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Background: PACS1 neurodevelopmental disorder (PACS1-NDD) (MIM# 615009) is a rare autosomal dominant disease characterized by neurodevelopmental delay, dysmorphic facial features, and congenital malformations. Heart disease (HD) is frequently present in individuals with PACS1-NDD, but a compressive review of these anomalies and an evaluation of cardiac function in a cohort of patients are lacking. Methods: (i) Cardiac evaluation in 11 PACS1-NDD patients was conducted using conventional echocardiography. (ii) Heart function was assessed by tissue Doppler imaging, and two-dimensional speckle tracking was performed in seven patients and matched controls. (iii) This systematic review focused on determining HD prevalence in individuals with PACS1-NDD. Results: In our cohort, 7 of 11 patients presented HD. (Among them, three cases of ascending aortic dilatation (AAD) were detected and one mitral valve prolapse (MVP).) None of the patients showed echocardiographic pathological values, and the left global longitudinal strain was not significantly different between patients and controls (patients −24.26 ± 5.89% vs. controls −20.19 ± 1.75%, p = 0.3176). In the literature review, almost 42% (42/100) of individuals with PACS1-NDD reportedly experienced HD. Septal defects were the most common malformation, followed by patent ductus arteriosus. Conclusions: Our results show a high prevalence of HD in PACS1-NDD patients; in this way, AAD and MVP are reported for the first time in this syndrome. Furthermore, a detailed cardiac function evaluation in our cohort did not reveal evidence of cardiac dysfunction in individuals with PACS1-NDD. Cardiology evaluation should be included for all individuals with Schuurs-Hoeijmakers syndrome.

Ultimate advances in genetic technologies have permitted the detection of transmitted cases of congenital diseases due to parental gonadosomatic mosaicism. Regarding Cornelia de Lange syndrome (CdLS), up to date, only a few cases are known to follow this inheritance pattern. However, the high prevalence of somatic mosaicism recently reported in this syndrome (∼13%), together with the disparity observed in tissue distribution of the causal variant, suggests that its prevalence in this disorder could be underestimated. Here, we report a new case of parental gonadosomatic mosaicism in SMC1A gene that causes inherited CdLS, in which the mother of the patient carries the causative variant in very low allele frequencies in buccal swab and blood. While the affected child presents with typical CdLS phenotype, his mother does not show any clinical manifestations. As regards SMC1A, the difficulty of clinical identification of carrier females has been already recognized, as well as the gender differences observed in CdLS expressivity when the causal variant is found in this gene. Currently, the use of DNA deep-sequencing techniques is highly recommended when it comes to molecular diagnosis of patients, as well as in co-segregation studies. These enable us to uncover gonadosomatic mosaic events in asymptomatic or oligosymptomatic parents that had been overlooked so far, which might have great implications regarding genetic counseling for recurrence risk.

15 páginas, 7 figuras. The online version contains supplementary material available at https://doi.org/10.1038/s41467-021-24808-z. The data that support this study are available from the corresponding authors upon reasonable request. ChIP-seq data generated in the course of this work have been deposited in the Gene Expression Omnibus (GEO) under the accession number GSE145966. Encode data for RAD21 (ENCFF361FUX) and MNase (ENCFF000VLK), GEO data for CTCF (GSM733672) and DNase (GSM816655), and Enhancer Atlas database for enhancer information (http://www.enhanceratlas.org/) were used for Fig. 5 and Supplementary Fig. 7. GEO data for CTCF (GSM935404) and the high-resolution Hi-C data for IMR90 cell lines (GSE63525) were used for the intra-TAD prediction tool for Fig. 7 and Supplementary Fig. 8. Other data supporting the findings of this study are available within the paper, its supplementary information files, and the source data file. Source data are provided with this paper. The custom scripts generated during the current study are available from https:// bitbucket.org/qgenomics/smc1a-nipbl., Cornelia de Lange syndrome (CdLS) is a rare disease affecting multiple organs and systems during development. Mutations in the cohesin loader, NIPBL/Scc2, were first described and are the most frequent in clinically diagnosed CdLS patients. The molecular mechanisms driving CdLS phenotypes are not understood. In addition to its canonical role in sister chromatid cohesion, cohesin is implicated in the spatial organization of the genome. Here, we investigate the transcriptome of CdLS patient-derived primary fibroblasts and observe the downregulation of genes involved in development and system skeletal organization, providing a link to the developmental alterations and limb abnormalities characteristic of CdLS patients. Genome-wide distribution studies demonstrate a global reduction of NIPBL at the NIPBL-associated high GC content regions in CdLS-derived cells. In addition, cohesin accumulates at NIPBL-occupied sites at CpG islands potentially due to reduced cohesin translocation along chromosomes, and fewer cohesin peaks colocalize with CTCF., This work was funded by the Spanish Ministry of Economy, Industry and Competitiveness (MINECO), which is part of the State Agency, through the projects BFU2013-43132-P and BFU2016-77975-R to E.Q., and BFU2016-79841 to A.L. (co-funded by the European Regional Development Fund, ERDF, a way to build Europe) and the MaratóTV3 (101030 FMTV3) to E.Q. A.L.-P., B.P., F.R., and J.P. are funded by the Spanish Ministry of Health ISCIIIFIS (Ref. PI19/01860) and by the Gobierno de Aragon (Ref. B32_17R) and belong to the GCV02 of CIBERER. J.L.M. is a recipient of a grant from the Instituto Carlos III, which is part of the State Agency, grant number CA18/00045 (co-funded by the European Regional Development Fund, ERDF, a way to build Europe) and M.M. is a recipient of the fellowship “Personal Técnico de Apoyo” number PTA2018-016371-I funded by the Spanish Ministry of Science, Innovation and Universities (MCIU), which is part of the State Agency.

There are three human enzymes with HMG-CoA lyase activity that are able to synthesize ketone bodies in different subcellular compartments. The mitochondrial HMG-CoA lyase was the first to be described, and catalyzes the cleavage of 3-hydroxy-3-methylglutaryl CoA to acetoacetate and acetyl-CoA, the common final step in ketogenesis and leucine catabolism. This protein is mainly expressed in the liver and its function is metabolic, since it produces ketone bodies as energetic fuels when glucose levels are low. Another isoform is encoded by the same gene for the mitochondrial HMG-CoA lyase (HMGCL), but it is located in peroxisomes. The last HMG-CoA lyase to be described is encoded by a different gene, HMGCLL1, and is located in the cytosolic side of the endoplasmic reticulum membrane. Some activity assays and tissue distribution of this enzyme have shown the brain and lung as key tissues for studying its function. Although the roles of the peroxisomal and cytosolic HMG-CoA lyases remain unknown, recent studies highlight the role of ketone bodies in metabolic remodeling, homeostasis, and signaling, providing new insights into the molecular and cellular function of these enzymes.