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Dyskeratosis congenita (DKC) is an inherited bone marrow failure (BMF) syndrome typified by reticulated skin pigmentation, nail dystrophy, and mucosal leukoplakia. Hoyeraal-Hreidarsson syndrome (HHS) is considered to be a severe form of DKC. Unconventional forms of DKC, which develop slowly in adulthood but without the physical anomalies characteristic of DKC (cryptic DKC), have been reported. Clinical and genetic features of DKC have been investigated in Caucasian, Black, and Hispanic populations, but not in Asian populations. The present study aimed to determine the clinical and genetic features of DKC, HHS, and cryptic DKC among Japanese patients. We analyzed 16 patients diagnosed with DKC, three patients with HHS, and 15 patients with cryptic DKC. We found that platelet count was significantly more depressed than neutrophil count or hemoglobin value in DKC patients, and identified DKC patients with large deletions in the telomerase reverse transcriptase and cryptic DKC patients with RTEL1 mutations on both alleles. This led to some patients previously considered to have unclassifiable BMF being diagnosed with cDKC through identification of new gene mutations. It thus seems important from a clinical viewpoint to re-examine the clinical characteristics, frequency of genetic mutations, and treatment efficacy in DKC, HHS, and cDKC. [ABSTRACT FROM AUTHOR]

Primary immunodeficiency disease (PID) is caused by mutations of more than two hundred immunity-related genes. In addition to the heterogeneity of the diseases, the atypical presentation of each disease caused by hypomorphic mutations or somatic mosaicism makes genetic diagnosis challenging. Next-generation sequencing tests all genes simultaneously and has proven its innovative efficacy in genomics. We describe a male PID patient without any family history of immunodeficiency. This patient suffered from recurrent infections from 1 year of age. Laboratory analysis showed hypogammaglobulinemia. T, B, and NK cells were present, but the T cell proliferative response decreased. Whole-exome sequencing analysis identified an IL2RG p.P58T missense mutation. CD8 and CD56 cells showed revertant somatic mosaicism to the wild-type allele. A late-onset and atypical presentation of the X-linked severe combined immunodeficiency (X-SCID) phenotype might be associated with revertant somatic mosaicism in T and NK cells. This patient is the seventh reported case of X-SCID with revertant somatic mosaicism. His classical clinical management did not result in a molecular diagnosis because of the atypical presentation. The coverage that is provided by whole-exome sequencing of most PID genes effectively excluded differential diagnoses other than X-SCID. As next-generation sequencing becomes available in clinical practice, it will enhance our knowledge of PID and rescue currently undiagnosed patients. [ABSTRACT FROM AUTHOR]

ABSTRACT Drug-resistant cytomegalovirus appears during prolonged anti-cytomegalovirus therapy. Assays for human cytomegalovirus viral protein kinase (UL97) and viral DNA polymerase (UL54) gene mutations conferring drug resistance have been used rather than susceptibility assays to assess clinical specimens. In this study a sensitive system for genotype assay of UL97 and UL54 in clinical specimens with as few as six copies/µg of DNA was developed. [ABSTRACT FROM AUTHOR]

Myelodysplastic/myeloproliferative uclassifiable ( MDS/ MPN- U) is a rare myeloid neoplasm characterized by myelodysplasia and myeloproliferation at the time of initial presentation, which is usually a diagnosis of exclusion. The molecular pathogenesis of MDS/ MPN- U patients remains to be elucidated. Among five patients diagnosed with MDS/ MPN- U, three patients harboured RUNX1 ( AML1) mutations; one carried somatic mosaicism of RUNX1 mutation with JAK2V617F mutation and one had dual RUNX1 and FLT3-internal tandem duplication mutations with progression to acute myeloid leukaemia ( AML). Germline mutation of TP53 was detected as a sole genetic lesion in one patient. JAK2V617F and somatic mosaicism of KRAS and TET2 mutations co-existed in one patient. Otherwise, no alterations were detected in PTPN11, NRAS, CBL and ASXL1 genes. ETV6- PDGFRB fusion transcript was not detected in all patients. Four patients recieved haematopoietic stem cell transplantation ( HSCT); three patients relapsed and one achieved complete remission after three donor lymphocyte infusions. Our findings suggest that the mutational spectrum observed in childhood MDS/ MPN- U is quite different from that seen in juvenile myelomonocytic leukaemia and, to some extent, resemble chronic myelomonocytic leukaemia. Moreover, two patients had constitutional alterations of genes frequently found in AML. Further investigations are required to define the roles of these genetic alterations in the pathogenesis of childhood MDS/ MPN- U. [ABSTRACT FROM AUTHOR]

Summary While acute megakaryoblastic leukaemia (AMKL) occurs in children with (DS-AMKL) and without (paediatric non-DS-AMKL) Down syndrome, it can also affect adults without DS (adult non-DS-AMKL). We have analysed these subgroups of patients (11 children with DS-AMKL, 12 children and four adults with non-DS-AMKL) for the presence of molecular lesions, including mutations and chromosomal abnormalities studied by sequencing and single nucleotide polymorphism array-based karyotyping, respectively. In children, AMKL was associated with trisomy 21 (somatic in non-DS-AMKL), while numerical aberrations of chromosome 21 were only rarely associated with adult AMKL. DS-AMKL was also associated with recurrent somatic gains of 1q (4/11 DS-AMKL patients). In contrast to trisomy 21 and gains of 1q, other additional chromosomal lesions were evenly distributed between children and adults with AMKL. A mutational screen found GATA1 mutations in 11/12 DS-AMKL, but mutations were rare in paediatric non-DS-AMKL (1/12) and adult AMKL (0/4). JAK3 (1/11), JAK2 (1/11), and TP53 mutations (1/11) were found only in patients with DS-AMKL. ASXL1, IDH1/2, DNMT3A, RUNX1 and CBL mutations were not found in any of the patient group studied, while NRAS mutation was identified in two patients with paediatric non-DS-AMKL. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented concerning a case of MYH9 gene mutation associated with macrothrombocytopenia without Alport manifestation.

