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Ectrodactyly and Lethal Pulmonary Acinar Dysplasia Associated with Homozygous FGFR2 Mutations Identified by Exome Sequencing
Author(s) -
Barnett Christopher P.,
Nataren Nathalie J.,
KlinglerHoffmann Manuela,
Schwarz Quenten,
Chong ChanEng,
Lee Young K.,
Bruno Damien L.,
Lipsett Jill,
McPhee Andrew J.,
Schreiber Andreas W.,
Feng Jinghua,
Hahn Christopher N.,
Scott Hamish S.
Publication year - 2016
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.23032
Subject(s) - ectrodactyly , exome sequencing , biology , missense mutation , mutation , ectodermal dysplasia , genetics , loss function , exome , hypoplasia , phenotype , bronchopulmonary dysplasia , dysplasia , pathology , anatomy , medicine , gene , pregnancy , gestational age
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.