Functionally compromised CHD7 alleles in patients with isolated GnRH deficiency

Ravikumar Balasubramanian, Jin Ho Choi, Ludmila Francescatto, Jason Willer, Edward R. Horton, Eleni P. Asimacopoulos, Konstantina M. Stankovic, Lacey Plummer, Cassandra L. Buck, Richard Quinton, Todd D. Nebesio, Veronica Mericq, Paulina M. Merino, Brian F. Meyer, Dorota Monies, James F. Gusella, Nada Al Tassan, Nicholas Katsanis, William F. Crowley

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

Inactivating mutations in chromodomain helicase DNA binding protein 7 (CHD7) cause CHARGE syndrome, a severe multiorgan system disorder of which Isolated gonadotropin-releasing hormone (GnRH) deficiency (IGD) is a minor feature. Recent reports have described predominantly missense CHD7 alleles in IGD patients, but it is unclear if these alleles are relevant to causality or overall genetic burden of Kallmann syndrome (KS) and normosmic form of IGD. To address this question, we sequenced CHD7 in 783 well-phenotyped IGD patients lacking full CHARGE features; we identified nonsynonymous rare sequence variants in 5.2% of the IGD cohort (73% missense and 27% splice variants). Functional analyses in zebrafish using a surrogate otolith assay of a representative set of these CHD7 alleles showed that rare sequence variants observed in controls showed no altered function. In contrast, 75% of the IGD-associated alleles were deleterious and resulted in both KS and normosmic IGD. In two families, pathogenic mutations in CHD7 coexisted with mutations in other known IGD genes. Taken together, our data suggest that rare deleterious CHD7 alleles contribute to the mutational burden of patients with both KS and normosmic forms of IGD in the absence of full CHARGE syndrome. These findings (i) implicate a unique role or preferential sensitivity for CHD7 in the ontogeny of GnRH neurons, (ii) reiterate the emerging genetic complexity of this family of IGD disorders, and (iii) demonstrate how the coordinated use of well-phenotyped cohorts, families, and functional studies can inform genetic architecture and provide insights into the developmental biology of cellular systems.

Original languageEnglish (US)
Pages (from-to)17953-17958
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number50
DOIs
StatePublished - Dec 16 2014

Fingerprint

DNA-Binding Proteins
Gonadotropin-Releasing Hormone
Alleles
Kallmann Syndrome
CHARGE Syndrome
Mutation
Otolithic Membrane
Developmental Biology
Zebrafish
Causality
Neurons
Genes

Keywords

  • CHARGE syndrome
  • CHD7
  • Idiopathic hypogonadotropic hypogondism
  • Kallmann syndrome
  • Missense mutations

ASJC Scopus subject areas

  • General

Cite this

Balasubramanian, R., Choi, J. H., Francescatto, L., Willer, J., Horton, E. R., Asimacopoulos, E. P., ... Crowley, W. F. (2014). Functionally compromised CHD7 alleles in patients with isolated GnRH deficiency. Proceedings of the National Academy of Sciences of the United States of America, 111(50), 17953-17958. https://doi.org/10.1073/pnas.1417438111

Functionally compromised CHD7 alleles in patients with isolated GnRH deficiency. / Balasubramanian, Ravikumar; Choi, Jin Ho; Francescatto, Ludmila; Willer, Jason; Horton, Edward R.; Asimacopoulos, Eleni P.; Stankovic, Konstantina M.; Plummer, Lacey; Buck, Cassandra L.; Quinton, Richard; Nebesio, Todd D.; Mericq, Veronica; Merino, Paulina M.; Meyer, Brian F.; Monies, Dorota; Gusella, James F.; Al Tassan, Nada; Katsanis, Nicholas; Crowley, William F.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 111, No. 50, 16.12.2014, p. 17953-17958.

