Delineating the Clinical Spectrum Associated With Xq25q26.2 Duplications: Report of 2 Families and Review of the Literature

Abstract

To date, 13 patients with interstitial microduplications involving Xq25q26.2 have been reported. Here, we report 6 additional patients from 2 families with duplications involving Xq25q26.2. Family I carries a 5.3-Mb duplication involving 26 genes. This duplication was identified in 3 patients and was associated with microcephaly, growth failure, developmental delay, and dysmorphic features. Family II carries an overlapping 791-kb duplication that involves 3 genes. This duplication was identified in 3 patients and was associated with learning disability and speech delay. The size and gene content of published overlapping Xq25q26.2 duplications vary, making it difficult to define a critical region or establish a genotype-phenotype correlation. However, patients with overlapping duplications have been found to share common clinical features including microcephaly, growth failure, intellectual disability, learning difficulties, and dysmorphic features. The 2 families presented here provide additional insight into the phenotypic spectrum and clinical significance of duplications in this region.

RLIM Is a Candidate Dosage-Sensitive Gene for Individuals with Varying Duplications of Xq13, Intellectual Disability, and Distinct Facial Features

“…Confirmation of these findings in a larger clinical cohort will be required to clarify the significance, genotypic-phenotypic spectrum, and reproductive counseling implications of this previously undescribed X chromosome-linked condition. This study, along with the studies describing phenotypes associated with duplications of HUWE1, STAG2 (MIM: 300826), and MECP2 (MIM: 300005) and the Xq25q26 duplication syndrome containing both GPC3 (MIM: 300037) and IGSF1 (MIM: 300137) 22,[44][45][46][47] supports the hypothesis that X chromosome duplications involving highly constrained and known ID genes are worthy of further investigations. email from decipher@sanger.ac.uk.…”

Forged by DXZ4, FIRRE, and ICCE: How Tandem Repeats Shape the Active and Inactive X Chromosome

“…Because additional cases may help to better resolve this region, we queried the DECIPHER database (Firth et al, 2009) and collated all short (<1 Mb) overlapping CNVs (Figure 2A). Tabulating phenotypes, transmission and sex only in patients who lack any other CNVs, these entries illustrate that: (1) almost all CNVs are gains that overlap FIRRE, (2) the associated phenotypes primarily involve the nervous system, and (3) most (12/14) patients are males who inherited the FIRRE-overlapping gain from weakly -or non-manifesting maternal carriers, where reported (Abe et al, 2014;Herriges et al, 2019). In contrast, among >5000 control individuals without pediatric disease in gnomAD-SV (Collins et al, 2019), 8/12 FIRRE duplications were present in heterozygous females, leaving one homozygous female and three males.…”

“…At present, there are two identified developmental roles that can serve as a basis for positive selection: (1) an established trans-acting function for FIRRE RNA in common lymphoid progenitors (Lewandowski et al, 2019), and (2) a hypothesized role in brain development, for which we refer readers to clinical reports of patients with copy-number gains in Xq26 (Schroer et al, 2012;Abe et al, 2014;Ha et al, 2019;Herriges et al, 2019). The latest of these reports summarizes sex-biased ID associated with duplications in this genomic region (Herriges et al, 2019), the shortest of which overlaps only IGSF1, olfactory receptor gene OR1H, and FIRRE (Abe et al, 2014).…”