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Contains fulltext : 252023.pdf (Publisher’s version ) (Open Access), Chromatin is essentially an array of nucleosomes, each of which consists of the DNA double-stranded fiber wrapped around a histone octamer. This organization supports cellular processes such as DNA replication, DNA transcription, and DNA repair in all eukaryotes. Human histone H4 is encoded by fourteen canonical histone H4 genes, all differing at the nucleotide level but encoding an invariant protein. Here, we present a cohort of 29 subjects with de novo missense variants in six H4 genes (H4C3, H4C4, H4C5, H4C6, H4C9, and H4C11) identified by whole-exome sequencing and matchmaking. All individuals present with neurodevelopmental features of intellectual disability and motor and/or gross developmental delay, while non-neurological features are more variable. Ten amino acids are affected, six recurrently, and are all located within the H4 core or C-terminal tail. These variants cluster to specific regions of the core H4 globular domain, where protein-protein interactions occur with either other histone subunits or histone chaperones. Functional consequences of the identified variants were evaluated in zebrafish embryos, which displayed abnormal general development, defective head organs, and reduced body axis length, providing compelling evidence for the causality of the reported disorder(s). While multiple developmental syndromes have been linked to chromatin-associated factors, missense-bearing histone variants (e.g., H3 oncohistones) are only recently emerging as a major cause of pathogenicity. Our findings establish a broader involvement of H4 variants in developmental syndromes.

BACKGROUND: Achondroplasia is associated with disproportionate short stature and significant and potentially severe medical complications. Vosoritide is the first medicine to treat the underlying cause of achondroplasia and data from phase 3 and phase 2 extension studies showed effects on growth and body proportions. However, there are currently no long-term data available on the direct impact on endpoints such as medical complications and health-related quality of life (HRQoL). This study explored the perceived impact of achondroplasia on medical complications, HRQoL, healthcare resource use and mortality, and potential modifying effects of vosoritide, based on published evidence and expert opinion. Structured expert opinion was obtained by an international modified Delphi study among 14 experts in managing achondroplasia performed on a virtual platform and consisting of an explorative phase followed by an anonymous individual rating round. RESULTS: Overall, the panelists expect that in individuals starting long-term treatment between 2 years of age and puberty, growth velocity increases observed in the clinical trials will be maintained until final height is reached (92% agreement) and will likely result in clinically meaningful improvements in upper-to-lower body segment ratio (85%). Earlier treatment initiation will likely result in a greater final height (100%) and more likely improve proportionality (92%) than later treatment. Although current data are limited, ≥ 75% of panelists find it conceivable that the earlier long-term treatment is started, the greater the probability of a positive effect on the lifetime incidence of symptomatic spinal stenosis, kyphosis, obstructive sleep apnea, and foramen magnum stenosis. These are among the most clinically important complications of achondroplasia because of their high impact on comorbidity, mortality, and/or HRQoL. A positive effect of vosoritide on the incidence of surgeries through lifetime was considered more li

PURPOSE: This study was undertaken to collect baseline growth parameters in children with achondroplasia who might enroll in interventional trials of vosoritide, and to establish a historical control. METHODS: In this prospective, observational study, participants (≤17 years) underwent a detailed medical history and physical examination and were followed every 3 months until they finished participating in the study by enrolling in an interventional trial or withdrawing. RESULTS: A total of 363 children were enrolled (28 centers, 8 countries). Mean (SD) follow up was 20.4 (15.0) months. In participants <1 year, mean annualized growth velocity (AGV) was 11.6 cm/year for girls and 14.6 cm/year for boys. By age 1 year, mean AGV decreased to 7.4 cm/year in girls and 7.1 cm/year in boys. By age 10 years, mean AGV decreased to 3.6 cm/year for both sexes. Mean height z-score in participants <1 year was -2.5 for girls and -3.2 for boys and decreased up to the age 5 years (-5.3 for girls; -4.6 for boys). Girls and boys had a disproportionate upper-to-lower body segment ratio. Mean ratio was highest in participants aged <1 year (2.9 for girls; 2.8 for boys) and decreased gradually to approximately 2 in both sexes from 4 years of age onward. CONCLUSION: This study represents one of the largest datasets of prospectively collected medical and longitudinal growth data in children with achondroplasia. It serves as a robust historical control to measure therapeutic interventions against and to further delineate the natural history of this condition.

