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

Genes (Basel). 2020 Jan 2;11(1):51. 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: HUWE1, IQSEC2, MAOA, MED12, PHF8, SLC6A8, SLC9A6, and SYN1. 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.

Keywords: HUWE1; IQSEC2; MED12; PHF8; SLC6A8; SLC9A6; SYN1; X-linked intellectual disability; gene panel; next-generation sequencing.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Child
  • Child, Preschool
  • Cohort Studies
  • Exome / genetics
  • Exome Sequencing / methods
  • Fragile X Syndrome
  • Genes, X-Linked / genetics
  • Guanine Nucleotide Exchange Factors / genetics
  • High-Throughput Nucleotide Sequencing / methods*
  • Humans
  • Infant
  • Intellectual Disability / genetics
  • Male
  • Mediator Complex / genetics
  • Mental Retardation, X-Linked / diagnosis*
  • Mental Retardation, X-Linked / genetics*
  • Monoamine Oxidase / genetics
  • Mutation / genetics
  • Nerve Tissue Proteins / genetics
  • Pedigree
  • Plasma Membrane Neurotransmitter Transport Proteins / genetics
  • Retrospective Studies
  • Sodium-Hydrogen Exchangers / genetics
  • Transcription Factors


  • Guanine Nucleotide Exchange Factors
  • IQSEC2 protein, human
  • MED12 protein, human
  • Mediator Complex
  • Nerve Tissue Proteins
  • Plasma Membrane Neurotransmitter Transport Proteins
  • SLC6A8 protein, human
  • SLC9A6 protein, human
  • Sodium-Hydrogen Exchangers
  • Transcription Factors
  • Monoamine Oxidase
  • monoamine oxidase A, human