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Interpretation of the significance of maternally inherited X chromosome variants in males with neurocognitive phenotypes continues to present a challenge to clinical geneticists and diagnostic laboratories. Here we report 14 males from 9 families with duplications at the Xq13.2-q13.3 locus with a common facial phenotype, intellectual disability (ID), distinctive behavioral features, and a seizure disorder in two cases. All tested carrier mothers had normal intelligence. The duplication arose de novo in three mothers where grandparental testing was possible. In one family the duplication segregated with ID across three generations. RLIM is the only gene common to our duplications. However, flanking genes duplicated in some but not all the affected individuals included the brain-expressed genes NEXMIF, SLC16A2, and the long non-coding RNA gene FTX. The contribution of the RLIM-flanking genes to the phenotypes of individuals with different size duplications has not been fully resolved. Missense variants in RLIM have recently been identified to cause X-linked ID in males, with heterozygous females typically having normal intelligence and highly skewed X chromosome inactivation. We detected consistent and significant increase of RLIM mRNA and protein levels in cells derived from seven affected males from five families with the duplication. Subsequent analysis of MDM2, one of the targets of the RLIM E3 ligase activity, showed consistent downregulation in cells from the affected males. All the carrier mothers displayed normal RLIM mRNA levels and had highly skewed X chromosome inactivation. We propose that duplications at Xq13.2-13.3 including RLIM cause a recognizable but mild neurocognitive phenotype in hemizygous males.

Background Steroid sulfatase ( STS ) gene disruption causes X-linked ichthyosis (XLI). Interrogating the entire genome through chromosomal microarray (CMA), a test primarily used to screen patients with noncutaneous congenital anomalies, may detect STS deletions incidentally. Objective We sought to determine the variability of skin features associated with STS deletions diagnosed through CMA and to compare these findings with XLI cases reported in the literature and recognized in a dermatology clinic. Methods Male patients with an STS deletion were identified from 23,172 consecutive postnatal blood samples tested with CMA at Mayo Clinic. A comparison group of male patients with biochemically confirmed XLI was ascertained in the dermatology clinic. The available patient medical records, skin histopathology, and photographs were evaluated and a literature search of patients with XLI was conducted. Results Children whose diagnosis was made incidentally through CMA had milder skin phenotypes, including dryness or eczema, or both, and did not manifest the polygonal or "dirty" scale described as typical of XLI in the literature. Limitations The small sample size, limited clinical information, and assessment by nondermatologists in a subset of cases may have influenced the results. Conclusion STS deletions may cause a milder skin phenotype than the typical presentation of XLI.

Chromosomal microarray (CMA) is widely used to detect and refine chromosome abnormalities in both congenital and neoplastic cases. Recently, a blood sample from a newborn male with no apparent dysmorphic features was sent to the Mayo Clinic Cytogenetics laboratory for G-banded karyotype analysis to clarify prenatal findings of a positive trisomy 21 noninvasive prenatal screening (NIPS) result. Chromosome analysis of 20 metaphases revealed 13 were normal (46,XY) and 7 had a satellited supernumerary marker chromosome (47,XY,+mar). To further characterize the marker chromosome, CMA studies were performed, which revealed an 8.6 megabase mosaic duplication from 21q11.2 to 21q21.1. Subsequent metaphase FISH studies demonstrated that the duplicated region was present on the supernumerary marker chromosome, indicating that the marker chromosome is derived from chromosome 21. Interphase FISH studies showed that the marker was present in 68% of interphase nuclei. Despite its large size, the duplicated region contains only 30 known genes. In addition, similar duplications involving this region have not been previously described, making the clinical significance of this duplication uncertain. Importantly, the duplicated interval does not include the Down syndrome critical region (21q22.1 to 22q22.3), consistent with this patient’s lack of dysmorphic features. This report highlights the importance of diagnostic follow-up testing and the clinical utility of conventional and molecular cytogenetic techniques in the setting of abnormal NIPS results.