Homozygous mutations in a predicted endonuclease are a novel cause of congenital dyserythropoietic anemia type I.

The congenital dyserythropoietic anemias are a heterogeneous group of rare disorders primarily affecting erythropoiesis with characteristic morphological abnormalities and a block in erythroid maturation. Mutations in the CDAN1 gene, which encodes Codanin-1, underlie the majority of congenital dyserythropoietic anemia type I cases. However, no likely pathogenic CDAN1 mutation has been detected in approximately 20% of cases, suggesting the presence of at least one other locus. We used whole genome sequencing and segregation analysis to identify a homozygous T to A transversion (c.533T>A), predicted to lead to a p.L178Q missense substitution in C15ORF41, a gene of unknown function, in a consanguineous pedigree of Middle-Eastern origin. Sequencing C15ORF41 in other CDAN1 mutation-negative congenital dyserythropoietic anemia type I pedigrees identified a homozygous transition (c.281A>G), predicted to lead to a p.Y94C substitution, in two further pedigrees of SouthEast Asian origin. The haplotype surrounding the c.281A>G change suggests a founder effect for this mutation in Pakistan. Detailed sequence similarity searches indicate that C15ORF41 encodes a novel restriction endonuclease that is a member of the Holliday junction resolvase family of proteins.

Two unique cases of metastatic malignant melanoma of the gastrointestinal tract.

INTRODUCTION AND IMPORTANCE: Gastrointestinal tract (GIT) is a common site for malignant melanoma metastasis, with small bowel being the most common. It is usually difficult to diagnose at an early stage because of the anatomical location of the disease. It is also challenging for pathologists to diagnose due to the small amount of biopsy samples. Survival rates of melanoma patients with distant metastasis are very poor. CASE PRESENTATION: This study presents two males, aged 67 and 69 years old, who have metastatic melanoma within the GIT. One was metastasis to the esophagus and another with metastasis to the jejunum presenting as intraluminal masses. Their clinical history and pathologic features of the metastasis are evaluated to give an insight into this disease. CLINICAL DISCUSSION: Gastrointestinal melanoma is hard to detect due to its anatomical location and limited ability to biopsy. Typically, they present at an advanced stage when diagnosed. Approximately 60 % of patients with cutaneous melanoma will have GIT metastasis at the time of autopsy. The small bowel was found to have an affinity for malignant melanoma due to the expression of the CCR9 ligand, CCL25. BRAF mutations are much less observed in GIT mucosal melanomas as compared to cutaneous melanomas. Furthermore, AKAP13-NTRK3 fusion has been reported specifically in the GIT mucosal melanomas. NTRK fusions in general can be observed in metastatic melanomas and have been reported in GIT metastatic melanomas. CONCLUSION: GIT malignant melanomas are difficult to detect due to their anatomical location, with poor prognosis, and have a unique genetic profile.

Frequency of congenital dyserythropoietic anemias in Europe.

Congenital dyserythropoietic anemias (CDAs) are rare hereditary disorders characterized by ineffective erythropoiesis and striking abnormalities of erythroblast morphology. The mutated genes are known for the most frequent types, CDA I and II, but data about their frequency do not exist. The objective of this retrospective study was to estimate the frequency of CDA I and II, based on all cases reported in the last 42 yr in publications and identified registries or surveys. Reports were collected of 124 and 377 confirmed cases of CDA I and CDA II cases, respectively. The cumulated incidence of both types combined varied widely between European regions, with minimal values of 0.08 cases/million in Scandinavia and 2.60 cases/million in Italy. CDA II is more frequent than CDA I, with an overall ratio of approximately 3.2, but the ratio also varied between different regions. The most likely explanations for the differences are both differences in the availability of advanced diagnostic procedures and different levels of the awareness for the diagnosis of the CDAs. The estimations reported here are most probably below the true incidence rates, because of failure to make the correct diagnosis and to underreporting. Limited data do not suggest differing levels of risk in identified ethnic groups.

