Genomic and phenotypic characterization of 404 individuals with neurodevelopmental disorders caused by CTNNB1 variants.
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Kayumi Sayaka, Pérez-Jurado Luis A, Palomares María, Rangu Sneha, Sheppard Sarah E, Chung Wendy K, Kruer Michael C, Kharbanda Mira, Amor David J, McGillivray George, Cohen Julie S, García-Miñaúr Sixto, van Eyk Clare L, Harper Kelly, Jolly Lachlan A, Webber Dani L, Barnett Christopher P, Santos-Simarro Fernando, Pacio-Míguez Marta, Pozo Angela Del, Bakhtiari Somayeh, Deardorff Matthew, Dubbs Holly A, Izumi Kosuke, Grand Katheryn, Gray Christopher, Mark Paul R, Bhoj Elizabeth J, Li Dong, Ortiz-Gonzalez Xilma R, Keena Beth, Zackai Elaine H, Goldberg Ethan M, Perez de Nanclares Guiomar, Pereda Arrate, Llano-Rivas Isabel, Arroyo Ignacio, Fernández-Cuesta María Ángeles, Thauvin-Robinet Christel, Faivre Laurence, Garde Aurore, Mazel Benoit, Bruel Ange-Line, Tress Michael L, Brilstra Eva, Fine Amena Smith, Crompton Kylie E, Stegmann Alexander P A, Sinnema Margje, Stevens Servi C J, Nicolai Joost, Lesca Gaetan, Lion-François Laurence, Haye Damien, Chatron Nicolas, Piton Amelie, Nizon Mathilde, Cogne Benjamin, Srivastava Siddharth, Bassetti Jennifer, Muss Candace, Gripp Karen W, Procopio Rebecca A, Millan Francisca, Morrow Michelle M, Assaf Melissa, Moreno-De-Luca Andres, Joss Shelagh, Hamilton Mark J, Bertoli Marta, Foulds Nicola, McKee Shane, MacLennan Alastair H, Gecz Jozef, Corbett Mark A
Аннотация
METHODS: Genetic information from 404 individuals with collectively 392 pathogenic CTNNB1 variants were ascertained for the study. From these, detailed phenotypes for 52 previously unpublished individuals were collected and combined with 68 previously published individuals with comparable clinical information. The functional effects of selected CTNNB1 missense variants were assessed using TOPFlash assay.
RESULTS: The phenotypes associated with pathogenic CTNNB1 variants were similar. A diagnosis of CP was not significantly associated with any set of traits that defined a specific phenotypic subgroup, indicating that CP is not additional to NEDSDV. Two CTNNB1 missense variants were dominant negative regulators of WNT signaling, highlighting the utility of the TOPFlash assay to functionally assess variants.
CONCLUSION: NEDSDV is a clinically homogeneous disorder irrespective of initial clinical diagnoses, including CP, or entry points for genetic testing.