Haploinsufficiency of SOX5 at 12p12.1 is associated with developmental delays with prominent language delay, behavior problems, and mild dysmorphic features

Allen N. Lamb, Jill A. Rosenfeld, Nicholas J. Neill, Michael E. Talkowski, Ian Blumenthal, Santhosh Girirajan, Debra Keelean-Fuller, Zheng Fan, Jill Pouncey, Cathy Stevens, Loren Mackay-Loder, Deborah Terespolsky, Patricia I. Bader, Kenneth Rosenbaum, Stephanie E. Vallee, John B. Moeschler, Roger Ladda, Susan Sell, Judith Martin, Shawnia Ryan & 23 others Marilyn C. Jones, Rocio Moran, Amy Shealy, Suneeta Madan-Khetarpal, Juliann Mcconnell, Urvashi Surti, Andrée Delahaye, Bénédicte Heron-Longe, Eva Pipiras, Brigitte Benzacken, Sandrine Passemard, Alain Verloes, Bertrand Isidor, Cedric Le Caignec, Gwen M. Glew, Kent E. Opheim, Maria Descartes, Evan E. Eichler, Cynthia C. Morton, James F. Gusella, Roger A. Schultz, Blake C. Ballif, Lisa G. Shaffer

Research output: Contribution to journalArticle

46 Citations (Scopus)

Abstract

SOX5 encodes a transcription factor involved in the regulation of chondrogenesis and the development of the nervous system. Despite its important developmental roles, SOX5 disruption has yet to be associated with human disease. We report one individual with a reciprocal translocation breakpoint within SOX5, eight individuals with intragenic SOX5 deletions (four are apparently de novo and one inherited from an affected parent), and seven individuals with larger 12p12 deletions encompassing SOX5. Common features in these subjects include prominent speech delay, intellectual disability, behavior abnormalities, and dysmorphic features. The phenotypic impact of the deletions may depend on the location of the deletion and, consequently, which of the three major SOX5 protein isoforms are affected. One intragenic deletion, involving only untranslated exons, was present in a more mildly affected subject, was inherited from a healthy parent and grandparent, and is similar to a deletion found in a control cohort. Therefore, some intragenic SOX5 deletions may have minimal phenotypic effect. Based on the location of the deletions in the subjects compared to the controls, the de novo nature of most of these deletions, and the phenotypic similarities among cases, SOX5 appears to be a dosage-sensitive, developmentally important gene.

Original languageEnglish (US)
Pages (from-to)728-740
Number of pages13
JournalHuman mutation
Volume33
Issue number4
DOIs
StatePublished - Apr 1 2012

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Language Development Disorders
Haploinsufficiency
Chondrogenesis
Intellectual Disability
Nervous System
Exons
Protein Isoforms
Transcription Factors
Genes
Problem Behavior
Grandparents

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)

