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

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.

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Publication Details

Journal
Clinical Genetics
Published
2025-06-11
DOI
https://doi.org/10.1111/cge.14777
Citations
1
Primary Topic
Genomics and Rare Diseases
Type
article
Field-Weighted Citation Impact
1.82

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article

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

Maria Betânia Pereira Toralles, Maria Isabel Melaragno, Gustavo Marquezani Spolador, Juan Clinton Llerena et al.
1 citations
Clinical Genetics
Genomics and Rare Diseases
1.82
article

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

Maria Betânia Pereira Toralles, Maria Isabel Melaragno, Gustavo Marquezani Spolador, Juan Clinton Llerena, Salmo Raskin, Davi Mendes Campo Fialho, Larissa Sampaio de Athayde, Érika Cristina Pavarino, Carla Rosenberg, Ana Cristina Victorino Krepischi, Matheus Augusto Araújo Castro, Eny Maria Goloni‐Bertollo, Laura Machado Lara Carvalho, Paulo Alberto Otto, Cecília Barbosa Buck, Fernando Kok, Débora Romeo Bertola, Mariluce Riegel, Caroline Brandão Piai, Giovana Manilli Toccoli, Chong Ae Kim, Sofia de Oliveira Farias, Maísa Ganz Sanchez Sennes, Ceres Schmitz Cechella
article en
1 citations

Abstract

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.

Clinical GeneticsVol. 108(6)
Universidade Federal da Bahia (BR), Faculdade de Medicina de São José do Rio Preto (BR), Universidade de São Paulo (BR), Anhembi Morumbi University (BR), Santa Casa Hospital (BR), Novo Nordisk (Mexico) (MX), Mendelics (BR), Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (BR), Fundação Oswaldo Cruz (BR), Universidade Federal do Paraná (BR), Universidade Federal de São Paulo (BR)
Fundação de Amparo à Pesquisa do Estado de São Paulo, Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
Openalex Percentile: Top 15%
Genomics and Rare Diseases
1.82
DOIOpen Access PDFOpenAlex
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