Ectrodactyly and Lethal Pulmonary Acinar Dysplasia Associated with Homozygous FGFR2 Mutations Identified by Exome Sequencing

Christopher P. Barnett, Nathalie J. Nataren, Manuela Klingler-Hoffmann, Quenten Schwarz, Chan Eng Chong, Young K. Lee, Damien L. Bruno, Jill Lipsett, Andrew McPhee, Andreas W. Schreiber, Jinghua Feng, Christopher N. Hahn, Hamish S. Scott

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Ectrodactyly/split hand-foot malformation is genetically heterogeneous with more than 100 syndromic associations. Acinar dysplasia is a rare congenital lung lesion of unknown etiology, which is frequently lethal postnatally. To date, there have been no reports of combinations of these two phenotypes. Here, we present an infant from a consanguineous union with both ectrodactyly and autopsy confirmed acinar dysplasia. SNP array and whole-exome sequencing analyses of the affected infant identified a novel homozygous Fibroblast Growth Factor Receptor 2 (FGFR2) missense mutation (p.R255Q) in the IgIII domain (D3). Expression studies of Fgfr2 in development show localization to the affected limbs and organs. Molecular modeling and genetic and functional assays support that this mutation is at least a partial loss-of-function mutation, and contributes to ectrodactyly and acinar dysplasia only in homozygosity, unlike previously reported heterozygous activating FGFR2 mutations that cause Crouzon, Apert, and Pfeiffer syndromes. This is the first report of mutations in a human disease with ectrodactyly with pulmonary acinar dysplasia and, as such, homozygous loss-of-function FGFR2 mutations represent a unique syndrome.

LanguageEnglish
Pages955-963
Number of pages9
JournalHuman Mutation
Volume37
Issue number9
DOIs
Publication statusPublished - 1 Sep 2016

Keywords

  • FGFR2
  • acinar dysplasia
  • ectrodactyly
  • whole-exome sequencing

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Barnett, C. P., Nataren, N. J., Klingler-Hoffmann, M., Schwarz, Q., Chong, C. E., Lee, Y. K., ... Scott, H. S. (2016). Ectrodactyly and Lethal Pulmonary Acinar Dysplasia Associated with Homozygous FGFR2 Mutations Identified by Exome Sequencing. Human Mutation, 37(9), 955-963. https://doi.org/10.1002/humu.23032
Barnett, Christopher P. ; Nataren, Nathalie J. ; Klingler-Hoffmann, Manuela ; Schwarz, Quenten ; Chong, Chan Eng ; Lee, Young K. ; Bruno, Damien L. ; Lipsett, Jill ; McPhee, Andrew ; Schreiber, Andreas W. ; Feng, Jinghua ; Hahn, Christopher N. ; Scott, Hamish S. / Ectrodactyly and Lethal Pulmonary Acinar Dysplasia Associated with Homozygous FGFR2 Mutations Identified by Exome Sequencing. In: Human Mutation. 2016 ; Vol. 37, No. 9. pp. 955-963.
@article{4f52a52fb94c424fb3fad5086dd135fa,
title = "Ectrodactyly and Lethal Pulmonary Acinar Dysplasia Associated with Homozygous FGFR2 Mutations Identified by Exome Sequencing",
abstract = "Ectrodactyly/split hand-foot malformation is genetically heterogeneous with more than 100 syndromic associations. Acinar dysplasia is a rare congenital lung lesion of unknown etiology, which is frequently lethal postnatally. To date, there have been no reports of combinations of these two phenotypes. Here, we present an infant from a consanguineous union with both ectrodactyly and autopsy confirmed acinar dysplasia. SNP array and whole-exome sequencing analyses of the affected infant identified a novel homozygous Fibroblast Growth Factor Receptor 2 (FGFR2) missense mutation (p.R255Q) in the IgIII domain (D3). Expression studies of Fgfr2 in development show localization to the affected limbs and organs. Molecular modeling and genetic and functional assays support that this mutation is at least a partial loss-of-function mutation, and contributes to ectrodactyly and acinar dysplasia only in homozygosity, unlike previously reported heterozygous activating FGFR2 mutations that cause Crouzon, Apert, and Pfeiffer syndromes. This is the first report of mutations in a human disease with ectrodactyly with pulmonary acinar dysplasia and, as such, homozygous loss-of-function FGFR2 mutations represent a unique syndrome.",
keywords = "FGFR2, acinar dysplasia, ectrodactyly, whole-exome sequencing",
author = "Barnett, {Christopher P.} and Nataren, {Nathalie J.} and Manuela Klingler-Hoffmann and Quenten Schwarz and Chong, {Chan Eng} and Lee, {Young K.} and Bruno, {Damien L.} and Jill Lipsett and Andrew McPhee and Schreiber, {Andreas W.} and Jinghua Feng and Hahn, {Christopher N.} and Scott, {Hamish S.}",
year = "2016",
month = "9",
day = "1",
doi = "10.1002/humu.23032",
language = "English",
volume = "37",
pages = "955--963",
journal = "Human mutation",
issn = "1059-7794",
publisher = "Wiley-Liss Inc.",
number = "9",