Research output: Contribution to journalArticle

Balasubramanian, R, Choi, JH, Francescatto, L, Willer, J, Horton, ER, Asimacopoulos, EP, Stankovic, KM, Plummer, L, Buck, CL, Quinton, R, Nebesio, TD, Mericq, V, Merino, PM, Meyer, BF, Monies, D, Gusella, JF, Al Tassan, N, Katsanis, N & Crowley, WF 2014, 'Functionally compromised CHD7 alleles in patients with isolated GnRH deficiency', Proceedings of the National Academy of Sciences of the United States of America, vol. 111, no. 50, pp. 17953-17958. https://doi.org/10.1073/pnas.1417438111
Balasubramanian, Ravikumar ; Choi, Jin Ho ; Francescatto, Ludmila ; Willer, Jason ; Horton, Edward R. ; Asimacopoulos, Eleni P. ; Stankovic, Konstantina M. ; Plummer, Lacey ; Buck, Cassandra L. ; Quinton, Richard ; Nebesio, Todd D. ; Mericq, Veronica ; Merino, Paulina M. ; Meyer, Brian F. ; Monies, Dorota ; Gusella, James F. ; Al Tassan, Nada ; Katsanis, Nicholas ; Crowley, William F. / Functionally compromised CHD7 alleles in patients with isolated GnRH deficiency. In: Proceedings of the National Academy of Sciences of the United States of America. 2014 ; Vol. 111, No. 50. pp. 17953-17958.
@article{89aa33e58b5f4ca1b13a96c33e63ef68,
title = "Functionally compromised CHD7 alleles in patients with isolated GnRH deficiency",
abstract = "Inactivating mutations in chromodomain helicase DNA binding protein 7 (CHD7) cause CHARGE syndrome, a severe multiorgan system disorder of which Isolated gonadotropin-releasing hormone (GnRH) deficiency (IGD) is a minor feature. Recent reports have described predominantly missense CHD7 alleles in IGD patients, but it is unclear if these alleles are relevant to causality or overall genetic burden of Kallmann syndrome (KS) and normosmic form of IGD. To address this question, we sequenced CHD7 in 783 well-phenotyped IGD patients lacking full CHARGE features; we identified nonsynonymous rare sequence variants in 5.2{\%} of the IGD cohort (73{\%} missense and 27{\%} splice variants). Functional analyses in zebrafish using a surrogate otolith assay of a representative set of these CHD7 alleles showed that rare sequence variants observed in controls showed no altered function. In contrast, 75{\%} of the IGD-associated alleles were deleterious and resulted in both KS and normosmic IGD. In two families, pathogenic mutations in CHD7 coexisted with mutations in other known IGD genes. Taken together, our data suggest that rare deleterious CHD7 alleles contribute to the mutational burden of patients with both KS and normosmic forms of IGD in the absence of full CHARGE syndrome. These findings (i) implicate a unique role or preferential sensitivity for CHD7 in the ontogeny of GnRH neurons, (ii) reiterate the emerging genetic complexity of this family of IGD disorders, and (iii) demonstrate how the coordinated use of well-phenotyped cohorts, families, and functional studies can inform genetic architecture and provide insights into the developmental biology of cellular systems.",
keywords = "CHARGE syndrome, CHD7, Idiopathic hypogonadotropic hypogondism, Kallmann syndrome, Missense mutations",
author = "Ravikumar Balasubramanian and Choi, {Jin Ho} and Ludmila Francescatto and Jason Willer and Horton, {Edward R.} and Asimacopoulos, {Eleni P.} and Stankovic, {Konstantina M.} and Lacey Plummer and Buck, {Cassandra L.} and Richard Quinton and Nebesio, {Todd D.} and Veronica Mericq and Merino, {Paulina M.} and Meyer, {Brian F.} and Dorota Monies and Gusella, {James F.} and {Al Tassan}, Nada and Nicholas Katsanis and Crowley, {William F.}",
year = "2014",
month = "12",
day = "16",
doi = "10.1073/pnas.1417438111",
language = "English (US)",
volume = "111",
pages = "17953--17958",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "50",

}

TY - JOUR

T1 - Functionally compromised CHD7 alleles in patients with isolated GnRH deficiency

AU - Balasubramanian, Ravikumar

AU - Choi, Jin Ho

AU - Francescatto, Ludmila

AU - Willer, Jason

AU - Horton, Edward R.

AU - Asimacopoulos, Eleni P.

