Maria Wilbe1, Sara Ekvall1, Karin Eurenius2, Katharina Ericson3, Olivera Casar-Borota3, Joakim Klar1, Niklas Dahl1, Adam Ameur1, Göran Annerén1, Marie-Louise Bondeson1. 1. Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden. 2. Department of Women's and Children's Health, Uppsala University, Uppsala, Sweden. 3. Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden Department of Pathology and Cytology, Uppsala University Hospital, Uppsala, Sweden.
Abstract
BACKGROUND: Fetal akinesia deformation sequence syndrome (FADS, OMIM 208150) is characterised by decreased fetal movement (fetal akinesia) as well as intrauterine growth restriction, arthrogryposis, and developmental anomalies (eg, cystic hygroma, pulmonary hypoplasia, cleft palate, and cryptorchidism). Mutations in components of the acetylcholine receptor (AChR) pathway have previously been associated with FADS. METHODS AND RESULTS: We report on a family with recurrent fetal loss, where the parents had five affected fetuses/children with FADS and one healthy child. The fetuses displayed no fetal movements from the gestational age of 17 weeks, extended knee joints, flexed hips and elbows, and clenched hands. Whole exome sequencing of one affected fetus and the parents was performed. A novel homozygous frameshift mutation was identified in muscle, skeletal receptor tyrosine kinase (MuSK), c.40dupA, which segregated with FADS in the family. Haplotype analysis revealed a conserved haplotype block suggesting a founder mutation. MuSK (muscle-specific tyrosine kinase receptor), a component of the AChR pathway, is a main regulator of neuromuscular junction formation and maintenance. Missense mutations in MuSK have previously been reported to cause congenital myasthenic syndrome (CMS) associated with AChR deficiency. CONCLUSIONS: To our knowledge, this is the first report showing that a mutation in MuSK is associated with FADS. The results support previous findings that CMS and/or FADS are caused by complete or severe functional disruption of components located in the AChR pathway. We propose that whereas milder mutations of MuSK will cause a CMS phenotype, a complete loss is lethal and will cause FADS. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
BACKGROUND:Fetal akinesia deformation sequence syndrome (FADS, OMIM 208150) is characterised by decreased fetal movement (fetal akinesia) as well as intrauterine growth restriction, arthrogryposis, and developmental anomalies (eg, cystic hygroma, pulmonary hypoplasia, cleft palate, and cryptorchidism). Mutations in components of the acetylcholine receptor (AChR) pathway have previously been associated with FADS. METHODS AND RESULTS: We report on a family with recurrent fetal loss, where the parents had five affected fetuses/children with FADS and one healthy child. The fetuses displayed no fetal movements from the gestational age of 17 weeks, extended knee joints, flexed hips and elbows, and clenched hands. Whole exome sequencing of one affected fetus and the parents was performed. A novel homozygous frameshift mutation was identified in muscle, skeletal receptor tyrosine kinase (MuSK), c.40dupA, which segregated with FADS in the family. Haplotype analysis revealed a conserved haplotype block suggesting a founder mutation. MuSK (muscle-specific tyrosine kinase receptor), a component of the AChR pathway, is a main regulator of neuromuscular junction formation and maintenance. Missense mutations in MuSK have previously been reported to cause congenital myasthenic syndrome (CMS) associated with AChR deficiency. CONCLUSIONS: To our knowledge, this is the first report showing that a mutation in MuSK is associated with FADS. The results support previous findings that CMS and/or FADS are caused by complete or severe functional disruption of components located in the AChR pathway. We propose that whereas milder mutations of MuSK will cause a CMS phenotype, a complete loss is lethal and will cause FADS. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
Authors: Yavuz Bayram; Ender Karaca; Zeynep Coban Akdemir; Elif Ozdamar Yilmaz; Gulsen Akay Tayfun; Hatip Aydin; Deniz Torun; Sevcan Tug Bozdogan; Alper Gezdirici; Sedat Isikay; Mehmed M Atik; Tomasz Gambin; Tamar Harel; Ayman W El-Hattab; Wu-Lin Charng; Davut Pehlivan; Shalini N Jhangiani; Donna M Muzny; Ali Karaman; Tamer Celik; Ozge Ozalp Yuregir; Timur Yildirim; Ilhan A Bayhan; Eric Boerwinkle; Richard A Gibbs; Nursel Elcioglu; Beyhan Tuysuz; James R Lupski Journal: J Clin Invest Date: 2016-01-11 Impact factor: 14.808
Authors: Sunayna Best; Karen Wou; Neeta Vora; Ignatia B Van der Veyver; Ronald Wapner; Lyn S Chitty Journal: Prenat Diagn Date: 2017-07-25 Impact factor: 3.050
Authors: Emily J Todd; Kyle S Yau; Royston Ong; Jennie Slee; George McGillivray; Christopher P Barnett; Goknur Haliloglu; Beril Talim; Zuhal Akcoren; Ariana Kariminejad; Anita Cairns; Nigel F Clarke; Mary-Louise Freckmann; Norma B Romero; Denise Williams; Caroline A Sewry; Alison Colley; Monique M Ryan; Cathy Kiraly-Borri; Padma Sivadorai; Richard J N Allcock; David Beeson; Susan Maxwell; Mark R Davis; Nigel G Laing; Gianina Ravenscroft Journal: Orphanet J Rare Dis Date: 2015-11-17 Impact factor: 4.123