Journal
EUROPEAN JOURNAL OF PAEDIATRIC NEUROLOGY
Volume 21, Issue 5, Pages 745-753Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.ejpn.2017.04.641
Keywords
Fetal akinesia; Arthrogryposis multiplex congenita; RAPSN; PDHA1; Next generation sequencing
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Funding
- University Hospitals Leuven
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Introduction: Fetal akinesia deformation sequence (FADS) or arthrogryposis multiplex congenita (AMC) is characterized by clinical ambiguity and genetic heterogeneity, hampering genetic diagnosis via traditional sequencing methods. Next generation sequencing (NGS) of all known disease-causing genes offers an elegant solution to identify the genetic etiology of AMC/FADS in a diagnostic setting. Methods: An in-house developed disease-associated gene panel was conducted in two unrelated fetuses with FADS. First, a de novo analysis was performed on the entire disease associated gene panel. If no pathogenic mutation was identified, analysis of variants retained in a specific subpanel with arthrogryposis/fetal akinesia-causing genes was performed. Results: In the first family, FADS relates to a homozygous c.484G > A (p.G1u162Lys) mutation in the gene RAPSN. The second case concerns a sporadic patient with brain anomalies and arthrogryposis due to a de novo hemizygous c.498C > T splice-site mutation in the pyruvate dehydrogenase-alpha 1 (PDHA1) gene. Discussion: NGS facilitated genetic diagnosis, and hence genetic counseling, for both families with AMC/FADS. Biallelic RAPSN mutations typically result in congenital myasthenia syndrome, or occasionally in FADS. This is the first report attributing the RAPSN mutation c.484G > A, identified in a homozygous state in patient 1, to FADS. The second patient represents the first case of AMC due to a PDHA1 mutation, advocating that pyruvate dehydrogenase deficiency should be considered in the differential diagnosis of fetal aidnesia. This study illustrates the relevance of a disease-associated-gene panel as a diagnostic tool in pregnancies complicated by this genetically heterogeneous condition. (C) 2017 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
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