title: Identification of three novel FGF16 mutations in X-linked recessive fusion of the fourth and fifth metacarpals and possible correlation with heart disease.
abstract: Nonsense mutations in FGF16 have recently been linked to X-linked recessive hand malformations with fusion between the fourth and the fifth metacarpals and hypoplasia of the fifth digit (MF4; MIM#309630). The purpose of this study was to perform careful clinical phenotyping and to define molecular mechanisms behind X-linked recessive MF4 in three unrelated families. We performed whole-exome sequencing, and identified three novel mutations in FGF16. The functional impact of FGF16 loss was further studied using morpholino-based suppression of fgf16 in zebrafish. In addition, clinical investigations revealed reduced penetrance and variable expressivity of the MF4 phenotype. Cardiac disorders, including myocardial infarction and atrial fibrillation followed the X-linked FGF16 mutated trait in one large family. Our findings establish that a mutation in exon 1, 2 or 3 of FGF16 results in X-linked recessive MF4 and expand the phenotypic spectrum of FGF16 mutations to include a possible correlation with heart disease.
authors.affiliation: Department of Molecular Medicine and Surgery and Center of Molecular Medicine, Karolinska Institutet Stockholm, Sweden ; Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet Stockholm, Sweden ; Department of Hand Surgery, Södersjukhuset Stockholm, Sweden.
authors.forename: Tobias
authors.initials: T
authors.lastname: Laurell
authors.affiliation: Department of Molecular Medicine and Surgery and Center of Molecular Medicine, Karolinska Institutet Stockholm, Sweden ; Department of Clinical Genetics, Karolinska University Hospital Stockholm, Sweden ; Science for Life Laboratory, Karolinska Institutet Science Park Stockholm, Sweden.
authors.forename: Daniel
authors.initials: D
authors.lastname: Nilsson
authors.affiliation: Department of Molecular Medicine and Surgery and Center of Molecular Medicine, Karolinska Institutet Stockholm, Sweden.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Hofmeister
authors.affiliation: Department of Molecular Medicine and Surgery and Center of Molecular Medicine, Karolinska Institutet Stockholm, Sweden ; Department of Clinical Genetics, Karolinska University Hospital Stockholm, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Lindstrand
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, University of California San Francisco San Francisco ; Institute for Human Genetics, University of California San Francisco San Francisco.
authors.forename: Nadav
authors.initials: N
authors.lastname: Ahituv
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, University of California San Francisco San Francisco ; Institute for Human Genetics, University of California San Francisco San Francisco.
authors.forename: Julia
authors.initials: J
authors.lastname: Vandermeer
authors.affiliation: Department of Hand Surgery, Örebro University Hospital Örebro, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Amilon
authors.affiliation: Department of Immunology Genetics and Pathology Science for Life Laboratory, Uppsala University Uppsala, Sweden.
authors.forename: Göran
authors.initials: G
authors.lastname: Annerén
authors.affiliation: Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet Stockholm, Sweden ; Department of Hand Surgery, Södersjukhuset Stockholm, Sweden.
authors.forename: Marianne
authors.initials: M
authors.lastname: Arner
authors.affiliation: Department of Molecular Medicine and Surgery and Center of Molecular Medicine, Karolinska Institutet Stockholm, Sweden.
authors.forename: Maria
authors.initials: M
authors.lastname: Pettersson
authors.affiliation: Department of Molecular Medicine and Surgery and Center of Molecular Medicine, Karolinska Institutet Stockholm, Sweden.
authors.forename: Nina
authors.initials: N
authors.lastname: Jäntti
authors.affiliation: Department of Clinical Sciences Malmö Section of Hand Surgery, Lund University Malmö, Sweden ; Department of Hand Surgery, Skåne University Hospital Malmö, Sweden.
authors.forename: Hans-Eric
authors.initials: HE
authors.lastname: Rosberg
authors.affiliation: Department of Physiology, University of Manitoba Canada.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Cattini
authors.affiliation: Department of Women's and Children's Health and Center of Molecular Medicine, Karolinska Institutet Stockholm, Sweden ; Unit of Paediatric Surgery Astrid Lindgren Children's Hospital, Karolinska University Hospital Stockholm, Sweden.
authors.forename: Agneta
authors.initials: A
authors.lastname: Nordenskjöld
authors.affiliation: Department of Molecular Medicine and Surgery and Center of Molecular Medicine, Karolinska Institutet Stockholm, Sweden ; Department of Clinical Genetics, Karolinska University Hospital Stockholm, Sweden ; Folkhälsan Institute of Genetics Helsinki, Finland.
authors.forename: Outi
authors.initials: O
authors.lastname: Mäkitie
authors.affiliation: Department of Molecular Medicine and Surgery and Center of Molecular Medicine, Karolinska Institutet Stockholm, Sweden ; Department of Clinical Genetics, Karolinska University Hospital Stockholm, Sweden.
authors.forename: Giedre
authors.initials: G
authors.lastname: Grigelioniene
authors.affiliation: Department of Molecular Medicine and Surgery and Center of Molecular Medicine, Karolinska Institutet Stockholm, Sweden ; Department of Clinical Genetics, Karolinska University Hospital Stockholm, Sweden.
authors.forename: Ann
authors.initials: A
authors.lastname: Nordgren
keywords: FGF16; MF4; heart; metacarpal fusion