Cite this

Lamb, Allen N. ; Rosenfeld, Jill A. ; Neill, Nicholas J. ; Talkowski, Michael E. ; Blumenthal, Ian ; Girirajan, Santhosh ; Keelean-Fuller, Debra ; Fan, Zheng ; Pouncey, Jill ; Stevens, Cathy ; Mackay-Loder, Loren ; Terespolsky, Deborah ; Bader, Patricia I. ; Rosenbaum, Kenneth ; Vallee, Stephanie E. ; Moeschler, John B. ; Ladda, Roger ; Sell, Susan ; Martin, Judith ; Ryan, Shawnia ; Jones, Marilyn C. ; Moran, Rocio ; Shealy, Amy ; Madan-Khetarpal, Suneeta ; Mcconnell, Juliann ; Surti, Urvashi ; Delahaye, Andrée ; Heron-Longe, Bénédicte ; Pipiras, Eva ; Benzacken, Brigitte ; Passemard, Sandrine ; Verloes, Alain ; Isidor, Bertrand ; Le Caignec, Cedric ; Glew, Gwen M. ; Opheim, Kent E. ; Descartes, Maria ; Eichler, Evan E. ; Morton, Cynthia C. ; Gusella, James F. ; Schultz, Roger A. ; Ballif, Blake C. ; Shaffer, Lisa G. / Haploinsufficiency of SOX5 at 12p12.1 is associated with developmental delays with prominent language delay, behavior problems, and mild dysmorphic features. In: Human mutation. 2012 ; Vol. 33, No. 4. pp. 728-740.
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title = "Haploinsufficiency of SOX5 at 12p12.1 is associated with developmental delays with prominent language delay, behavior problems, and mild dysmorphic features",
abstract = "SOX5 encodes a transcription factor involved in the regulation of chondrogenesis and the development of the nervous system. Despite its important developmental roles, SOX5 disruption has yet to be associated with human disease. We report one individual with a reciprocal translocation breakpoint within SOX5, eight individuals with intragenic SOX5 deletions (four are apparently de novo and one inherited from an affected parent), and seven individuals with larger 12p12 deletions encompassing SOX5. Common features in these subjects include prominent speech delay, intellectual disability, behavior abnormalities, and dysmorphic features. The phenotypic impact of the deletions may depend on the location of the deletion and, consequently, which of the three major SOX5 protein isoforms are affected. One intragenic deletion, involving only untranslated exons, was present in a more mildly affected subject, was inherited from a healthy parent and grandparent, and is similar to a deletion found in a control cohort. Therefore, some intragenic SOX5 deletions may have minimal phenotypic effect. Based on the location of the deletions in the subjects compared to the controls, the de novo nature of most of these deletions, and the phenotypic similarities among cases, SOX5 appears to be a dosage-sensitive, developmentally important gene.",
author = "Lamb, {Allen N.} and Rosenfeld, {Jill A.} and Neill, {Nicholas J.} and Talkowski, {Michael E.} and Ian Blumenthal and Santhosh Girirajan and Debra Keelean-Fuller and Zheng Fan and Jill Pouncey and Cathy Stevens and Loren Mackay-Loder and Deborah Terespolsky and Bader, {Patricia I.} and Kenneth Rosenbaum and Vallee, {Stephanie E.} and Moeschler, {John B.} and Roger Ladda and Susan Sell and Judith Martin and Shawnia Ryan and Jones, {Marilyn C.} and Rocio Moran and Amy Shealy and Suneeta Madan-Khetarpal and Juliann Mcconnell and Urvashi Surti and Andr{\'e}e Delahaye and B{\'e}n{\'e}dicte Heron-Longe and Eva Pipiras and Brigitte Benzacken and Sandrine Passemard and Alain Verloes and Bertrand Isidor and {Le Caignec}, Cedric and Glew, {Gwen M.} and Opheim, {Kent E.} and Maria Descartes and Eichler, {Evan E.} and Morton, {Cynthia C.} and Gusella, {James F.} and Schultz, {Roger A.} and Ballif, {Blake C.} and Shaffer, {Lisa G.}",
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Lamb, AN, Rosenfeld, JA, Neill, NJ, Talkowski, ME, Blumenthal, I, Girirajan, S, Keelean-Fuller, D, Fan, Z, Pouncey, J, Stevens, C, Mackay-Loder, L, Terespolsky, D, Bader, PI, Rosenbaum, K, Vallee, SE, Moeschler, JB, Ladda, R, Sell, S, Martin, J, Ryan, S, Jones, MC, Moran, R, Shealy, A, Madan-Khetarpal, S, Mcconnell, J, Surti, U, Delahaye, A, Heron-Longe, B, Pipiras, E, Benzacken, B, Passemard, S, Verloes, A, Isidor, B, Le Caignec, C, Glew, GM, Opheim, KE, Descartes, M, Eichler, EE, Morton, CC, Gusella, JF, Schultz, RA, Ballif, BC & Shaffer, LG 2012, 'Haploinsufficiency of SOX5 at 12p12.1 is associated with developmental delays with prominent language delay, behavior problems, and mild dysmorphic features', Human mutation, vol. 33, no. 4, pp. 728-740. https://doi.org/10.1002/humu.22037

Haploinsufficiency of SOX5 at 12p12.1 is associated with developmental delays with prominent language delay, behavior problems, and mild dysmorphic features. / Lamb, Allen N.; Rosenfeld, Jill A.; Neill, Nicholas J.; Talkowski, Michael E.; Blumenthal, Ian; Girirajan, Santhosh; Keelean-Fuller, Debra; Fan, Zheng; Pouncey, Jill; Stevens, Cathy; Mackay-Loder, Loren; Terespolsky, Deborah; Bader, Patricia I.; Rosenbaum, Kenneth; Vallee, Stephanie E.; Moeschler, John B.; Ladda, Roger; Sell, Susan; Martin, Judith; Ryan, Shawnia; Jones, Marilyn C.; Moran, Rocio; Shealy, Amy; Madan-Khetarpal, Suneeta; Mcconnell, Juliann; Surti, Urvashi; Delahaye, Andrée; Heron-Longe, Bénédicte; Pipiras, Eva; Benzacken, Brigitte; Passemard, Sandrine; Verloes, Alain; Isidor, Bertrand; Le Caignec, Cedric; Glew, Gwen M.; Opheim, Kent E.; Descartes, Maria; Eichler, Evan E.; Morton, Cynthia C.; Gusella, James F.; Schultz, Roger A.; Ballif, Blake C.; Shaffer, Lisa G.

