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. 2020 Jul;98(1):43-55.
doi: 10.1111/cge.13755. Epub 2020 May 29.

Further delineation of the female phenotype with KDM5C disease causing variants: 19 new individuals and review of the literature

Virginie Carmignac  1   2 , Sophie Nambot  1   3   4   5 , Daphné Lehalle  3 , Patrick Callier  1   4   5 , Stephanie Moortgat  6 , Valérie Benoit  6 , Jamal Ghoumid  7   8 , Bruno Delobel  9 , Thomas Smol  8   10 , Caroline Thuillier  10 , Cécile Zordan  11 , Sophie Naudion  11 , Thierry Bienvenu  12   13   14 , Renaud Touraine  15 , Francis Ramond  15 , Christiane Zweier  16 , André Reis  16 , Cornelia Kraus  16 , Mathilde Nizon  17 , Benjamin Cogné  17 , Alain Verloes  18 , Frédéric Tran Mau-Them  1   4 , Arthur Sorlin  1   3   4 , Thibaud Jouan  1 , Yannis Duffourd  1   5 , Emilie Tisserant  1   5 , Christophe Philippe  1   4 , Antonio Vitobello  1   4 , Julien Thevenon  1   3   5 , Laurence Faivre  1   3   4   5 , Christel Thauvin-Robinet  1   4   5   19
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Further delineation of the female phenotype with KDM5C disease causing variants: 19 new individuals and review of the literature

Virginie Carmignac et al. Clin Genet. 2020 Jul.

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.

Keywords: KDM5C; X-linked intellectual disability; data-sharing; exome; females.

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References

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