Int22h1/Int22h2-mediated Xq28 duplication syndrome: de novo duplications, prenatal diagnoses, and additional phenotypic features

Hum Mutat. 2020 Jul;41(7):1238-1249. doi: 10.1002/humu.24009. Epub 2020 Mar 12.


Int22h1/Int22h2-mediated Xq28 duplication syndrome is a relatively new X-linked intellectual disability syndrome, arising from duplications of the subregion flanked by intron 22 homologous regions 1 and 2 on the q arm of chromosome X. Its primary manifestations include variable cognitive deficits, distinct facial dysmorphia, and neurobehavioral abnormalities that mainly include hyperactivity, irritability, and autistic behavior. Affected males are hemizygous for the duplication, which explains their often more severe manifestations compared with heterozygous females. In this report, we describe the cases of nine individuals recently identified having the syndrome, highlighting unique and previously unreported findings of this syndrome. Specifically, we report for the first time in this syndrome, two cases with de novo duplications, three receiving prenatal diagnosis with the syndrome, and three others having atypical versions of the duplication. Among the latter, one proband has a shortened version spanning only the centromeric half of the typical duplication, while the other two cases have a nearly identical length duplication as the classical duplication, with the exception that their duplication's breakpoints are telomerically shifted by about 0.2 Mb. Finally, we shed light on two new manifestations in this syndrome, vertebral anomalies and multiple malignancies, which possibly expand the phenotypic spectrum of the syndrome.

Keywords: BRCC3; CLIC2; MECP2; RAB39B; autism; gene dosage; intellectual disability; sex chromosome.

Publication types

  • Case Reports
  • Research Support, N.I.H., Intramural

MeSH terms

  • Child
  • Child, Preschool
  • Chromosome Duplication*
  • Female
  • Genetic Diseases, X-Linked / genetics*
  • Humans
  • Infant
  • Intellectual Disability / genetics*
  • Male
  • Middle Aged
  • Prenatal Diagnosis
  • Syndrome