In: Human mutation, Vol. 33, No. 4, 01.04.2012, p. 728-740.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Haploinsufficiency of SOX5 at 12p12.1 is associated with developmental delays with prominent language delay, behavior problems, and mild dysmorphic features

AU - Lamb, Allen N.

AU - Rosenfeld, Jill A.

AU - Neill, Nicholas J.

AU - Talkowski, Michael E.

AU - Blumenthal, Ian

AU - Girirajan, Santhosh

AU - Keelean-Fuller, Debra

AU - Fan, Zheng

AU - Pouncey, Jill

AU - Stevens, Cathy

AU - Mackay-Loder, Loren

AU - Terespolsky, Deborah

AU - Bader, Patricia I.

AU - Rosenbaum, Kenneth

AU - Vallee, Stephanie E.

AU - Moeschler, John B.

AU - Ladda, Roger

AU - Sell, Susan

AU - Martin, Judith

AU - Ryan, Shawnia

AU - Jones, Marilyn C.

AU - Moran, Rocio

AU - Shealy, Amy

AU - Madan-Khetarpal, Suneeta

AU - Mcconnell, Juliann

AU - Surti, Urvashi

AU - Delahaye, Andrée

AU - Heron-Longe, Bénédicte

AU - Pipiras, Eva

AU - Benzacken, Brigitte

AU - Passemard, Sandrine

AU - Verloes, Alain

AU - Isidor, Bertrand

AU - Le Caignec, Cedric

AU - Glew, Gwen M.

AU - Opheim, Kent E.

AU - Descartes, Maria

AU - Eichler, Evan E.

AU - Morton, Cynthia C.

AU - Gusella, James F.

AU - Schultz, Roger A.

AU - Ballif, Blake C.

AU - Shaffer, Lisa G.

PY - 2012/4/1

Y1 - 2012/4/1

N2 - SOX5 encodes a transcription factor involved in the regulation of chondrogenesis and the development of the nervous system. Despite its important developmental roles, SOX5 disruption has yet to be associated with human disease. We report one individual with a reciprocal translocation breakpoint within SOX5, eight individuals with intragenic SOX5 deletions (four are apparently de novo and one inherited from an affected parent), and seven individuals with larger 12p12 deletions encompassing SOX5. Common features in these subjects include prominent speech delay, intellectual disability, behavior abnormalities, and dysmorphic features. The phenotypic impact of the deletions may depend on the location of the deletion and, consequently, which of the three major SOX5 protein isoforms are affected. One intragenic deletion, involving only untranslated exons, was present in a more mildly affected subject, was inherited from a healthy parent and grandparent, and is similar to a deletion found in a control cohort. Therefore, some intragenic SOX5 deletions may have minimal phenotypic effect. Based on the location of the deletions in the subjects compared to the controls, the de novo nature of most of these deletions, and the phenotypic similarities among cases, SOX5 appears to be a dosage-sensitive, developmentally important gene.

AB - SOX5 encodes a transcription factor involved in the regulation of chondrogenesis and the development of the nervous system. Despite its important developmental roles, SOX5 disruption has yet to be associated with human disease. We report one individual with a reciprocal translocation breakpoint within SOX5, eight individuals with intragenic SOX5 deletions (four are apparently de novo and one inherited from an affected parent), and seven individuals with larger 12p12 deletions encompassing SOX5. Common features in these subjects include prominent speech delay, intellectual disability, behavior abnormalities, and dysmorphic features. The phenotypic impact of the deletions may depend on the location of the deletion and, consequently, which of the three major SOX5 protein isoforms are affected. One intragenic deletion, involving only untranslated exons, was present in a more mildly affected subject, was inherited from a healthy parent and grandparent, and is similar to a deletion found in a control cohort. Therefore, some intragenic SOX5 deletions may have minimal phenotypic effect. Based on the location of the deletions in the subjects compared to the controls, the de novo nature of most of these deletions, and the phenotypic similarities among cases, SOX5 appears to be a dosage-sensitive, developmentally important gene.

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