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

Abstract

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.

A Newly Identified Int22h1/Int22h2‐Mediated Xq28 Duplication Syndrome Case Misdiagnosed as Cerebral Palsy

“…While it is most often inherited in an X-linked fashion, individuals with de novo duplications have also been reported. [22][23][24][25][26] We observed an atypical MRI finding consisting of bilateral thalamic T2 hyperintensities (►Fig. 1), which have been previously reported in the case of cerebral insults, albeit not in isolation.…”

Genetic Evidence for Endolysosomal Dysfunction in Parkinson’s Disease: A Critical Overview

“…It is to be noted that RAB39B -related parkinsonism is caused by large-scale deletions, splicing abnormalities, and frameshift, nonsense, and missense mutations resulting in LOF. Duplications and triplications of RAB39B may result in a pathologic GOF leading to complex syndromes with ID and behavioral abnormalities [ 200 , 203 , 204 , 205 , 206 , 207 , 208 ].…”

Skewed X-Chromosome Inactivation as a Possible Marker of X-Linked CNV in Women with Pregnancy Loss

“…The identified duplication affects a region that was previously described as "Xq28 Duplication Syndrome, Int22h1/Int22h2 Mediated Syndrome." There are 35 cases described worldwide with this duplication with various types of XLID syndromes, depending on the subset of genes involved in the duplication [El-Hattab et al, 1993;Ballout et al, 2020]. Moreover, 3 out of 35 cases were diagnosed prenatally due to a reproductive problem in their mothers.…”