Novel syndromic neurodevelopmental disorder caused by de novo deletion of CHASERR, a long noncoding RNA.

Genes encoding long non-coding RNAs (lncRNAs) comprise a large fraction of the human genome, yet haploinsufficiency of a lncRNA has not been shown to cause a Mendelian disease. CHASERR is a highly conserved human lncRNA adjacent to CHD2-a coding gene in which de novo loss-of-function variants cause developmental and epileptic encephalopathy. Here we report three unrelated individuals each harboring an ultra-rare heterozygous de novo deletion in the CHASERR locus. We report similarities in severe developmental delay, facial dysmorphisms, and cerebral dysmyelination in these individuals, distinguishing them from the phenotypic spectrum of CHD2 haploinsufficiency. We demonstrate reduced CHASERR mRNA expression and corresponding increased CHD2 mRNA and protein in whole blood and patient-derived cell lines-specifically increased expression of the CHD2 allele in cis with the CHASERR deletion, as predicted from a prior mouse model of Chaserr haploinsufficiency. We show for the first time that de novo structural variants facilitated by Alu-mediated non-allelic homologous recombination led to deletion of a non-coding element (the lncRNA CHASERR) to cause a rare syndromic neurodevelopmental disorder. We also demonstrate that CHD2 has bidirectional dosage sensitivity in human disease. This work highlights the need to carefully evaluate other lncRNAs, particularly those upstream of genes associated with Mendelian disorders.

The correlation between prenatal ultrasound and MRI in isolated periventricular pseudocysts: Analysis of 10 years' experience at the University Hospital of Angers.

BACKGROUND: Periventricular cysts are one of the most extensively documented antenatal brain lesions found through fetal ultrasound at the University Hospital of Angers. The main purpose of our study was to determine the contribution of fetal magnetic resonance imaging (MRI) and postnatal transfontanellar ultrasound (TFU) in the assessment of isolated periventricular cysts found on antenatal ultrasound at the University Hospital of Angers. METHODS: This retrospective, descriptive study was carried out over a 10-year period. Overall, 82 cases were included, divided into two groups according to the type of cysts found on the ultrasound: 13 cases of subependymal pseudocysts (SEPC) and 69 cases of frontal horn cysts (FHC). In all, 43 children underwent a postnatal TFU: seven in the SEPC group and 36 in the FHC group. RESULTS: Our study found excellent agreement between antenatal ultrasound and fetal MRI in the FHC group concerning classification of the cysts (approval rate [TA]: 98.60%; kappa coefficient [κ]: 0.85), their location (TA: 98.80%; κ: 0.91), their number (TA: 78.20%; κ: 0.73), and the detection of FHC (TA: 81.10%; κ: 0.74), as well as a good agreement concerning the detection of SEPC and temporal horn cysts (THC; TA: 99.40% and 95.60%, respectively). Fetal MRI proved to be better in the SEPC group for cyst classification (TA: 66.70%; κ: 0.33), their location (TA: 60%; κ: 0.41), and their number (TA: 53, 30%; κ: 0.45) and the detection of SEPC (TA: 23.10%; κ: 0.14). In both groups, postnatal TFU did not provide additional information compared to MRI. CONCLUSION: The finding of periventricular cysts in antenatal ultrasound should lead to a reference ultrasound, a key procedure for distinguishing between SEPC and FHC. In our study, no additional benefit from MRI and TFU was established for the evaluation of FHC. These findings should be considered as normal variants, thus limiting pre- and postnatal investigations. The visualization of SEPC, THC, or a parenchymal abnormality on the reference ultrasound should lead to an additional MRI being performed and a personalized follow-up of the child.