Clinical and Molecular Characterization of Xia-Gibbs Syndrome: Expanding the Phenotypic Spectrum in a Brazilian Cohort

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Sennes, Maisa Ganz Sanchez ; Carvalho, Laura Machado Lara ; Castro, Matheus Augusto Araujo ; Toccoli, Giovana Manilli ; Farias, Sofia de Oliveira ; Fialho, Davi Mendes Campo ; Bertollo, Eny Maria Goloni ; Pavarino, Erika Cristina ; de Athayde, Larissa Sampaio ; Buck, Cecilia Barbosa ; Toralles, Maria Betania Pereira ; Melaragno, Maria Isabel ; Riegel-Giugliani, Mariluce ; Spolador, Gustavo Marquezani ; Otto, Paulo Alberto ; Piai, Caroline Brandao ; Kok, Fernando ; Cechella, Ceres Schmitz ; Rosenberg, Carla ; Llerena, Juan Clinton ; Bertola, Debora Romeo ; Raskin, Salmo ; Kim, Chong Ae ; Krepischi, Ana Cristina Victorino

• Tipo de documento: Artigo Científico
• Fonte: Clinical Genetics; v. N/A, p. 10-pg., 2025-06-11.

Resumo

Xia-Gibbs syndrome (XGS) is a rare intellectual disability (ID) syndrome caused by de novo AHDC1 pathogenic variants. We characterized clinical and molecular features of 16 Brazilian patients with XGS. Patient data were collected through semistructured interviews with family members, reanalysis of previous health and genetic assessments, and clinical reports from physicians. Genomic variants and their segregation were validated via Sanger sequencing. Statistical analyses were conducted to evaluate genotype-phenotype associations. Twelve novel AHDC1 causative variants were documented. ID, hypotonia, motor developmental delay, and varied nonspecific facial dysmorphisms were observed in all patients, while speech impairment and autism spectrum disorder were present in nearly all. Three frequent phenotypes, not previously reported, were identified: hyperphagia/food obsession, genital/gonadal alterations in males, and shortening of the Achilles tendon. Additionally, our findings provide statistically significant support for previously reported genotype-phenotype associations between pathogenic variants in the first half of the AHDC1 coding region and the occurrence of epilepsy and scoliosis. We also propose a novel association between N-terminal variants and developmental regression. In summary, our results broaden the clinical phenotype of XGS, with musculoskeletal and genital/gonadal abnormalities highlighting the multisystem involvement in this condition, beyond neurodevelopmental deficits. Comprehensive phenotypic assessments in all identified XGS cases are recommended to accurately recognize and associate novel clinical signs with XGS. (AU)

• Processo FAPESP: 22/03980-5 - Estudo genômico e funcional de formas sindrômicas de deficiência intelectual
• Beneficiário: Laura Machado Lara Carvalho
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 23/16666-0 - Estudo funcional da síndrome de Xia-Gibbs: caracterização e análise de fenótipos do modelo de zebrafish ahdc1dsao1
• Beneficiário: Sofia de Oliveira Farias
• Modalidade de apoio: Bolsas no Brasil - Iniciação Científica
• Processo FAPESP: 23/07389-2 - Síndrome de Xia-Gibbs: caracterização molecular e clínica de série de casos brasileiros e estabelecimento de linhagens de células pluripotentes induzidas (iPSCs)
• Beneficiário: Maísa Ganz Sanchez Sennes
• Modalidade de apoio: Bolsas no Brasil - Iniciação Científica
• Processo FAPESP: 13/08028-1 - CEGH-CEL - Centro de Estudos do Genoma Humano e de Células-Tronco
• Beneficiário: Mayana Zatz
• Modalidade de apoio: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs
• Processo FAPESP: 23/16839-1 - Estudo transcriptômico de modelo de zebrafish para investigar mecanismos fisiopatológicos da síndrome de xia-gibbs
• Beneficiário: Davi Mendes Campos Fialho
• Modalidade de apoio: Bolsas no Brasil - Iniciação Científica
• Processo FAPESP: 23/09879-7 - Mecanismos genéticos e fisiopatológicos em distúrbios mendelianos do neurodesenvolvimento: investigação dos genes AHDC1 e EHMT2
• Beneficiário: Ana Cristina Victorino Krepischi
• Modalidade de apoio: Auxílio à Pesquisa - Regular