Sacral agenesis: a pilot whole exome sequencing and copy number study

Background: Caudal regression syndrome (CRS) or sacral agenesis is a rare congenital disorder characterized by a constellation of congenital caudal anomalies affecting the caudal spine and spinal cord, the hindgut, the urogenital system, and the lower limbs. CRS is a complex condition, attributed to an abnormal development of the caudal mesoderm, likely caused by the effect of interacting genetic and environmental factors. A well-known risk factor is maternal type 1 diabetes. Method: Whole exome sequencing and copy number variation (CNV) analyses were conducted on 4 Caucasian trios to identify de novo and inherited rare mutations. Results: In this pilot study, exome sequencing and copy number variation (CNV) analyses implicate a number of candidate genes, including SPTBN5, MORN1, ZNF330, CLTCL1 and PDZD2. De novo mutations were found in SPTBN5, MORN1 and ZNF330 and inherited predicted damaging mutations in PDZD2 (homozygous) and CLTCL1 (compound heterozygous). Importantly, predicted damaging mutations in PTEN (heterozygous), in its direct regulator GLTSCR2 (compound heterozygous) and in VANGL1 (heterozygous) were identified. These genes had previously been linked with the CRS phenotype. Two CNV deletions, one de novo (chr3q13.13) and one homozygous (chr8p23.2), were detected in one of our CRS patients. These deletions overlapped with CNVs previously reported in patients with similar phenotype. Conclusion: Despite the genetic diversity and the complexity of the phenotype, this pilot study identified genetic features common across CRS patients

Patient complexity and genotype-phenotype correlations in biliary atresia: a cross-sectional analysis

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Regulation of APC development, immune response, and autoimmunity by Bach1/HO-1 pathway in mice

APCs are essential for innate and adaptive immunity as well as self-immune tolerance. Here, we show that the Cap’n’collar member Bach1 regulates the generation of APCs, specifically macrophages and dendritic cells, in mice. The impaired APC development in Bach1^(-/-) mice was accompanied by defects in downstream T-cell responses and partial protection from experimental autoimmune encephalomyelitis. Genomewide analyses identified a panel of Bach1 target genes and ablation of the direct Bach1 target gene HO-1 exacerbated the impaired APC development observed in Bach1^(-/-) mice. This was attributed to the impaired ability of HO-1^(-/-)Bach1^(-/-) double mutants to produce upstreamAPC progenitor cells, including common myeloid progenitor (CMP)–Flk2^+. By contrast, we observed an increase in hematopoietic stem-progenitor cells (HSPCs) in these mice, suggesting a developmental block in the progression of HSPCs to CMP-Flk2^+ and subsequently APCs

Genetic study of congenital bile-duct dilatation identifies de novo and inherited variants in functionally related genes

Background: Congenital dilatation of the bile-duct (CDD) is a rare, mostly sporadic, disorder that results in bile retention with severe associated complications. CDD affects mainly Asians. To our knowledge, no genetic study has ever been conducted. Methods: We aim to identify genetic risk factors by a “trio-based” exome-sequencing approach, whereby 31 CDD probands and their unaffected parents were exome-sequenced. Seven-hundred controls from the local population were used to detect gene-sets significantly enriched with rare variants in CDD patients. Results: Twenty-one predicted damaging de novo variants (DNVs; 4 protein truncating and 17 missense) were identified in several evolutionarily constrained genes (p < 0.01). Six genes carrying DNVs were associated with human developmental disorders involving epithelial, connective or bone morphologies (PXDN, RTEL1, ANKRD11, MAP2K1, CYLD, ACAN) and four linked with cholangio- and hepatocellular carcinomas (PIK3CA, TLN1 CYLD, MAP2K1). Importantly, CDD patients have an excess of DNVs in cancer-related genes (p < 0.025). Thirteen genes were recurrently mutated at different sites, forming compound heterozygotes or functionally related complexes within patients. Conclusions: Our data supports a strong genetic basis for CDD and show that CDD is not only genetically heterogeneous but also non-monogenic, requiring mutations in more than one genes for the disease to develop. The data is consistent with the rarity and sporadic presentation of CDD

Fatal Peripheral Candidal Suppurative Thrombophlebitis in a Postoperative Patient

