There has been a dramatic increase in the number of insect-specific flaviviruses (ISFs) discovered in the last decade. Historically, these viruses have generated limited interest due to their inability to infect vertebrate cells. This viewpoint has changed in recent years because some ISFs have been shown to enhance or suppress the replication of medically important flaviviruses in co-infected mosquito cells. Additionally, comparative studies between ISFs and medically important flaviviruses can provide a unique perspective as to why some flaviviruses possess the ability to infect and cause devastating disease in humans while others do not. ISFs have been isolated exclusively from mosquitoes in nature but the detection of ISF-like sequences in sandflies and chironomids indicates that they may also infect other dipterans. ISFs can be divided into two distinct phylogenetic groups. The first group currently consists of approximately 12 viruses and includes cell fusing agent virus, Kamiti River virus and Culex flavivirus. These viruses are phylogenetically distinct from all other known flaviviruses. The second group, which is apparently not monophyletic, currently consists of nine viruses and includes Chaoyang virus, Nounané virus and Lammi virus. These viruses phylogenetically affiliate with mosquito/vertebrate flaviviruses despite their apparent insect-restricted phenotype. This article provides a review of the discovery, host range, mode of transmission, superinfection exclusion ability and genomic organization of ISFs. This article also attempts to clarify the ISF nomenclature because some of these viruses have been assigned more than one name due to their simultaneous discoveries by independent research groups.

Two proα1(IV) chains, encoded by COL4A1, form trimers that contain, in addition, a proα2(IV) chain encoded by COL4A2 and are the major component of the basement membrane in many tissues. Since 2005, COL4A1 mutations have been known as an autosomal dominant cause of hereditary porencephaly. COL4A1 and COL4A2 mutations have been reported with a broader spectrum of cerebrovascular, renal, ophthalmological, cardiac, and muscular abnormalities, indicated as \"COL4A1 mutation-related disorders.\" Genetic counseling is challenging because of broad phenotypic variation and reduced penetrance. At the Erasmus University Medical Center, diagnostic DNA analysis of both COL4A1 and COL4A2 in 183 index patients was performed between 2005 and 2013. In total, 21 COL4A1 and 3 COL4A2 mutations were identified, mostly in children with porencephaly or other patterns of parenchymal hemorrhage, with a high de novo mutation rate of 40% (10/24). The observations in 13 novel families harboring either COL4A1 or COL4A2 mutations prompted us to review the clinical spectrum. We observed recognizable phenotypic patterns and propose a screening protocol at diagnosis. Our data underscore the importance of COL4A1 and COL4A2 mutations in cerebrovascular disease, also in sporadic patients. Follow-up data on symptomatic and asymptomatic mutation carriers are needed for prognosis and appropriate surveillance.

We describe seven patients with KDM6A (located on Xp11.3 and encodes UTX) mutations, a rare cause of Kabuki syndrome (KS2, MIM 300867) and report, for the first time, germ-line missense and splice-site mutations in the gene. We demonstrate that less than 5% cases of Kabuki syndrome are due to KDM6A mutations. Our work shows that similar to the commoner Type 1 Kabuki syndrome (KS1, MIM 147920) caused by KMT2D (previously called MLL2) mutations, KS2 patients are characterized by hypotonia and feeding difficulties during infancy and poor postnatal growth and short stature. Unlike KS1, developmental delay and learning disability are generally moderate-severe in boys but mild-moderate in girls with KS2. Some girls may have a normal developmental profile. Speech and cognition tend to be more severely affected than motor development. Increased susceptibility to infections, join laxity, heart, dental and ophthalmological anomalies are common. Hypoglycaemia is more common in KS2 than in KS1. Facial dysmorphism with KDM6A mutations is variable and diagnosis on facial gestalt alone may be difficult in some patients. Hypertrichosis, long halluces and large central incisors may be useful clues to an underlying KDM6A mutation in some patients.

