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We report two series of individuals with DDX3X variations, one (48 individuals) from physicians and one (44 individuals) from caregivers. These two series include several symptoms in common, with fairly similar distribution, which suggests that caregivers’ data are close to physicians’ data. For example, both series identified early childhood symptoms that were not previously described: feeding difficulties, mean walking age and age at first words. Each of the two datasets provide complementary knowledge. We confirmed that symptoms are similar to those in the literature and provide more details on feeding difficulties. Caregivers considered that the symptom attention-deficit/hyperactivity disorder was most worrisome. Both series also reported sleep disturbance. Recently, anxiety has been reported in individuals with DDX3X variants. We strongly suggest that attention-deficit/hyperactivity disorder, anxiety and sleep disorders need to be treated. In addition, we demonstrate preliminary evidence of a mild genome-wide DNA methylation profile in patients carrying mutations in DDX3X.

Mutations in the PQBP1 gene (polyglutamine-binding protein 1) are responsible for a syndromic X-linked form of intellectual disability (XLID), the Renpenning syndrome. PQBP1 encodes a protein that plays a role in the regulation of gene expression, splicing and mRNA translation. To investigate the consequences of variants in PQBP1, we performed transcriptomic studies in 1) patients’ lymphoblastoid cell lines (LCL) carrying pathogenic variants in PQBP1 and 2) in human neural stem cells (hNSC) knocked-down (KD) for PQBP1. This led to the identification of a hundred dysregulated genes. In particular, we identified an increase in the expression of a non-canonical isoform of another XLID gene, UPF3B. UPF3B plays a crucial role during neurodevelopment by coding for an important actor of the nonsense mRNA mediated decay (NMD) system involved in regulation of protein translation, however, the exact function of the non-canonical isoform,UPF3B_S, is currently unknown. In order to investigate the role of UPF3B_S isoform, we compared the protein interactome of UPF3B_S to the canonical isoform (UPF3B_L). We confirmed that, on the contrary to UPF3B_L, UPF3B_S does not interact with the UPF2/UPF1 complex while it still interacts with exon junction complexes (EJC). However, no notable decrease of NMD pathways was observed in patient’s LCL or in hNSC KD for PQBP1. We identified several additional protein interactors specific to UPF3B_S. Moreover, we used the increase of UPF3B_S mRNA as a molecular marker to test the pathogenicity of variants of unknown clinical significance identified in individuals with ID in PQPB1. We analyzed patients’ LCL mRNA as well as blood mRNA samples and performed complementation studies in HeLa cells by overexpressing Wild-type and mutant PQBP1 cDNA. We showed that all these three approaches were efficient to test the effect of variants, at least for variants affecting the CTD domain of the protein. In conclusion, our study provides information on how PQBP1 deficiency may affect the expression of genes and isoforms, such as UPF3B. This informs about the pathological mechanisms involved in Renpenning syndrome but also allows to propose a functional test for variants of unknown significance identified in PQBP1.

Purpose: Exome sequencing has a diagnostic yield ranging from 25% to 70% in rare diseases and regularly implicates genes in novel disorders. Prospective data reanalysis has demonstrated strong efficacy in improving diagnosis, but poses organizational difficulties for clinical laboratories. We applied a reanalysis strategy based on intensive prospective bibliographic monitoring, and directly applied the Globally search for a Regular Expression and Print matching lines (GREP) command-line to a massive ES database. Methods: For 18 months, we submitted daily the same 5 keywords of interest (( intellectual disability, ( neuro)developmental delay, (neuro)developmental disorder)) to PubMed, to identify recently published, novel disease-gene associations, or new phenotypes in genes already implicated in human pathology. We used the Linux GREP command-line and an in-house script, to collect all variants in these genes from our 5459 exome database. Results: We grepped 128 genes and collected 56 candidate variants in 53 individuals. We confirmed causal diagnosis for 19/128 genes (15%) in 21 individuals, and identified variants of unknown significance for 19/128 genes (15%) in 23 individuals. Altogether, we confirmed pathogenicity in 21/2875 undiagnosed affected probands (0.7%). Conclusion: The GREP command-line is efficient, and less tedious than complete periodical reanalysis. It is an interesting reanalysis strategy to improve diagnosis.

Disease gene discovery on chromosome (chr) X is challenging owing to its unique modes of inheritance. We undertook a systematic analysis of human chrX genes. We observe a higher proportion of disorder-associated genes and an enrichment of genes involved in cognition, language, and seizures on chrX compared to autosomes. We analyze gene constraints, exon and promoter conservation, expression and paralogues, and report 127 genes sharing one or more attributes with known chrX disorder genes. Using a neural network trained to distinguish disease-associated from dispensable genes, we classify 235 genes, including 121 of the 127, as having high probability of being disease-associated. We provide evidence of an excess of variants in predicted genes in existing databases. Finally, we report damaging variants in CDK16 and TRPC5 in patients with intellectual disability or autism spectrum disorders. This study predicts large-scale gene-disease associations that could be used for prioritization of X-linked pathogenic variants.