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.

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. P., Leuzzi, V., Selicorni, A., Maitz, S., Brunetti-Pierri, N., Banfi, S., Montomoli, M., Milani, D., Romano, M. C., Tummolo, A. A., De Brasi, D., Coppola, A., Santoro, C., Scala, M., Romano, F., Capra, V., Nigro, V., Zollino, M., CHAMP1-related disorders: pathomechanisms triggered by different genomic alterations define distinct nosological categories, <<EUROPEAN JOURNAL OF HUMAN GENETICS>>, 2023; (N/A): N/A-N/A. [doi:10.1038/s41431-023-01305-z] [https://hdl.handle.net/10807/232272]

CHAMP1-related disorders: pathomechanisms triggered by different genomic alterations define distinct nosological categories

Amenta, Simona;Marangi, Giuseppe
Primo
;
Frangella, Silvia;Gurrieri, Fiorella;Mutarelli, Massimiano;Parenti, Gian Paolo;Milani, Daniela;Romano, Maria Concetta;Tummolo, Aida Angela;Romano, Federica;Zollino, Marcella
Ultimo
2023

Abstract

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.
2023
Inglese
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. P., Leuzzi, V., Selicorni, A., Maitz, S., Brunetti-Pierri, N., Banfi, S., Montomoli, M., Milani, D., Romano, M. C., Tummolo, A. A., De Brasi, D., Coppola, A., Santoro, C., Scala, M., Romano, F., Capra, V., Nigro, V., Zollino, M., CHAMP1-related disorders: pathomechanisms triggered by different genomic alterations define distinct nosological categories, <<EUROPEAN JOURNAL OF HUMAN GENETICS>>, 2023; (N/A): N/A-N/A. [doi:10.1038/s41431-023-01305-z] [https://hdl.handle.net/10807/232272]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10807/232272
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