible for the position effect is discussed.",
author = "Velagaleti, {Gopalrao V N} and Bien-Willner, {Gabriel A.} and Northup, {Jill K.} and Lillian Lockhart and Hawkins, {Judy C.} and Jalal, {Syed M.} and Marjorie Withers and Lupski, {James R.} and Pawel Stankiewicz",
year = "2005",
month = "4",
doi = "10.1086/429252",
language = "English (US)",
volume = "76",
pages = "652--662",
journal = "American Journal of Human Genetics",
issn = "0002-9297",
publisher = "Cell Press",
number = "4",

}

TY - JOUR

T1 - Position effects due to chromosome breakpoints that map ∼900 Kb upstream and ∼1.3 Mb downstream of SOX9 in two patients with campomelic dysplasia

AU - Velagaleti, Gopalrao V N

AU - Bien-Willner, Gabriel A.

AU - Northup, Jill K.

AU - Lockhart, Lillian

AU - Hawkins, Judy C.

AU - Jalal, Syed M.

AU - Withers, Marjorie

AU - Lupski, James R.

AU - Stankiewicz, Pawel

PY - 2005/4

Y1 - 2005/4

N2 - Campomelic dysplasia (CD) is a semilethal skeletal malformation syndrome with or without XY sex reversal. In addition to the multiple mutations found within the sex-determining region Y-related high-mobility group box gene (SOX9) on 17q24.3, several chromosome anomalies (translocations, inversions, and deletions) with breakpoints scattered over 1 Mb upstream of SOX9 have been described. Here, we present a balanced translocation, t(4;17)(q28.3;q24.3), segregating in a family with a mild acampomelic CD with Robin sequence. Both chromosome breakpoints have been identified by fluorescence in situ hybridization and have been sequenced using a somatic cell hybrid. The 17q24.3 breakpoint maps ∼900 kb upstream of SOX9, which is within the same bacterial artificial chromosome clone as the breakpoints of two other reported patients with mild CD. We also report a prenatal identification of acampomelic CD with male-to-female sex reversal in a fetus with a de novo balanced complex karyotype, 46,XY,t(4;7;8;17)(4qter→4p15.1::17q25. 1→17qter;7qter→7p15.3::4p15.1→4pter;8pter→8q12.1:: 7p15.3→7pter;17pter→17q25.1::8q12.1→8qter). Surprisingly, the 17q breakpoint maps ∼1.3 Mb downstream of SOX9, making this the longest-range position effect found in the field of human genetics and the first report of a patient with CD with the chromosome breakpoint mapping 3′ of SOX9. By using the Regulatory Potential score in conjunction with analysis of the rearrangement breakpoints, we identified a candidate upstream cis-regulatory element, SOX9cre1. We provide evidence that this 1.1-kb evolutionarily conserved element and the downstream breakpoint region colocalize with SOX9 in the interphase nucleus, despite being located 1.1 Mb upstream and 1.3 Mb downstream of it, respectively. The potential molecular mechanism responsible for the position effect is discussed.

AB - Campomelic dysplasia (CD) is a semilethal skeletal malformation syndrome with or without XY sex reversal. In addition to the multiple mutations found within the sex-determining region Y-related high-mobility group box gene (SOX9) on 17q24.3, several chromosome anomalies (translocations, inversions, and deletions) with breakpoints scattered over 1 Mb upstream of SOX9 have been described. Here, we present a balanced translocation, t(4;17)(q28.3;q24.3), segregating in a family with a mild acampomelic CD with Robin sequence. Both chromosome breakpoints have been identified by fluorescence in situ hybridization and have been sequenced using a somatic cell hybrid. The 17q24.3 breakpoint maps ∼900 kb upstream of SOX9, which is within the same bacterial artificial chromosome clone as the breakpoints of two other reported patients with mild CD. We also report a prenatal identification of acampomelic CD with male-to-female sex reversal in a fetus with a de novo balanced complex karyotype, 46,XY,t(4;7;8;17)(4qter→4p15.1::17q25. 1→17qter;7qter→7p15.3::4p15.1→4pter;8pter→8q12.1:: 7p15.3→7pter;17pter→17q25.1::8q12.1→8qter). Surprisingly, the 17q breakpoint maps ∼1.3 Mb downstream of SOX9, making this the longest-range position effect found in the field of human genetics and the first report of a patient with CD with the chromosome breakpoint mapping 3′ of SOX9. By using the Regulatory Potential score in conjunction with analysis of the rearrangement breakpoints, we identified a candidate upstream cis-regulatory element, SOX9cre1. We provide evidence that this 1.1-kb evolutionarily conserved element and the downstream breakpoint region colocalize with SOX9 in the interphase nucleus, despite being located 1.1 Mb upstream and 1.3 Mb downstream of it, respectively. The potential molecular mechanism responsible for the position effect is discussed.

UR - http://www.scopus.com/inward/record.url?scp=15944402131&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=15944402131&partnerID=8YFLogxK

U2 - 10.1086/429252

DO - 10.1086/429252

M3 - Article

VL - 76

SP - 652

EP - 662

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

SN - 0002-9297

IS - 4

ER -