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DST variants are responsible for neurogenic arthrogryposis multiplex congenita enlarging the spectrum of type VI hereditary sensory autonomic neuropathy |
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| Authors: | Yline Capri Lucas Bourmance Céline Dupont Marie-Hélène Saint-Frison Fabien Guimiot Sarah Grotto Yvon Chitrit Annie Laquerrière Judith Melki |
| Affiliation: | 1. Clinical Genetics Unit, AP-HP Nord, Hôpital Robert Debré, Paris, France;2. Institut National de la Santé et de la Recherche Médicale (INSERM), UMR-1195, Université Paris Saclay, Le Kremlin Bicêtre, France;3. Cytogenetics Unit, AP-HP Nord, Hôpital Robert Debré, Paris, France;4. Foetopathology Unit, AP-HP Nord, Hôpital Robert Debré, Paris, France;5. Foetopathology Unit, AP-HP Nord, Hôpital Robert Debré, Paris, France INSERM UMR-1141, Université Paris Nord, Hôpital Robert Debré, Paris, France;6. Maternité Port-Royal, AP-HP Centre, Université Paris Cité, Hôpital Cochin, Paris, France;7. Obstetric Department, AP-HP Nord, Hôpital Robert Debré, Paris, France;8. Department of Pathology, Normandie Université, INSERM U1245, Rouen University Hospital, Rouen, France |
| Abstract: | Arthrogryposis multiplex congenita (AMC) is a developmental condition characterized by multiple joint contractures resulting from reduced or absent fetal movements. Through whole-exome sequencing combined with arrayCGH from DNA of a fetus presenting with early onset AMC, we identified biallelic loss of function variants in Dystonin (DST): a stop gain variant (NM_001144769.5:c.12208G > T:p.(Glu4070Ter)) on the neuronal isoform and a 175 kb microdeletion including exons 25–96 of this isoform on the other allele [NC_000006.11:g.(56212278_56323554)_(56499398_56507586)del]. Transmission electron microscopy of the sciatic nerve revealed abnormal morphology of the peripheral nerve with severe hypomyelination associated with dramatic reduction of fiber density which highlights the critical role of DST in peripheral nerve axonogenesis during development in human. Variants in the neuronal isoforms of DST cause hereditary sensory and autonomic neuropathy which has been reported in several unrelated families with highly variable age of onset from fetal to adult onset. Our data enlarge the disease mechanisms of neurogenic AMC. |
| Keywords: | arthrogryposis axogenesis DST gene HSAN6 whole exome sequencing |