AU - Stankovic, Konstantina M.

AU - Plummer, Lacey

AU - Buck, Cassandra L.

AU - Quinton, Richard

AU - Nebesio, Todd D.

AU - Mericq, Veronica

AU - Merino, Paulina M.

AU - Meyer, Brian F.

AU - Monies, Dorota

AU - Gusella, James F.

AU - Al Tassan, Nada

AU - Katsanis, Nicholas

AU - Crowley, William F.

PY - 2014/12/16

Y1 - 2014/12/16

N2 - Inactivating mutations in chromodomain helicase DNA binding protein 7 (CHD7) cause CHARGE syndrome, a severe multiorgan system disorder of which Isolated gonadotropin-releasing hormone (GnRH) deficiency (IGD) is a minor feature. Recent reports have described predominantly missense CHD7 alleles in IGD patients, but it is unclear if these alleles are relevant to causality or overall genetic burden of Kallmann syndrome (KS) and normosmic form of IGD. To address this question, we sequenced CHD7 in 783 well-phenotyped IGD patients lacking full CHARGE features; we identified nonsynonymous rare sequence variants in 5.2% of the IGD cohort (73% missense and 27% splice variants). Functional analyses in zebrafish using a surrogate otolith assay of a representative set of these CHD7 alleles showed that rare sequence variants observed in controls showed no altered function. In contrast, 75% of the IGD-associated alleles were deleterious and resulted in both KS and normosmic IGD. In two families, pathogenic mutations in CHD7 coexisted with mutations in other known IGD genes. Taken together, our data suggest that rare deleterious CHD7 alleles contribute to the mutational burden of patients with both KS and normosmic forms of IGD in the absence of full CHARGE syndrome. These findings (i) implicate a unique role or preferential sensitivity for CHD7 in the ontogeny of GnRH neurons, (ii) reiterate the emerging genetic complexity of this family of IGD disorders, and (iii) demonstrate how the coordinated use of well-phenotyped cohorts, families, and functional studies can inform genetic architecture and provide insights into the developmental biology of cellular systems.

AB - Inactivating mutations in chromodomain helicase DNA binding protein 7 (CHD7) cause CHARGE syndrome, a severe multiorgan system disorder of which Isolated gonadotropin-releasing hormone (GnRH) deficiency (IGD) is a minor feature. Recent reports have described predominantly missense CHD7 alleles in IGD patients, but it is unclear if these alleles are relevant to causality or overall genetic burden of Kallmann syndrome (KS) and normosmic form of IGD. To address this question, we sequenced CHD7 in 783 well-phenotyped IGD patients lacking full CHARGE features; we identified nonsynonymous rare sequence variants in 5.2% of the IGD cohort (73% missense and 27% splice variants). Functional analyses in zebrafish using a surrogate otolith assay of a representative set of these CHD7 alleles showed that rare sequence variants observed in controls showed no altered function. In contrast, 75% of the IGD-associated alleles were deleterious and resulted in both KS and normosmic IGD. In two families, pathogenic mutations in CHD7 coexisted with mutations in other known IGD genes. Taken together, our data suggest that rare deleterious CHD7 alleles contribute to the mutational burden of patients with both KS and normosmic forms of IGD in the absence of full CHARGE syndrome. These findings (i) implicate a unique role or preferential sensitivity for CHD7 in the ontogeny of GnRH neurons, (ii) reiterate the emerging genetic complexity of this family of IGD disorders, and (iii) demonstrate how the coordinated use of well-phenotyped cohorts, families, and functional studies can inform genetic architecture and provide insights into the developmental biology of cellular systems.

KW - CHARGE syndrome

KW - CHD7

KW - Idiopathic hypogonadotropic hypogondism

KW - Kallmann syndrome

KW - Missense mutations

UR - http://www.scopus.com/inward/record.url?scp=84918576772&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84918576772&partnerID=8YFLogxK

U2 - 10.1073/pnas.1417438111

DO - 10.1073/pnas.1417438111

M3 - Article

C2 - 25472840

AN - SCOPUS:84918576772

VL - 111

SP - 17953

EP - 17958

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 50

ER -