Published 2023
| Version v1
Publication
CHAMP1-related disorders: pathomechanisms triggered by different genomic alterations define distinct nosological categories
Creators
- Amenta, S.
- Marangi, G.
- Orteschi, D.
- Frangella, S.
- Gurrieri, F.
- Paccagnella, E.
- Torella, A.
- Cappuccio, G.
- Musacchia, F.
- Mutarelli, M.
- Carrella, D.
- Vitiello, G.
- Parenti, G.
- Leuzzi, V.
- Selicorni, A.
- Maitz, S.
- Brunetti-Pierri, N.
- Banfi, S.
- Montomoli, M.
- Milani, D.
- Romano, C.
- Tummolo, A.
- De Brasi, D.
- Coppola, A.
- Santoro, C.
- Scala, M.
- Romano, F.
- Capra, V.
- Nigro, V.
- Zollino, M.
Contributors
Others:
- Amenta, S.
- Marangi, G.
- Orteschi, D.
- Frangella, S.
- Gurrieri, F.
- Paccagnella, E.
- Torella, A.
- Cappuccio, G.
- Musacchia, F.
- Mutarelli, M.
- Carrella, D.
- Vitiello, G.
- Parenti, G.
- Leuzzi, V.
- Selicorni, A.
- Maitz, S.
- Brunetti-Pierri, N.
- Banfi, S.
- Montomoli, M.
- Milani, D.
- Romano, C.
- Tummolo, A.
- De Brasi, D.
- Coppola, A.
- Santoro, C.
- Scala, M.
- Romano, F.
- Capra, V.
- Nigro, V.
- Zollino, M.
Description
Loss-of-function variants in CHAMP1 were recently described as cause of a neurodevelopmental disorder characterized by intellectual disability (ID), autism, and distinctive facial characteristics. By exome sequencing (ES), we identified a truncating variant in CHAMP1, c.1858A > T (p.Lys620*), in a patient who exhibited a similar phenotype of severe ID and dysmorphisms. Whether haploinsufficiency or a dominant negative effect is the underlying pathomechanism in these cases is a question that still needs to be addressed. By array-CGH, we detected a 194 kb deletion in 13q34 encompassing CHAMP1, CDC16 and UPF3, in another patient who presented with borderline neurodevelopmental impairment and with no dysmorphisms. In a further patient suffering from early onset refractory seizures, we detected by ES a missense variant in CHAMP1, c.67 G > A (p.Gly23Ser). Genomic abnormalities were all de novo in our patients. We reviewed the clinical and the genetic data of patients reported in the literature with: loss-of-function variants in CHAMP1 (total 40); chromosome 13q34 deletions ranging from 1.1 to 4 Mb (total 7) and of the unique patient with a missense variant. We could infer that loss-of-function variants in CHAMP1 cause a homogeneous phenotype with severe ID, autism spectrum disorders (ASD) and highly distinctive facial characteristics through a dominant negative effect. CHAMP1 haploinsufficiency results in borderline ID with negligible consequences on the quality of life. Missense variants give rise to a severe epileptic encephalopathy through gain-of-function mechanism, most likely. We tentatively define for the first time distinct categories among the CHAMP1-related disorder on the basis of pathomechanisms.
Additional details
Identifiers
- URL
- https://hdl.handle.net/11567/1119309
- URN
- urn:oai:iris.unige.it:11567/1119309
Origin repository
- Origin repository
- UNIGE