HUWE1 variants cause dominant X-linked intellectual disability
2018
Whole-
gene duplicationsand missense variants in the HUWE1 gene (NM_031407.6) have been reported in association with intellectual disability (ID). Increased
gene dosagehas been observed in males with non-syndromic mild to moderate ID with
speech delay. Missense variants reported previously appear to be associated with severe ID in males and mild or no ID in
obligate carrierfemales. Here, we report the largest cohort of patients with HUWE1 variants, consisting of 14 females and 7 males, with 15 different missense variants and one splice site variant. Clinical assessment identified common clinical features consisting of moderate to profound ID, delayed or absent speech,
short staturewith small hands and feet and
facial dysmorphismconsisting of a broad nasal tip, deep set eyes,
epicanthic folds, short
palpebral fissures, and a short
philtrum. We describe for the first time that females can be severely affected, despite preferential inactivation of the affected X chromosome. Three females with the c.329 G > A p.Arg110Gln variant, present with a phenotype of mild ID, specific facial features, scoliosis and
craniosynostosis, as reported previously in a single patient. In these females, the
X inactivationpattern appeared skewed in favour of the affected transcript. In summary, HUWE1 missense variants may cause syndromic ID in both males and females.
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