Single nucleotide polymorphism (SNP) analysis demonstrates a significant association of tumour necrosis factor-alpha (TNFA) with primary immune thrombocytopenia among Caucasian adults.

T-helper 1 polarization in patients with primary immune thrombocytopenia (ITP) is well documented. However, the genetic contribution to this imbalance remains unclear. To address this question, we selected six candidate single nucleotide polymorphisms within cytokine or cytokine receptor genes for association testing among Caucasian adults. Patients from the United Kingdom Adult ITP Registry were gender-matched (1:3) with healthy controls from the Wellcome Trust Case Control Consortium. Variants IL10 -819 c>t, TNFA -308 g>a, TGFB1 -509 c>t, IL1A -889 c>t, IL10 -592 c>t, and IL4R q576r were measured in cases and retrieved for controls from the European Genome-phenome Archive. Associations were evaluated using logistic regression models. In total, 206 patients with primary ITP were matched with 618 controls. A significant per allele odds ratio of 1·34 (95% confidence interval, 1·03-1·75; P = 0·03) was observed for TNFA -308 g>a, implicating an increased disease susceptibility among Caucasian carriers of the rare allele.

Global down-regulation of HOX gene expression in PML-RARalpha + acute promyelocytic leukemia identified by small-array real-time PCR.

Acute promyelocytic leukemia (APL) is associated with a reciprocal and balanced translocation involving the retinoic acid receptor-alpha (RARalpha). All-trans retinoic acid (ATRA) is used to treat APL and is a potent morphogen that regulates HOX gene expression in embryogenesis and organogenesis. HOX genes are also involved in hematopoiesis and leukemogenesis. Thirty-nine mammalian HOX genes have been identified and classified into 13 paralogous groups clustered on 4 chromosomes. They encode a complex network of transcription regulatory proteins whose precise targets remain poorly understood. The overall function of the network appears to be dictated by gene dosage. To investigate the mechanisms involved in HOX gene regulation in hematopoiesis and leukemogenesis by precise measurement of individual HOX genes, a small-array real-time HOX (SMART-HOX) quantitative polymerase chain reaction (PCR) platform was designed and validated. Application of SMART-HOX to 16 APL bone marrow samples revealed a global down-regulation of 26 HOX genes compared with normal controls. HOX gene expression was also altered during differentiation induced by ATRA in the PML-RARalpha(+) NB4 cell line. PML-RARalpha fusion proteins have been reported to act as part of a repressor complex during myeloid cell differentiation, and a model linking HOX gene expression to this PML-RARalpha repressor complex is now proposed.

Natural history of GATA1 mutations in Down syndrome.

Acquired mutations in megakaryocyte transcription factor GATA1 have recently been reported in Down syndrome (DS), transient myeloproliferative disorder (TMD), and acute megakaryoblastic leukemia (AMKL). To provide novel insight into GATA1 mutations in DS, genomic DNA was assayed from 12 AMKL and 4 TMD cases (including neonatal, prediagnosis samples in 4 of 16), neonatal blood spots from 21 DS children without clinically evident TMD or AMKL, and 62 non-DS cord blood samples, using techniques not previously employed with such samples. GATA1 mutations were present in all TMD and AMKL cases and at birth in 3 of 4 children without known clinical TMD, who later developed AMKL. They were present at birth in 2 of 21 DS neonates, who have not yet, but could still, develop AMKL (now 26 and 31 months). GATA1 mutations were not detected in 62 non-DS cord blood samples. In 4 AMKL patients multiple independent GATA1 mutations were observed. These data show GATA1 mutations occur in utero in most DS TMD and AMKL, that they may occur without clinical signs of disease, and that multiple separate GATA1 mutant clones can occur in an individual. The findings have implications for pathogenesis of DS TMD and AMKL and highlight parallels between DS AMKL and other childhood leukemias.