Exome analysis of Brazilian patients with intellectual disability born to consanguineous parents highlights candidate genes

Background Intellectual disability is a genetically heterogeneous condition in which molecular diagnosis plays a crucial role in guiding clinical management, prognosis, and reproductive planning. Consanguinity increases homozygosity, providing a unique context to uncover genes underlying recessive disorders. Methods We investigated 32 unrelated Brazilian individuals with intellectual disability born to consanguineous parents, all negative for copy number variants and fragile X syndrome. Exome sequencing was performed to identify causative variants and runs of homozygosity were analyzed to estimate parental relatedness. Results Clinically relevant variants—classified as pathogenic, likely pathogenic, or of uncertain significance (VUS)—were detected in 16 patients (50%). Pathogenic or likely pathogenic variants in established disease genes were identified in 12 patients, involving SCAF4, DOCK7, ADK, QRICH1, PUF60, PCNA, KIF7, MYO1H, SNX14, MTFMT, AP4S1 , and ARID1B . In addition, a likely pathogenic variant was identified in EHMT2 , an emerging candidate gene. Overall, molecular diagnosis was achieved in 13/32 patients, corresponding to a diagnostic yield of 41%; most diagnosed cases were associated with recessive inheritance (69%). Three patients carried VUS: one in an established disease gene ( MAN1B1 ) and two in candidate genes ( TRAPPC6A and WAPL ). Conclusion These findings further support the value of including individuals born to consanguineous parents in genomic studies of intellectual disability, as this can broaden the discovery of candidate disease genes for future functional studies and clinical validation and expand the knowledge base for molecular diagnosis, with potential implications for genetic counseling, reproductive planning, and clinical management. As a broader principle, these findings have diagnostic and biological relevance across populations.

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Journal
Frontiers in Genetics
Published
2026-11-08
DOI
https://doi.org/10.3389/fgene.2026.1834720
Primary Topic
Genomics and Rare Diseases
Type
article
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article

Exome analysis of Brazilian patients with intellectual disability born to consanguineous parents highlights candidate genes

Philip M. Boone, Marília O. Scliar, Sadegheh Haghshenas, Davi Mendes Campo Fialho et al.
2 links
Frontiers in Genetics
Genomics and Rare Diseases
article

Exome analysis of Brazilian patients with intellectual disability born to consanguineous parents highlights candidate genes

Philip M. Boone, Marília O. Scliar, Sadegheh Haghshenas, Davi Mendes Campo Fialho, Silvia Souza da Costa, Guilherme Lopes Yamamoto, Carla Rosenberg, Amanda Shinzato, Jaqueline Yu Ting Wang, Giovanna Cantini Tolezano, Laura Machado Lara Carvalho, Paulo Alberto Otto, Gabriel Pires, Débora Romeo Bertola, Angela Maria Vianna‐Morgante, Bekim Sadiković, Ana Claudia Dantas Machado, Gustavo Dib Dangoni, Luciana E. S. F. Machado, Haley McConkey, Sofia de Oliveira Farias, Maísa Ganz Sanchez Sennes, Bianca Mie Sato Kurashima, Beatriz Cristina de Oliveira, Esther Bordin Lupion, Ana Krepischi, Victor Hugo Calegari de Toledo, Priscila de Oliveira Candido
article en

Abstract

Background Intellectual disability is a genetically heterogeneous condition in which molecular diagnosis plays a crucial role in guiding clinical management, prognosis, and reproductive planning. Consanguinity increases homozygosity, providing a unique context to uncover genes underlying recessive disorders. Methods We investigated 32 unrelated Brazilian individuals with intellectual disability born to consanguineous parents, all negative for copy number variants and fragile X syndrome. Exome sequencing was performed to identify causative variants and runs of homozygosity were analyzed to estimate parental relatedness. Results Clinically relevant variants—classified as pathogenic, likely pathogenic, or of uncertain significance (VUS)—were detected in 16 patients (50%). Pathogenic or likely pathogenic variants in established disease genes were identified in 12 patients, involving SCAF4, DOCK7, ADK, QRICH1, PUF60, PCNA, KIF7, MYO1H, SNX14, MTFMT, AP4S1 , and ARID1B . In addition, a likely pathogenic variant was identified in EHMT2 , an emerging candidate gene. Overall, molecular diagnosis was achieved in 13/32 patients, corresponding to a diagnostic yield of 41%; most diagnosed cases were associated with recessive inheritance (69%). Three patients carried VUS: one in an established disease gene ( MAN1B1 ) and two in candidate genes ( TRAPPC6A and WAPL ). Conclusion These findings further support the value of including individuals born to consanguineous parents in genomic studies of intellectual disability, as this can broaden the discovery of candidate disease genes for future functional studies and clinical validation and expand the knowledge base for molecular diagnosis, with potential implications for genetic counseling, reproductive planning, and clinical management. As a broader principle, these findings have diagnostic and biological relevance across populations.

Frontiers in GeneticsVol. 17
Western University (CA), Boston Children's Hospital (US), Universidade de São Paulo (BR), Universidade Estadual de Campinas (UNICAMP) (BR), London Health Sciences Centre (CA), Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (BR)
Fundação de Amparo à Pesquisa do Estado de São Paulo, Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, Conselho Nacional de Desenvolvimento Científico e Tecnológico, Universidade de São Paulo
Good health and well-being
Genomics and Rare Diseases
DOIOpen Access PDFOpenAlex
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