}

Barnett, CP, Nataren, NJ, Klingler-Hoffmann, M, Schwarz, Q, Chong, CE, Lee, YK, Bruno, DL, Lipsett, J, McPhee, A, Schreiber, AW, Feng, J, Hahn, CN & Scott, HS 2016, 'Ectrodactyly and Lethal Pulmonary Acinar Dysplasia Associated with Homozygous FGFR2 Mutations Identified by Exome Sequencing', Human Mutation, vol. 37, no. 9, pp. 955-963. https://doi.org/10.1002/humu.23032

Ectrodactyly and Lethal Pulmonary Acinar Dysplasia Associated with Homozygous FGFR2 Mutations Identified by Exome Sequencing. / Barnett, Christopher P.; Nataren, Nathalie J.; Klingler-Hoffmann, Manuela; Schwarz, Quenten; Chong, Chan Eng; Lee, Young K.; Bruno, Damien L.; Lipsett, Jill; McPhee, Andrew; Schreiber, Andreas W.; Feng, Jinghua; Hahn, Christopher N.; Scott, Hamish S.

In: Human Mutation, Vol. 37, No. 9, 01.09.2016, p. 955-963.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Ectrodactyly and Lethal Pulmonary Acinar Dysplasia Associated with Homozygous FGFR2 Mutations Identified by Exome Sequencing

AU - Barnett, Christopher P.

AU - Nataren, Nathalie J.

AU - Klingler-Hoffmann, Manuela

AU - Schwarz, Quenten

AU - Chong, Chan Eng

AU - Lee, Young K.

AU - Bruno, Damien L.

AU - Lipsett, Jill

AU - McPhee, Andrew

AU - Schreiber, Andreas W.

AU - Feng, Jinghua

AU - Hahn, Christopher N.

AU - Scott, Hamish S.

PY - 2016/9/1

Y1 - 2016/9/1

N2 - Ectrodactyly/split hand-foot malformation is genetically heterogeneous with more than 100 syndromic associations. Acinar dysplasia is a rare congenital lung lesion of unknown etiology, which is frequently lethal postnatally. To date, there have been no reports of combinations of these two phenotypes. Here, we present an infant from a consanguineous union with both ectrodactyly and autopsy confirmed acinar dysplasia. SNP array and whole-exome sequencing analyses of the affected infant identified a novel homozygous Fibroblast Growth Factor Receptor 2 (FGFR2) missense mutation (p.R255Q) in the IgIII domain (D3). Expression studies of Fgfr2 in development show localization to the affected limbs and organs. Molecular modeling and genetic and functional assays support that this mutation is at least a partial loss-of-function mutation, and contributes to ectrodactyly and acinar dysplasia only in homozygosity, unlike previously reported heterozygous activating FGFR2 mutations that cause Crouzon, Apert, and Pfeiffer syndromes. This is the first report of mutations in a human disease with ectrodactyly with pulmonary acinar dysplasia and, as such, homozygous loss-of-function FGFR2 mutations represent a unique syndrome.

AB - Ectrodactyly/split hand-foot malformation is genetically heterogeneous with more than 100 syndromic associations. Acinar dysplasia is a rare congenital lung lesion of unknown etiology, which is frequently lethal postnatally. To date, there have been no reports of combinations of these two phenotypes. Here, we present an infant from a consanguineous union with both ectrodactyly and autopsy confirmed acinar dysplasia. SNP array and whole-exome sequencing analyses of the affected infant identified a novel homozygous Fibroblast Growth Factor Receptor 2 (FGFR2) missense mutation (p.R255Q) in the IgIII domain (D3). Expression studies of Fgfr2 in development show localization to the affected limbs and organs. Molecular modeling and genetic and functional assays support that this mutation is at least a partial loss-of-function mutation, and contributes to ectrodactyly and acinar dysplasia only in homozygosity, unlike previously reported heterozygous activating FGFR2 mutations that cause Crouzon, Apert, and Pfeiffer syndromes. This is the first report of mutations in a human disease with ectrodactyly with pulmonary acinar dysplasia and, as such, homozygous loss-of-function FGFR2 mutations represent a unique syndrome.

KW - FGFR2

KW - acinar dysplasia

KW - ectrodactyly

KW - whole-exome sequencing

UR - http://www.scopus.com/inward/record.url?scp=84982216595&partnerID=8YFLogxK

U2 - 10.1002/humu.23032

DO - 10.1002/humu.23032

M3 - Article

VL - 37

SP - 955

EP - 963

JO - Human mutation

T2 - Human mutation

JF - Human mutation

SN - 1059-7794

IS - 9

ER -