Loss-of-function variants in ARHGEF9 are associated with an X-linked intellectual disability dominant disorder.

ARHGEF9 defects lead to an X-linked intellectual disability (XLID) disorder related to inhibitory synaptic dysfunction. This condition is more frequent in males with a few affected females reported. Up-to now, sequence variants and gross deletions have been identified in males, while only chromosomal aberrations have been reported in affected females who showed a skewed pattern of X-chromosome inactivation (XCI), suggesting an X-linked recessive (XLR) disorder. We report three novel loss-of-function (LoF) variants in ARHGEF9: a de novo synonymous variant affecting splicing (NM_015185.2: c.1056G>A, p.(Lys352=)) in one female; a nonsense variant in another female (c.865C>T, p.(Arg289*)) that is also present as a somatically mosaic variant in her father, and a de novo nonsense variant in a boy (c.899G>A; p.(Trp300*)). Both females showed a random XCI. Thus, we suggest that missense variants are responsible for an XLR disorder affecting males and that LoF variants, mainly occuring de novo, may be responsible for an X-Linked dominant (XLD) disorder affecting males and females. This article is protected by copyright. All rights reserved.