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Gene: HUWE1

Green List (high evidence)

Turner-type X-linked syndromic intellectual developmental disorder (MRXST) is a neurodevelopmental disorder with a highly variable phenotype. Affected individuals show global developmental delay from infancy, with variably impaired intellectual development and poor or absent speech, often with delayed walking. Dysmorphic features are common and can include macrocephaly, microcephaly, deep-set eyes, hypotelorism, small palpebral fissures, dysplastic, large, or low-set ears, long face, bitemporal narrowing, high-arched palate, thin upper lip, and scoliosis or mild distal skeletal anomalies, such as brachydactyly or tapered fingers. Males tend to have cryptorchidism. Other features, such as hypotonia, seizures, and delayed bone age, are more variable.

Some affected families show X-linked recessive inheritance, with only males being affected and carrier females having no abnormal findings. In other affected families, males are severely affected, and female mutation carriers show milder cognitive abnormalities or dysmorphic features. In addition, there are female patients with de novo mutations who show the full phenotype, despite skewed X-chromosome inactivation.

Both LoF and GoF shown for missense variants (PMID:27130160), and duplications and microduplications involving HUWE1 leading to GoF have been reported. Primarily missense variants, only few PTVs reported (ClinVar) as it is thought that complete LoF is lethal (especially males).

Created: 15 Oct 2024, 11:19 p.m. | Last Modified: 15 Oct 2024, 11:19 p.m.

Panel Version: 1.420

Mode of inheritance
X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)

Phenotypes
Intellectual developmental disorder, X-linked syndromic, Turner type, MIM#309590

Publications

• 29180823
• 7943042
• 27130160

Mode of pathogenicity
Other