Ellis-van Creveld syndrome: Report of a case and recurrent variant.

BACKGROUND: Ellis-van Creveld syndrome (EvCS) is a rare autosomal recessive skeletal dysplasia that is characterized by short stature, short limbs, short ribs, polydactyly and structural heart defect. Despite locus heterogeneity, in the majority of the cases, the disorder segregates with mutations in the EVC and EVC2 genes, notably mutations with truncating protein as a final sequence. In the present study, we report the prenatal findings and genetic analysis of a terminated pregnancy affected by severe thoracic and skeletal dysplasia. METHODS: After detailed physical and clinical examination, whole exome sequencing (WES) was performed and the variant was confirmed by Sanger sequencing. RESULTS: One homozygote variant in EVC2 gene was identified in the fetus (NM_147127, c.942G>A, p.W314X). The EVC2 gene is strongly associated with EvCS, which is consistent with the sonographic findings of the fetus. CONCLUSIONS: The homozygous p.W314X mutation found in this family was recently reported to be segregated in a consanguineous family originating from Pakistan. The occurrence of the p.W314X mutation in two unrelated families (Iranian and Pakistani) may be the result of an old founder effect or arose because of a mutational hotspot and is supporting evidence for the pathogenicity of this variant. Because skeletal dysplasia belongs to a broad spectrum of syndromes and therefore exhibits considerable background locus and allelic heterogeneity, our report highlights the need for appropriate genetic counseling and supports the feasibility of WES to determine an accurate diagnosis, as well as precise recurrence risk prediction.

RPE65 and retinal dystrophy: Report of new and recurrent mutations.

BACHGROUND: Leber congenital amaurosis (LCA) is a severe and congenital or early onset form of inherited retinitis pigmentosa (RP). To date, approximately 25 genes have been introduced in relation to LCA. In this regard, retinal pigment epithelium-specific 65 kDa (RPE65) is a well-known gene mutation that plays a role in the pathogenesis of 5-10% of LCA cases. METHOS: Two individuals fromseparate families were subjected to ehole exome sequencing (WES). Causativevariants were searched further assessed using Sanger sequencing. RESULTS: Here, two families with mutations in the RPE65 gene show severe and early onset LCA, as expected. In addition to the characterization of the phenotype, by reporting a new mutation (c.1451-1G>A), we further expand the mutation spectrum of RPE65. Likewise, as an interesting aspect of our study, we report on a previously reported RP-linked mutation associated with severe early onset LCA (c.T200G:p.L67R). CONCLUSIONS: Considering this variant in different populations, it is likely that it represents a hotspot and affects the function of the coded protein. The variable expressivity of the phenotype can be assumed by the presence of the modifier allele(s) as a result of a different genetic background or the effect of different environments on phenotype expression.

A Clone with 5, 17 and 18 Monosomies as Stemline in a Patient with De novo Acute Myeloid Leukemia.

In brief, we present a case of acute myeloid leukemia (AML) with 5, 17 and 18 monosomies as stemline clonal abnormality in his cytogenetic analysis. To the best of our knowledge, this is the first report of such a chromosomal abnormality as a clonal aberration in AML with M0 French-American-British (FAB) type. It seems that this monosomal karyotype imposed adverse prognosis on this patient and could be related to the rapid and malignant course of the disease as seen.

A mutational and expressional analysis of DNMT3A in acute myeloid leukemia cytogenetic subgroups.

OBJECTIVES: Despite numerous studies in order to determine the allele frequency and clinical impact of DNA methyltransferase 3 A (DNMT3A) gene mutations in acute myeloid leukemia (AML), reports about the expression analysis of this gene are rare and between the available, differences are evident. METHODS: In this study, we decided to investigate DNMT3A possible expression changes with regard to their mutation and cytogenetic status in a series of 96 AML patients. RESULTS: Mutations were founded in 17 of the 96 patients (17.7%) and associated with higher age and white blood cell count (P < 0.001). Our mutants have had shorter overall survival (OS) (P < 0.001) and relapse-free survival (RFS) (P = 0.011) than those without. Multivariate analysis showed that DNMT3A mutation is an independent prognostic indicator for OS and RFS (P < 0.001). In relation to expression results, we had over and under expression for our favorable and unfavorable cytogenetic subgroups, respectively (P = 0.005 and P < 0.001, respectively). In intermediate subgroup, total DNMT3A expression did not alter (P = 0.575). Interestingly, we noticed similar expression results for DNMT3A transcript 2, to that of the total. DISCUSSION AND CONCLUSION: In relation to DNMT3A expression, from the perspective of diagnostic application and its biological significance, it is difficult to accept its primacy over cytogenetic value in favorable and unfavorable subgroups and if so, we did not address this issue in our study due to sample size limitation. In intermediate subgroup, particularly in normal karyotype-AML, given the lack of convincing results, it seems unlikely that DNMT3A expression analysis could attract attention in diagnostic workup and risk prediction of AML.

Intact expression status of RASSF1A in acute myeloid leukemia.

As a typical tumor suppressor gene, transcriptional silencing of ras-association domain family 1, isoform A (RASSF1A) is caused by biallelic methylation or the condition that one allele is methylated and then the other allele lost by allelic loss, as second hit. RASSF1A is inactivated epigenetically and thus down-regulated in many solid tumors. In summary, for the first time, we analyzed the expression status of RASSF1A in a cohort of 56 de novo acute myeloid leukemia (AML) patients using quantitative real-time polymerase chain reaction. Results of our study indicate that patients with AML exhibited no differences in the RASSF1A gene expression comparing to normal controls. In conclusion, expression status of RASSF1A remained intact in our target samples, indicating that RASSF1A expression variation does not participate in the pathogenesis and the progression of AML.

Identification of homogeneously staining regions in leukemia patients.

Homogeneously staining regions (HSR) or double minute chromosomes (dmin) are autonomously replicating extra-chromosomal elements that are frequently associated with gene amplification in a variety of cancers. The diagnosis of leukemia patients was based on characterization of the leukemic cells obtained from bone marrow cytogenetics. This study report two cases, one with Acute Myeloblastic Leukemia without maturation (AML-M1), aged 23-year-old female, and the other with chronic myelogenous leukemia (CML)-blast crisis, a 28-year-old female associated with double minute chromosomes. Most cases of acute myeloid leukemia with dmin in the literature (including our cases) have been diagnosed as having acute myeloid leukemia.