Further delineation of the female phenotype with <scp> <i>KDM5C</i> </scp> disease causing variants: 19 new individuals and review of the literature
Virginie Carmignac, Sophie Nambot, Daphné Lehalle, Patrick Callier, Stéphanie Moortgat, Valérie Benoît, Jamal Ghoumid, Bruno Delobel, Thomas Smol, C. Thuillier, Cécile Zordan, Sophie Naudion, Thierry Bienvenu, Renaud Touraine, Francis Ramond, Christiane Zweier, André Reis, Cornelia Kraus, Mathilde Nizon, Benjamin Cogné, Alain Verloès, Frédéric Tran Mau‐Them, Arthur Sorlin, Thibaud Jouan, Yannis Duffourd, Émilie Tisserant, Christophe Philippe, Antonio Vitobello, Julien Thévenon, Laurence Faivre, Christel Thauvin‐Robinet
Abstract
X-linked intellectual disability (XLID) is a genetically heterogeneous condition involving more than 100 genes. To date, 35 pathogenic variants have been reported in the lysine specific demethylase 5C (KDM5C) gene. KDM5C variants are one of the major causes of moderate to severe XLID. Affected males present with short stature, distinctive facial features, behavioral disorders, epilepsy, and spasticity. For most of these variants, related female carriers have been reported, but phenotypic descriptions were poor. Here, we present clinical and molecular features of 19 females carrying 10 novel heterozygous variants affecting KDM5C function, including five probands with de novo variants. Four heterozygous females were asymptomatic. All affected individuals presented with learning disabilities or ID (mostly moderate), and four also had a language impairment mainly affecting expression. Behavioral disturbances were frequent, and endocrine disorders were more frequent in females. In conclusion, our findings provide evidence of the role of KDM5C in ID in females highlighting the increasing implication of XLID genes in females, even in sporadic affected individuals. Disease expression of XLID in females should be taken into consideration for genetic counseling.