Pontocerebellar hypoplasias (PCH) represent a heterogeneous group of autosomal recessive neurodegenerative disorders characterized by hypoplasia of the cerebellum and pons, variable cerebral involvement, microcephaly, severe delay in cognitive and motor development, and seizures. Seven different subtypes have been reported (PCH1-7) and mutations in three genes, TSEN2, TSEN34 and TSEN54 encoding three of four subunits of the tRNA splicing endonuclease complex have been found to underlie PCH2, PCH4 and PCH5. PCH2 is characterized by cerebellar hypoplasia affecting the hemispheres more severely than the vermis, progressive cerebral atrophy and microcephaly, dyskinesia, seizures, and death in early childhood. We describe a male patient with progressive microcephaly, severe hypotonia, and myoclonic-tonic seizures. Brain MRI confirmed microcephaly with simplified cortical gyration and revealed hypoplasia of the brainstem, cerebellum and cerebellar vermis. Sequencing of the TSEN2 gene detected the novel missense mutation c.934G > A (p.G312R) on one allele and the first nonsense mutation c.691C > T (p.Q231*) on the second allele. Although the cytosine-to-thymine transition results in introduction of a premature stop codon in the majority of annotated TSEN2 transcript variants, it could represent a splice site mutation (c.517-3C > T) in variant 4. However, by RT-PCR analysis we did not identify mRNAs representing TSEN2 transcript form 4 in leukocyte-derived RNA of the patient and healthy individuals. The clinical phenotype of the patient is comparable with PCH2. However, we noticed decreased cerebral volume with increased extra-axial cerebrospinal fluid spaces and wide-open Sylvian fissures indicating cerebral immaturity that might be associated with the TSEN2 null allele. We conclude that the severity of pontocerebellar hypoplasia in the patient fits PCH2, while the large involvement of the cerebrum better corresponds to PCH4 demonstrating the phenotypic spectrum of PCH2 and 4. To establish a possible genotype-phenotype correlation, more individuals with biallelic TSEN2 mutations need to be investigated.

We report on the clinical and array-based characterization of an interstitial 1p31.3 deletion in a 15-year-old male patient with obesity, behavioral problems including multiple psychiatric diagnoses, mild intellectual impairment, facial dysmorphism, and a strong family history of psychiatric illness. The deletion breakpoints were determined by molecular karyotyping, revealing a 3.2 Mb excision. Patients previously reported with hemizygous deletions including this cytogenetic band had intellectual impairment and some facial features that overlap with our patient\'s phenotype. However, their deletions were larger, encompassing several cytogenetic bands, making this case the smallest deletion to date that we are aware of sharing these phenotypic characteristics. There are 17 genes that map to the interval. Two genes within the interval, LEPR and PDE4B, are interesting candidates for these phenotypes because of their potential role in obesity and psychiatric illness, respectively. Identification of the smaller deletion underscores the importance of combining clinical investigation and array comparative genomic hybridization analysis for appropriate diagnosis, genetic counseling and potentially for prenatal diagnosis.

BACKGROUND: In the analysis of microarray data one generally produces a vector of p-values that for each gene give the likelihood of obtaining equally strong evidence of change by pure chance. The distribution of these p-values is a mixture of two components corresponding to the changed genes and the unchanged ones. The focus of this article is how to estimate the proportion unchanged and the false discovery rate (FDR) and how to make inferences based on these concepts. Six published methods for estimating the proportion unchanged genes are reviewed, two alternatives are presented, and all are tested on both simulated and real data. All estimates but one make do without any parametric assumptions concerning the distributions of the p-values. Furthermore, the estimation and use of the FDR and the closely related q-value is illustrated with examples. Five published estimates of the FDR and one new are presented and tested. Implementations in R code are available.
RESULTS: A simulation model based on the distribution of real microarray data plus two real data sets were used to assess the methods. The proposed alternative methods for estimating the proportion unchanged fared very well, and gave evidence of low bias and very low variance. Different methods perform well depending upon whether there are few or many regulated genes. Furthermore, the methods for estimating FDR showed a varying performance, and were sometimes misleading. The new method had a very low error.
CONCLUSIONS: The concept of the q-value or false discovery rate is useful in practical research, despite some theoretical and practical shortcomings. However, it seems possible to challenge the performance of the published methods, and there is likely scope for further developing the estimates of the FDR. The new methods provide the scientist with more options to choose a suitable method for any particular experiment. The article advocates the use of the conjoint information regarding false positive and negative rates as well as the proportion unchanged when identifying changed genes.