The article informs that mutation in THPO gene which encodes thrombopoietin is not associated with Aplastic Anaemia (AA). It mentions that THPO is the causative gene for congenital amegakaryocytic thrombocytopenia (CAMT). It further mentions that for the determination of THPO association, the gene sequence consisting of 12 exons were analyzed and these exons were amplified by polymerase chain reaction of genomic DNA from patients with AA. It concludes that no THPO mutations were found.

The article discusses the pathological mutation of the human gene SIPA1 in patients with juvenile myelomonocytic leukemia (JMML). Although the malignancy is typically associated with constructive activation of the granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor/Ras/Raf/MEK/ERK signaling, the researchers claim that its correlation with the SIPA1 gene is unlikely.

Abstract Background Supravalvular aortic stenosis (SVAS) is a congenital heart disease affecting approximately 1:25,000 live births. SVAS may occur sporadically, be inherited in an autosomal dominant manner, or be associated with Williams-Beuren syndrome, a complex developmental disorder caused by a microdeletion of chromosome 7q11.23. ELN on 7q11.23, which encodes elastin, is the only known gene to be recurrently mutated in less than half of SVAS patients. Methods Whole-exome sequencing (WES) was performed for seven familial SVAS families to identify other causative gene mutations of SVAS. Results Three truncating mutations and three intragenic deletions affecting ELN were identified, yielding a diagnostic efficiency of 6/7 (85%). The deletions, which explained 3/7 of the present cohort, spanned 1–29 exons, which might be missed in the course of mutational analysis targeting point mutations. The presence of such deletions was validated by both WES-based copy number estimation and multiplex ligation-dependent probe amplification analyses, and their pathogenicity was reinforced by co-segregation with clinical presentations. Conclusions The majority of familial SVAS patients appear to carry ELN mutations, which strongly indicates that elastin is the most important causative gene for SVAS. The frequency of intragenic deletions highlights the need for quantitative tests to analyze ELN for efficient genetic diagnosis of SVAS. Highlights • Six novel mutations affecting ELN were identified in seven families with SVAS. • Intragenic deletions of ELN were frequent (3/7) in cases with familial SVAS. • Quantitative tests of ELN should be performed for genetic diagnosis of SVAS. [ABSTRACT FROM AUTHOR]

Congenital macrothrombocytopenia (CMTP) is a heterogeneous group of rare platelet disorders characterized by a congenital reduction of platelet counts and abnormally large platelets, for which CMTP-causing mutations are only found in approximately half the cases. We herein performed whole-exome sequencing and targeted Sanger sequencing to identify mutations that cause CMTP, in which a dominant mode of transmission had been suspected but for which no known responsible mutations have been documented. In 13 Japanese CMTP-affected pedigrees, we identified six (46%) affected by ACTN1 variants cosegregating with CMTP. In the entire cohort, ACNT1 variants accounted for 5.5% of the dominant forms of CMTP cases and represented the fourth most common cause in Japanese individuals. Individuals with ACTN1 variants presented with moderate macrothrombocytopenia with anisocytosis but were either asymptomatic or had only a modest bleeding tendency. ACTN1 encodes a-actinin-1, a member of the actin-crosslinking protein superfamily that participates in the organization of the cytoskeleton. In vitro transfection experiments in Chinese hamster ovary cells demonstrated that altered α-actinin-1 disrupted the normal actin-based cytoskeletal structure. Moreover, transduction of mouse fetal liver-derived megakaryocytes with disease-associated ACTN1 variants caused a disorganized actin-based cytoskeleton in megakaryocytes, resulting in the production of abnormally large proplatelet tips, which were reduced in number. Our findings provide an insight into the pathogenesis of CMTP. [ABSTRACT FROM AUTHOR]

Juvenile myelomonocytic leukemia (JMML) is a rare pediatric myeloid neoplasm char-acterized by excessive proliferation of myelomonocytic cells. Somatic muta-tions in genes involved in GM-CSF signal transduction, such as NRAS, KRAS, PTPN11, NF1, and CBL, have been identi-fied in more than 70% of children with JMML. In the present study, we report 2 patients with somatic mosaicism for oncogenic NRAS mutations (G12D and G12S) associated with the development of JMML. The mutated allele frequencies quantified by pyrosequencing were vari-ous and ranged from 3%-50% in BM and other somatic cells (ie, buccal smear cells, hair bulbs, or nails). Both patients experi-enced spontaneous improvement of clinical symptoms and leukocytosis due to JMML without hematopoietic stem cell transplantation. These patients are the first reported to have somatic mosaicism for oncogenic NRAS mutations. The clini-cal course of these patients suggests that NRAS mosaicism may be associated with a mild disease phenotype in JMML. [ABSTRACT FROM AUTHOR]