Massive parallel sequencing identifies RAPSN and PDHA1 mutations causing fetal akinesia deformation sequence

European Journal of Paediatric Neurology : EJPN : Official Journal of the European Paediatric Neurology Society
Lore WintersJeroen Breckpot

Abstract

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. 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. In the first family, FADS relates to a homozygous c.484G > A (p.Glu162Lys) 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. 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 r...Continue Reading

Citations

Jul 1, 2018·Journal of Medical Genetics·Sarah Jane BeecroftGianina Ravenscroft
Oct 31, 2019·Case Reports in Obstetrics and Gynecology·Masatake ToshimitsuJun Murotsuki
Nov 11, 2020·Scientific Reports·Ramona JühlenBirthe Fahrenkrog
Feb 15, 2020·European Journal of Medical Genetics·Berardo RinaldiKoenraad Devriendt

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