Vosoritide is a drug developed for the treatment of achondroplasia and has demonstrated increases in the growth velocity of children with this condition. Achondroplasia is a skeletal dysplasia (a condition affecting children’s bones and joints meaning they do not grow in the typical way) and is also referred to as dwarfism. There are currently no approved treatments for achondroplasia, except for growth hormone in Japan. When a new drug is being developed, it is essential to conduct clinical studies after many other steps to assess how well the drug works and whether it has any side effects. These studies of new drugs are carried out before the drug is approved to treat, improve, or reduce physical problems of certain conditions. This summary reports the results from two clinical studies looking at vosoritide as a potential treatment for children with achondroplasia. Study A compared different doses of vosoritide to find out which is the safest and shows the best results with the fewest side effects. Study B looked at how well vosoritide works compared with a nonactive medicine (known as a placebo) and the side effects. In these studies, vosoritide increased bone growth velocity in children with achondroplasia. Children receiving the drug every day generally only had mild side effects. Serious health conplications were generally medical events seen in children with achondroplasia even if they do not take vosoritide. No children stopped taking vosoritide during the studies due to safety reasons. How well vosoritide works and the side effects in children over a longer period of time are still being studied. ClinicalTrials.gov NCT numbers: NCT02055157 and NCT03197766 .

Contains fulltext : 218274.pdf (Publisher’s version ) (Closed access), Genetic syndromes frequently present with overlapping clinical features and inconclusive or ambiguous genetic findings which can confound accurate diagnosis and clinical management. An expanding number of genetic syndromes have been shown to have unique genomic DNA methylation patterns (called "episignatures"). Peripheral blood episignatures can be used for diagnostic testing as well as for the interpretation of ambiguous genetic test results. We present here an approach to episignature mapping in 42 genetic syndromes, which has allowed the identification of 34 robust disease-specific episignatures. We examine emerging patterns of overlap, as well as similarities and hierarchical relationships across these episignatures, to highlight their key features as they are related to genetic heterogeneity, dosage effect, unaffected carrier status, and incomplete penetrance. We demonstrate the necessity of multiclass modeling for accurate genetic variant classification and show how disease classification using a single episignature at a time can sometimes lead to classification errors in closely related episignatures. We demonstrate the utility of this tool in resolving ambiguous clinical cases and identification of previously undiagnosed cases through mass screening of a large cohort of subjects with developmental delays and congenital anomalies. This study more than doubles the number of published syndromes with DNA methylation episignatures and, most significantly, opens new avenues for accurate diagnosis and clinical assessment in individuals affected by these disorders.

Contains fulltext : 218289.pdf (Publisher’s version ) (Closed access), MN1 encodes a transcriptional co-regulator without homology to other proteins, previously implicated in acute myeloid leukaemia and development of the palate. Large deletions encompassing MN1 have been reported in individuals with variable neurodevelopmental anomalies and non-specific facial features. We identified a cluster of de novo truncating mutations in MN1 in a cohort of 23 individuals with strikingly similar dysmorphic facial features, especially midface hypoplasia, and intellectual disability with severe expressive language delay. Imaging revealed an atypical form of rhombencephalosynapsis, a distinctive brain malformation characterized by partial or complete loss of the cerebellar vermis with fusion of the cerebellar hemispheres, in 8/10 individuals. Rhombencephalosynapsis has no previously known definitive genetic or environmental causes. Other frequent features included perisylvian polymicrogyria, abnormal posterior clinoid processes and persistent trigeminal artery. MN1 is encoded by only two exons. All mutations, including the recurrent variant p.Arg1295* observed in 8/21 probands, fall in the terminal exon or the extreme 3' region of exon 1, and are therefore predicted to result in escape from nonsense-mediated mRNA decay. This was confirmed in fibroblasts from three individuals. We propose that the condition described here, MN1 C-terminal truncation (MCTT) syndrome, is not due to MN1 haploinsufficiency but rather is the result of dominantly acting C-terminally truncated MN1 protein. Our data show that MN1 plays a critical role in human craniofacial and brain development, and opens the door to understanding the biological mechanisms underlying rhombencephalosynapsis.

Contains fulltext : 220500.pdf (Publisher’s version ) (Open Access)