We report a case of fatal fungal peripheral suppurative thrombophlebitis, caused by Candida albicans, which was disseminated to the blood, lungs, eyes, and spine. Clinical suspicion and aggressive management are important in managing fungal peripheral suppurative thrombophlebitis. Early clinical suspicion is important in managing fungal peripheral suppurative thrombophlebitis, and radical excision of the affected veins, recognition of metastatic foci, and use of systemic antifungal agents are essential to avoid septic shock and death

Genetic study of congenital bile-duct dilatation identifies de novo and inherited variants in functionally related genes

published_or_final_versio

Dual mechanisms by which MiR-125b represses IRF4 to induce myeloid and B cell leukemias

The oncomir microRNA-125b (miR-125b) is up-regulated in a variety of human neoplastic blood disorders and constitutive up-regulation of miR-125b in mice can promote myeloid and B cell leukemia. We found that miR-125b promotes myeloid and B cell neoplasm by inducing tumorigenesis in hematopoietic progenitor cells. Our study demonstrates that miR-125b induces myeloid leukemia by enhancing myeloid progenitor output from stem cells as well as inducing immortality, self-renewal, and tumorigenesis in myeloid progenitors. Through functional and genetic analyses, we demonstrated that miR-125b induces myeloid and B cell leukemia by inhibiting IRF4 but through distinct mechanisms; it induces myeloid leukemia through repressing IRF4 at the mRNA level without altering the genomic DNA and induces B cell leukemia via genetic deletion of the gene encoding IRF4

Haplotype Analysis Reveals a Possible Founder Effect of RET Mutation R114H for Hirschsprung's Disease in the Chinese Population

Background Hirschsprung's disease (HSCR) is a congenital disorder associated with the lack of intramural ganglion cells in the myenteric and sub-mucosal plexuses along varying segments of the gastrointestinal tract. The RET gene is the major gene implicated in this gastrointestinal disease. A highly recurrent mutation in RET (RETR114H) has recently been identified in ~6-7% of the Chinese HSCR patients which, to date, has not been found in Caucasian patients or controls nor in Chinese controls. Due to the high frequency of RETR114H in this population, we sought to investigate whether this mutation may be a founder HSCR mutation in the Chinese population. Methodology and Principal Findings To test whether all RETR114H were originated from a single mutational event, we predicted the approximate age of RETR114H by applying a Bayesian method to RET SNPs genotyped in 430 Chinese HSCR patients (of whom 25 individuals had the mutation) to be between 4-23 generations old depending on growth rate. We reasoned that if RETR114H was a founder mutation then those with the mutation would share a haplotype on which the mutation resides. Including SNPs spanning 509.31 kb across RET from a recently obtained 500 K genome-wide dataset for a subset of 181 patients (14 RETR114H patients), we applied haplotype estimation methods to determine whether there were any segments shared between patients with RETR114H that are not present in those without the mutation or controls. Analysis yielded a 250.2 kb (51 SNP) shared segment over the RET gene (and downstream) in only those patients with the mutation with no similar segments found among other patients. Conclusions This suggests that RETR114H is a founder mutation for HSCR in the Chinese population. © 2010 Cornes et al.published_or_final_versio

Strongly anisotropic spin relaxation in graphene/transition metal dichalcogenide heterostructures at room temperature

Graphene has emerged as the foremost material for future two-dimensional spintronics due to its tuneable electronic properties. In graphene, spin information can be transported over long distances and, in principle, be manipulated by using magnetic correlations or large spin-orbit coupling (SOC) induced by proximity effects. In particular, a dramatic SOC enhancement has been predicted when interfacing graphene with a semiconducting transition metal dechalcogenide, such as tungsten disulphide (WS$_2$). Signatures of such an enhancement have recently been reported but the nature of the spin relaxation in these systems remains unknown. Here, we unambiguously demonstrate anisotropic spin dynamics in bilayer heterostructures comprising graphene and WS$_2$. By using out-of-plane spin precession, we show that the spin lifetime is largest when the spins point out of the graphene plane. Moreover, we observe that the spin lifetime varies over one order of magnitude depending on the spin orientation, indicating that the strong spin-valley coupling in WS$_2$ is imprinted in the bilayer and felt by the propagating spins. These findings provide a rich platform to explore coupled spin-valley phenomena and offer novel spin manipulation strategies based on spin relaxation anisotropy in two-dimensional materials