A novel Xp11.22 duplication involving HUWE1 in a male with syndromic intellectual disability and additional neurological findings

• Published in: European journal of medical genetics 2023-04, Vol.66 (4), p.104716-104716, Article 104716
• Main Authors: Santos-Rebouças, Cíntia B., Boy, Raquel, Fernandes, Gabriela N.S., Gonçalves, Andressa P., Abdala, Bianca B., Gonzalez, Lucas G.C., dos Santos, Jussara M., Pimentel, Márcia M.G.
• Format: Article
• Language: English
• Subjects: Chromosomes, Human, X; Female; Genes, X-Linked; Humans; HUWE1; Intellectual disability; Intellectual Disability - genetics; Male; Phenotype; Tumor Suppressor Proteins - genetics; Ubiquitin-Protein Ligases - genetics; X-chromosome inactivation; X-chromosome intellectual disability; Xp11.22 duplication
• ISSN: 1769-7212; 1878-0849
• DOI: 10.1016/j.ejmg.2023.104716

Sequence variants and duplications in the HECT, UBA and WWE domain –containing 1 (HUWE1) E3 ubiquitin ligase gene have been associated with X-linked mild to severe intellectual disability (ID), but a solid phenotype pattern among the affected males is still remaining to be established. Here, we report a male patient with sporadic, severe and syndromic ID, carrying a novel and unique 842 kb duplication at Xp11.22, including the dosage-sensitive HUWE1 gene and other fifteen curated RefSeq genes. Expression analysis in the patient and his female relatives confirmed increased HUWE1 mRNA levels, with different X-chromosome inactivation patterns among the female carriers. Our patient differs from those previously described by us and others as he presents encephalomalacia at brain Magnetic Resonance Imaging and diffuse bilaterally and synchronous intercritical irritating paroxysms at electroencephalogram. Overall, our clinical, molecular, and neurological findings sum up the previous data, expanding the phenotype spectrum in Xp11.22 copy gains involving the whole HUWE1 gene in both males and female carriers in light of X-chromosome inactivation patterns. •A novel duplication at Xp11.22 was identified in a male with Intellectual Disability.•The rearrangement includes the dosage-sensitive HUWE1 gene and other fifteen genes.•Expression analysis confirmed increased HUWE1 mRNA levels in the patient.•Different X-chromosome inactivation patterns were observed among the female carriers.•Our findings expand the phenotype, molecular and neurological spectrum in HUWE1 gains.