OBJECTIVE: To systematically review the experience of therapeutic studies where alpha-interferon with or without ribavirin was administered to patients with lymphoproliferative disorders, in order to evaluate whether eradication of hepatitis C virus may induce regression of lymphoproliferative disorders.
METHODS: We used bibliographical searches in electronic databases and in the Cochrane Library to determine our results.
RESULTS: Sixteen studies where an anti-viral regimen was administered to 65 hepatitis C virus-infected patients with lymphoproliferative disorders were identified. Complete remission of the lymphoproliferative disorder was achieved in 75% of the cases. In contrast, hepatitis C virus-negative subjects did not respond to interferon, indicating that the response in the hepatitis C virus-infected patients is not merely due to the antiproliferative effect of interferon. Remission after HCV eradication was maintained, provided that infection did not reappear. In hepatitis C virus-infected patients with non-Hodgkin\'s lymphoma treated with corticosteroids/chemotherapy liver function tests deterioration did not occur. The addition of interferon to standard chemotherapy may decrease hepatic side-effects of chemotherapy.
CONCLUSIONS: Although it is evident that larger therapeutical trials of anti-viral therapy are needed to determine the role of this strategy in hepatitis C virus-infected patients with lymphoproliferative disorders, encouraging data emerge from recent studies showing that interferon (plus ribavirin) is an attractive therapeutic option for some hepatitis C virus-related low-grade lymphomas.

Most hereditary predispositions to tumours affect only one particular cell type of the body but the genes bearing the relevant germ-line mutation are not cell-type-specific. Some predisposition syndromes include increased risks of lesions (developmental or tumourous) of unrelated cell types, in any individual predisposed to the main lesion (e.g. osteosarcoma in patients predisposed to retinoblastoma). Other predispositions to additional lesions occur only in members of some families with the predisposition to the basic lesion (e.g. Gardner\'s syndrome in some families suffering familial adenomatous polyposis). In yet other predisposition syndromes, different mutations of the same gene are associated with markedly differing family-specific clinical syndromes. In particular, identical germline mutations (e.g. in APC, RET and PTEN genes), have been found associated with differing clinical syndromes in different families. This paper reviews previously suggested mechanisms of the cell-type specificity of inherited predispositions to tumour. Models of tumour formation in predisposition syndromes are discussed, especially those involving a germline mutation (the first \'hit\') of a tumour suppressor gene (TSG) and a second (somatic) hit on the second allele of the same TSG. A modified model is suggested, such that the second hit is a co-mutation of the second allele of the TSG and a regulator which is specific for growth and/or differentiation of the cell type which is susceptible to the tumour predisposition. In some cases of tumour, the second hit may be large enough to be associated with a cytogenetically-demonstrable abnormality of the part of the chromosome carrying the TSG, but in other cases, the co-mutation may be of \'sub-cytogenetic\' size (i.e. 10(2)-10(5) bases). For the latter, mutational mechanisms of frameshift and impaired fidelity of replication of DNA by DNA polyerases may sometimes be involved. Candidate cell-type-specific regulators may include microRNAs and perhaps transcription factors. It is suggested that searching the introns within 10(5)-10(6) bases either side of known of exonic mutations of TSGs associated with inherited tumour predisposition might reveal microRNA cell-type-specific regulators. Additional investigations may involve fluorescent in situ hybridisations on interphase tumour nuclei.