Targeted Next-Generation Sequencing in Patients with Suggestive X-Linked Intellectual Disability

• Published in: Genes Vol. 11; no. 1; p. 51
• Main Authors: Ibarluzea, Nekane, Hoz, Ana Belén de la, Villate, Olatz, Llano, Isabel, Ocio, Intzane, Martí, Itxaso, Guitart, Miriam, Gabau, Elisabeth, Andrade, Fernando, Gener, Blanca, Tejada, María-Isabel
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 02.01.2020; MDPI
• Subjects: Families & family life; Fragile X syndrome; gene panel; Genes; Genetic diversity; huwe1; Huwe1 protein; Intellectual disabilities; iqsec2; Males; med12; Mutation; Next-generation sequencing; phf8; slc6a8; slc9a6; Software; syn1; X chromosomes; x-linked intellectual disability; United States > US; MED12; SLC6A8; IQSEC2; SLC9A6; next-generation sequencing; HUWE1; X-linked intellectual disability; SYN1; PHF8; gene panel
• ISSN: 2073-4425; 2073-4425
• DOI: 10.3390/genes11010051

X-linked intellectual disability (XLID) is known to contribute up to 10% of intellectual disability (ID) in males and could explain the increased ratio of affected males observed in patients with ID. Over the past decade, next-generation sequencing has clearly stimulated the gene discovery process and has become part of the diagnostic procedure. We have performed targeted next-generation sequencing of 82 XLID genes on 61 non-related male patients with suggestive non-syndromic XLID. These patients were initially referred to the molecular genetics laboratory to exclude Fragile X Syndrome. The cohort includes 47 male patients with suggestive X-linked family history of ID meaning that they had half-brothers or maternal cousins or uncles affected; and 14 male patients with ID and affected brothers whose mothers show skewed X-inactivation. Sequencing data analysis identified 17 candidate variants in 16 patients. Seven families could be re-contacted and variant segregation analysis of the respective eight candidate variants was performed: , , , , , , and . Our results show the utility of targeted next-generation sequencing in unravelling the genetic origin of XLID, especially in retrospective cases. Variant segregation and additional studies like RNA sequencing and biochemical assays also helped in re-evaluating and further classifying the genetic variants found.