Expanding the clinical and molecular spectrum of lethal congenital contracture syndrome 8 associated with biallelic variants of ADCY6

• Published in: Clinical genetics 2020-04, Vol.97 (4), p.649-654
• Main Authors: Agolini, Emanuele, Cherchi, Claudio, Bellacchio, Emanuele, Martinelli, Diego, Cocciadiferro, Dario, Cutrera, Renato, Chiarini Testa, Maria B., Barone, Chiara, Bianca, Sebastiano, Novelli, Antonio
• Format: Article
• Language: English
• Subjects: Adenylate cyclase; Arthrogryposis; Fetuses; Molecular modelling; Myelination; Phenotypes; Structure-function relationships
• ISSN: 0009-9163; 1399-0004
• DOI: 10.1111/cge.13691

Arthrogryposis multiplex congenita (AMC) is defined as congenital, non‐progressive contractures in more than two joints and in multiple body areas, resulting from reduced fetal mobility. So far, more than 400 causative genes for AMC have been identified. Some isolated AMC phenotypes arise as a result of mutations in genes encoding components required for motor neuron structure, function, and myelination, as in the case of ADCY6 encoding the enzyme adenylyl cyclase type 6. ADCY6 inactivation, due to biallelic variants, have been previously associated with the lethal congenital contracture syndrome 8 (LCCS8). So far, only four LCCS8 patients, from two families, have been reported. Here, we describe a new patient affected by a severe form of AMC, harboring two novel compound heterozygous variants in ADCY6. Our findings expand the clinical and mutational spectrum of LCCS8, showing a possible correlation between the impact of the ADCY6 missense variants reported to date, predicted by molecular modeling, and the severity of the phenotype.