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Loss‐of‐function variants in ARHGEF9 are associated with an X‐linked intellectual disability dominant disorder
Author(s) -
Ghesh Leïla,
Besnard Thomas,
Nizon Mathilde,
Trochu Eva,
LandeauTrottier Gaëlle,
Breheret Flora,
ThauvinRobinet Christel,
Bruel AngeLine,
Kuentz Paul,
Coubes Christine,
Cuisset Laurence,
Mignot Cyril,
Keren Boris,
Bézieau Stéphane,
Cogné Benjamin
Publication year - 2021
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.24188
Subject(s) - biology , missense mutation , nonsense , genetics , intellectual disability , x chromosome , x inactivation , loss function , nonsense mutation , nonsense mediated decay , skewed x inactivation , mutation , rna splicing , phenotype , gene , rna
ARHGEF9 defects lead to an X‐linked intellectual disability 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 occurring de novo, may be responsible for an X‐linked dominant disorder affecting males and females.