Exome analysis of Brazilian patients with intellectual disability born to consanguineous parents highlights candidate genes
Year: 2026
Type: article
Study design: Observational Study
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.
Source: Frontiers in Genetics
Authors: Laura Machado Lara Carvalho, Ana Claudia Dantas Machado, Giovanna Cantini Tolezano, Davi Mendes Campos Fialho, Amanda Shinzato, Priscila de Oliveira Candido, Beatriz Cristina de Oliveira, Gustavo Dib Dangoni, Maisa Ganz Sanchez Sennes, Jaqueline Yu Ting Wang, Victor Hugo Calegari de Toledo, Marilia de Oliveira Scliar, Sofia de Oliveira Farias, Bianca Mie Sato Kurashima, Esther Bordin Lupion, Gabriel Pires, Luciana Elena de Souza Fraga Machado, Silvia Costa, Sadegheh Haghshenas, Haley McConkey, Bekim Sadikovic, Philip M. Boone, Paulo Alberto Otto, Angela M. Vianna-Morgante, Guilherme Yamamoto, Débora Romeo Bertola, Carla Rosenberg, Ana Cristina Victorino Krepischi
Language: English
Topic: Genomics and Rare Diseases
Subfield: Genetics
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,801
OpenAlex ID: W7225579500