Ectrodactyly and Lethal Pulmonary Acinar Dysplasia Associated with Homozygous FGFR2 Mutations Identified by Exome Sequencing.
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.
SA Clinical Genetics, Women's and Children's Hospital/SA Pathology, North Adelaide, SA, Australia.|School of Biological Sciences, University of Adelaide, SA, Australia.
Christopher P
CP
Barnett
School of Biological Sciences, University of Adelaide, SA, Australia.|Department of Genetics and Molecular Pathology, Centre for Cancer Biology, SA Pathology, Adelaide, SA, Australia.|Centre for Cancer Biology, An Alliance between SA Pathology and the University of South Australia, SA, Australia.
Nathalie J
NJ
Nataren
School of Biological Sciences, University of Adelaide, SA, Australia.|Department of Genetics and Molecular Pathology, Centre for Cancer Biology, SA Pathology, Adelaide, SA, Australia.|Centre for Cancer Biology, An Alliance between SA Pathology and the University of South Australia, SA, Australia.
Manuela
M
Klingler-Hoffmann
Centre for Cancer Biology, An Alliance between SA Pathology and the University of South Australia, SA, Australia.
Quenten
Q
Schwarz
Department of Genetics and Molecular Pathology, Centre for Cancer Biology, SA Pathology, Adelaide, SA, Australia.
Chan-Eng
CE
Chong
Department of Genetics and Molecular Pathology, Centre for Cancer Biology, SA Pathology, Adelaide, SA, Australia.
Young K
YK
Lee
Cytogenetics Laboratory, Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Australia.
Damien L
DL
Bruno
Department of Neonatal Medicine, Women's and Children's Hospital, North Adelaide, SA, Australia.
Jill
J
Lipsett
School of Medicine, University of Adelaide, SA, Australia.|Department of Anatomical Pathology, Women's and Children's Hospital/SA Pathology, North Adelaide, SA, Australia.
Andrew J
AJ
McPhee
School of Biological Sciences, University of Adelaide, SA, Australia.|Centre for Cancer Biology, An Alliance between SA Pathology and the University of South Australia, SA, Australia.|ACRF Cancer Genomics Facility, Centre for Cancer Biology, SA Pathology, SA, Australia.
Andreas W
AW
Schreiber
School of Biological Sciences, University of Adelaide, SA, Australia.|Centre for Cancer Biology, An Alliance between SA Pathology and the University of South Australia, SA, Australia.|ACRF Cancer Genomics Facility, Centre for Cancer Biology, SA Pathology, SA, Australia.
Jinghua
J
Feng
Department of Genetics and Molecular Pathology, Centre for Cancer Biology, SA Pathology, Adelaide, SA, Australia.|Centre for Cancer Biology, An Alliance between SA Pathology and the University of South Australia, SA, Australia.|School of Medicine, University of Adelaide, SA, Australia.
Christopher N
CN
Hahn
School of Biological Sciences, University of Adelaide, SA, Australia.|Department of Genetics and Molecular Pathology, Centre for Cancer Biology, SA Pathology, Adelaide, SA, Australia.|Centre for Cancer Biology, An Alliance between SA Pathology and the University of South Australia, SA, Australia.|School of Medicine, University of Adelaide, SA, Australia.|ACRF Cancer Genomics Facility, Centre for Cancer Biology, SA Pathology, SA, Australia.
Hamish S
HS
Scott
D003241:Consanguinity; D017809:Fatal Outcome; D005260:Female; D006720:Homozygote; D006801:Humans; D007231:Infant, Newborn; D017880:Limb Deformities, Congenital / Q000235:genetics*; D000073658:Loss of Function Mutation; D008171:Lung Diseases / Q000151:congenital* / Q000235:genetics*; D020125:Mutation, Missense; D000072417:Protein Domains; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000737:chemistry / Q000235:genetics*
C496353:FGFR2 protein, human; D051497:Receptor, Fibroblast Growth Factor, Type 2
FGFR2; acinar dysplasia; ectrodactyly; whole-exome sequencing