Titel: SCN1A-associated arthrogryposis multiplex cogenita – two new patients
ID: P-ClinG-072
Art: Postertalk
Redezeit: 2 min
Session: Poster Session
ClinG 2

Referent: Inga Nagel (Kiel/DE)

Abstract - Text


Arthrogryposis multiplex congenital (AMC) is the consequence of fetal akinesia with an incidence of 1:3000 to 1:5000. Apart from exogenous factors and maternal disease more than 400 genes are associated with this condition(1). Recently, three patients with AMC were described in whom a de novo pathogenic variant in SCN1A was diagnosed (2). SCN1A encodes the sodium channel protein type 1 subunit alpha which is a central component of the Nav 1.1. Pathogenic variants in SCN1A are associated with severe epilepsy disorders, including Dravet syndrome and generalised epilepsy with febrile seizures plus, but also other disorders such as hemiplegic migraine. Herein we present two patients with SCN1A-associated AMC.
Patient 1 is the first child of healthy non-consanguineous parents. The mother noticed no fetal movements. There was polyhydramnios. The child was born at 30+6 weeks of gestation by Caesarean section. She displayed nonimmunologic hydrops fetalis, akinesia and joint contractures of the distal upper and lower limbs. Clinical examinations revealed immature cortical gyration, enlarged cavum septum pellucidi, 11 pairs of ribs with a hypoplastic twelfth rib on the right, enlarged liver and fractures of the humerus and ribs. Due to the lack of self-breathing the infant was artificially ventilated. The patient died of multiple organ failure on the second day of life.
Patient 2 is the first child of healthy non-consanguineous parents. The father has two sons from an earlier partnership. At 27 weeks of gestation no fetal movements were present. Detailed sonography revealed polyhydramnios, hydrothorax, thin bones and retrognathia. Intrauterine fetal demise occurred in the 30th week of gestation. The prenatal findings could be confirmed.
In both patients chromosome analysis was performed, leading to a normal female (patient 1) respectively male karyotype (patient 2). In patient 1 trio exome sequencing was performed. In patient 2 a clinical exome was analysed with subsequent targeted analysis of the parents. In both families the affected child was diagnosed with a de novo variant in SCN1A confirmed by Sanger sequencing. The variant in patient 2 is identical to a variant which has already been reported in a patient with AMC (2).
Our results confirm that pathogenic variants in SCN1A are also associated with AMC. We propose that severe AMC should be added to the spectrum of phenotypes associated with pathogenic variants in SCN1A.

(1) Kiefer and Hall, Am J Med Genet 2019
(2) Jaber et al., J Med Genet 2021