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Danger-associated molecular patterns (DAMPs) are molecules that can initiate and maintain robust inflammatory responses and were investigated in the pathogenesis of graft versus host disease (GvHD). Uric acid (UA) and fibrinogen (Fib) are DAMPs released from damaged tissue during allogeneic hematopoietic stem cell transplantation (allo-HCT) and GvHD. We aimed to evaluate the effects of UA and Fib levels on survival in GvHD. One hundred seventy-four patients with grade 2-4 acute GvHD were included. UA and Fib levels were evaluated on allo-HCT day 0 and GvHD on days 0, 7, 14, and 28. Fib GvHD day 0 was the independent predictor for overall survival (OS), non-relapse mortality (NRM), and progression-free survival in multivariable models (HR 0.98, p < 0.001; HR 0.98, p = 0.001, HR 0.98, p = 0.006, respectively). Also UA GvHD day 28 was the independent predictor for OS and NRM (HR 0.77, p = 0.004; HR 0.76, p = 0.011, respectively). Our results indicated that hypouricemia and hypofibrinogenemia were associated with a significantly shorter OS and higher NRM. UA and Fib are remarkable molecules in GvHD because they are routinely utilized, readily available, can be therapeutic targets, and have DAMPs and antioxidant features., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

We report here a de novo missense variant in HIST1H4J resulting in a complex syndrome combining growth delay, microcephaly and intellectual disability. Trio whole exome sequencing (WES) revealed that the proband was heterozygous for a de novo c.274 A > G p.(K91E) variant in HIST1H4J, a gene not yet associated with human disease. The patient presented with profound intellectual disability, microcephaly, and dysmorphic facial features. Functional consequences of the identified de novo missense variant were evaluated in zebrafish embryos, where they affected general development, especially resulting in defective head organs and reduced body axis length. Our results show that the monoallelic p.K91E substitution on HIST1H4J underlies a human syndrome that is genetically and phenotypically akin to the HIST1H4C-associated neurodevelopmental disorder resulting from p.K91A and p.K91Q substitions in HIST1H4C. The highly overlapping patient phenotypes highlight functional similarities between HIST1H4J and HIST1H4C perturbations, establishing the singular importance of K91 across histone H4 genes for vertebrate development.

Blepharocheilodontic syndrome (BCDS) consists of lagophthalmia, ectropion of the lower eyelids, distichiasis, euryblepharon, cleft lip/palate and dental anomalies and has autosomal dominant inheritance with variable expression. We identified heterozygous variants in two genes of the cadherin-catenin complex, CDH1, encoding E-cadherin, and CTNND1, encoding p120 catenin delta1 in 15 of 17 BCDS index patients, as was recently described in a different publication. CDH1 plays an essential role in epithelial cell adherence; CTNND1 binds to CDH1 and controls the stability of the complex. Functional experiments in zebrafish and human cells showed that the CDH1 variants impair the cell adhesion function of the cadherin-catenin complex in a dominant-negative manner. Variants in CDH1 have been linked to familial hereditary diffuse gastric cancer and invasive lobular breast cancer; however, no cases of gastric or breast cancer have been reported in our BCDS cases. Functional experiments reported here indicated the BCDS variants comprise a distinct class of CDH1 variants. Altogether, we identified the genetic cause of BCDS enabling DNA diagnostics and counseling, in addition we describe a novel class of dominant negative CDH1 variants.

MED13L haploinsufficiency syndrome has been described in two patients and is characterized by moderate intellectual disability (ID), conotruncal heart defects, facial abnormalities and hypotonia. Missense mutations in MED13L are linked to transposition of the great arteries and non-syndromal intellectual disability. Here we describe two novel patients with de novo MED13L aberrations. The first patient has a de novo mutation in the splice acceptor site of exon 5 of MED13L. cDNA analysis showed this mutation results in an in-frame deletion, removing 15 amino acids in middle of the conserved MED13L N-terminal domain. The second patient carries a de novo deletion of exons 6-20 of MED13L. Both patients show features of the MED13L haploinsufficiency syndrome, except for the heart defects, thus further confirming the existence of the MED13L haploinsufficiency syndrome.

Recently, microarrays have replaced karyotyping as a first tier test in patients with idiopathic intellectual disability and/or multiple congenital abnormalities (ID/MCA) in many laboratories. Although in about 14-18% of such patients, DNA copy-number variants (CNVs) with clinical significance can be detected, microarrays have the disadvantage of missing balanced rearrangements, as well as providing no information about the genomic architecture of structural variants (SVs) like duplications and complex rearrangements. Such information could possibly lead to a better interpretation of the clinical significance of the SV. In this study, the clinical use of mate pair next-generation sequencing was evaluated for the detection and further characterization of structural variants within the genomes of 50 ID/MCA patients. Thirty of these patients carried a chromosomal aberration that was previously detected by array CGH or karyotyping and suspected to be pathogenic. In the remaining 20 patients no causal SVs were found and only benign aberrations were detected by conventional techniques. Combined cluster and coverage analysis of the mate pair data allowed precise breakpoint detection and further refinement of previously identified balanced and (complex) unbalanced aberrations, pinpointing the causal gene for some patients. We conclude that mate pair sequencing is a powerful technology that can provide rapid and unequivocal characterization of unbalanced and balanced SVs in patient genomes and can be essential for the clinical interpretation of some SVs.