title: Identification of KLHL40 mutations by targeted next-generation sequencing facilitated a prenatal diagnosis in a family with three consecutive affected fetuses with fetal akinesia deformation sequence.
abstract: BACKGROUND
  Fetal akinesia deformation sequence (FADS) refers to a broad spectrum of disorder with the absent fetal movement as the unifying feature. The etiology of FADS is heterogeneous, and the majority remains unknown. Prenatal diagnosis of FADS because of neuromuscular origin has relied on clinical features and fetal muscle pathology, which can be unrevealing. The recent advance of next-generation sequencing (NGS) can provide definitive molecular diagnosis effectively.
  
  
  RESULTS
  An 18-week-old fetus presented with akinesia and multiple contractures of joints. The mother had two previously aborted similarly affected fetuses. Clinical diagnosis of FADS was made. Molecular diagnosis using cord blood by NGS of genes related to neuromuscular diseases revealed two compound heterozygous mutations; c.602G > A(p.W201*) and c.1516A > C(p.T506P), in the Kelch-like 40 (KLHL40) gene. Based on this information, prenatal diagnosis was performed on the CVS of the subsequent pregnancy that resulted in an unaffected female baby, heterozygous for the c.1516A > C(p.T506P) mutation.
  
  
  CONCLUSIONS
  Identification of KLHL40 mutations in one of the aborted fetuses provided a confirmative diagnosis of FADS, facilitating the prenatal diagnosis of the subsequent pregnancy. This report underscores the importance of target NGS in providing FADS families with an affordable, precise molecular diagnosis for genetic counseling and options of prenatal diagnosis. © 2016 John Wiley & Sons, Ltd.
authors.affiliation: Division of Pediatric Emergency, Department of Emergency, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Tai-Heng
authors.initials: TH
authors.lastname: Chen
authors.affiliation: Baylor Genetics, Houston, TX, USA.
authors.forename: Xia
authors.initials: X
authors.lastname: Tian
authors.affiliation: Departments of Obstetrics and Gynecology, National Cheng Kung University Hospital, Tainan, Taiwan.
authors.forename: Pao-Lin
authors.initials: PL
authors.lastname: Kuo
authors.affiliation: Center for Medical Genetics, National Cheng Kung University Hospital, Tainan, Taiwan.
authors.forename: Hui-Ping
authors.initials: HP
authors.lastname: Pan
authors.affiliation: Baylor Genetics, Houston, TX, USA.|Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Lee-Jun C
authors.initials: LC
authors.lastname: Wong
authors.affiliation: Departments of Pediatrics and Laboratory Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.|Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.|Department of Biological Science and Technology, Institute of Molecular Medicine and Bioengineering, College of Biological Science and Technology, National Chiao Tung University, Hsinchu, Taiwan.
authors.forename: Yuh-Jyh
authors.initials: YJ
authors.lastname: Jong
mesh_terms: D000328:Adult; D001176:Arthrogryposis / Q000175:diagnosis / Q000235:genetics*; D015193:Chorionic Villi Sampling; D005260:Female; D005312:Fetal Blood; D005324:Fetal Movement; D006579:Heterozygote; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D009124:Muscle Proteins / Q000235:genetics*; D010375:Pedigree; D011247:Pregnancy; D011262:Pregnancy Trimester, Second; D011296:Prenatal Diagnosis
chemical_list: C000595273:KLHL40 protein, human; D009124:Muscle Proteins