Izabela Makowska

Clinical and molecular-cytogenetic evaluation of a family with partial Jacobsen syndrome without thrombocytopenia caused by an ∼5 Mb deletion del(11)(q24.3)†

Clinical manifestations of Jacobsen syndrome (JBS) depend on the size of the 11qter deletion, which usually varies between ∼7 and 20 Mb. Typical JBS features include developmental delay/mental retardation, short stature, congenital heart defects, thrombocytopenia, and characteristic dysmorphic facial features. We report on a family in which a 4‐year‐old girl as well as her mother and maternal uncle present with subtle features of JBS. Notably, neither thrombocytopenia nor congenital anomalies were detected in this family. Cytogenetic analyses revealed normal karyotypes. Using fluorescence in situ hybridization (FISH) and whole‐genome oligonucleotide array CGH analyses, we identified an ∼5 Mb deletion of the terminal part of chromosome 11q in all the three affected family members. The deletion breakpoint was mapped between 129,511,419 and 129,519,794 bp. This is the smallest deletion reported in a JBS patient. Interestingly, the FLI1 (friend leukemia virus integration 1) hematopoiesis factor gene located ∼6.5 Mb from 11qter and usually deleted in patients with JBS, is intact. Our data support previous hypotheses that FLI1 haploinsufficiency is responsible for thrombocytopenia in patients with JBS.

Basal cell carcinoma of the skin: whole genome screening by comparative genome hybridization revisited.

Basal cell carcinoma (BCC) of the skin is considered to be the most common malignancy in people of European ancestry. It is often not clinically aggressive and has been regarded as genetically stable. However, histopathologic subtypes of BCC differ in their ability to invade surrounding tissues and recur. The aim of this work was to present a comprehensive study of chromosomal imbalances of cutaneous BCC and to correlate the findings with their histopathologic and clinical features. In all, 101 tumor samples were classified according to the current microscopic classification of BCC and then analyzed by comparative genomic hybridization (CGH). Over 60% of BCC were found to carry chromosomal imbalances – partial or whole chromosome gains and losses. Different subtypes of BCC presented common chromosomal alterations. No single chromosomal imbalance was found to be characteristic of a particular subtype of BCC, although the frequency of some chromosomal changes differed from one group to the other. The significance of chromosome 2 gains as a phenomenon that does not coexist with the losses in 9q is discussed.

DNA methylation analysis of ade novo balanced X;13 translocation in a girl with abnormal phenotype: evidence for functional duplication of the whole short arm of the X chromosome

We report on a 13-month-old girl showing dysmorphic features and a delay in psychomotor development. She was diagnosed with a balancedde novo translocation 46, X, t(X;13)(p11. 2;p13) and non-random inactivation of the X chromosome. FISH analysis, employing the X chromosome centromere andXIST-region-specific probes, showed that theXIST locus was not involved in the translocation. Selective inactivation of paternal X, which was involved in translocation, was revealed by the HUMARA assay. The pattern of methylation of 5 genes located within Xp, which are normally silenced on an inactive X chromosome, corresponded to an active (unmethylated) X chromosome. These results revealed that in our proband the X chromosome involved in translocation (Xt) was preferentially inactivated. However, genes located on the translocated Xp did not includeXIST. This resulted in functional Xp disomy, which most probably accounts for the abnormal phenotype in our patient.

Somatic Mosaicism in Esophageal Atresia

patients and accessibility of direct-acting anti-HCV agents (DAA). Dr Muir has presented a timely and balanced review of the prevalence and treatment strategies for chronic HCV, but we have a long way to go in terms of treating a sizeable proportion of those affl icted ( 1 ) . While HCV is highly prevalent, aff ecting more than four million patients ( 2 ) , only 25% of these cases are known ( 3 ) . Active eff orts to detect cases using the new Centers for Disease Control and Prevention screening guidelines are needed. As we cannot wait to treat a certain group of patients with risk factors for rapid progress of fi brosis or with advanced fi brosis, DAA defi nitely have great value and excellent cost-saving potential in these cases in the short and long run. However, for asymptomatic 0–2 fi brosis cases the value of this treatment may be relatively lower, as two-thirds may have slow progression and one-third may not develop cirrhosis ( 4 ) ( http://www.cdc.gov/hepatitis/HCV/ HCVfaq.htm#section1 ). For asymptomatic patients with the early disease without risk factors, can we wait for short periods for the more cost-eff ective regimens to appear? In addition, as rightly stated by Dr Muir, there are concerns about the accessibility of DAA. Dr Muir’s article implies ~60% of HCV patients are likely uninsured or under Medicaid and/or Medicare. A sizeable number may not have any insurance due to some states’ rejection of federal money for Medicaid expansion ( 1 ) . Only one-third of the HCV patients have private insurance ( 1 ) . Th is could have chilling eff ects on both public (Medicaid/Medicare/health exchanges) and private healthcare funding agencies. Many payers do not have the money to fund these expensive treatments. For example, Oregon’s Medicaid needed

The PTPN13 Y2081D (T>G) (rs989902) polymorphism is associated with an increased risk of sporadic colorectal cancer

360 million to cover DAA alone, whereas its total annual prescription drug budget is only

Polymorphisms in nucleotide excision repair genes and basal cell carcinoma of the skin

370 million ( http://www.washingtonpost.com/blogs/ wonkblog/wp/2014/07/24/the-drugthats-forcing-americas-most-importantand-uncomfortable-health-care-debate/ ). Owing to high costs, many state Medicaid agencies have already restricted the use of DAA to solely stage 3–4 fi brosis cases. Th e inaccessibility of DAA cases also raises the following issue: what treatment options are available for Medicaid patients with stage 0–2 chronic HCV, or for patients supported by lower-budget county health plans that support older regimens through non-profi t foundations, since American Association for the Study of Liver Diseases/Infectious Diseases Society of America (AASLD/ IDSA) guidelines do not recommend older regimens like ribavirin/pegylated interferon/ 1st gen protease inhibitor treatment (even though they are 65–80% eff ective) ( http://www.hcvguidelines.org/full-report/ initial-treatment-hcv-infection-patientsstarting-treatment )? Hopefully, we will formulate a more pragmatic regimen within the next 18–24 months. By this time multiple new products will hopefully be approved, and free market competition will bring prices down to an aff ordable level. However, there is concern that a “shadow pricing” strategy may limit the decline in price ( http://www.washingtonpost.com/blogs/wonkblog/wp/2014/07/24/ the-drug-thats-forcing-americas-mostimportant-and-uncomfortable-health-caredebate/ ). As providers, we should continue to seek better coverage for our vulnerable patients and work to improve detection of this disease.

[Rapid diagnosis of the most common fetal aneuploidies with the QF-PCR method--a study of 100 cases].

Colorectal cancer (CRC) is one of the most common cancers worldwide and, although the majority of cases are sporadic, its development and progression depends on a range of factors: environmental, genetic and epigenetic. A variety of genetic pathways have been described as being crucial in CRC, including protein tyrosine phosphatases (PTPs). PTPN13 (also called FAP‐1) is a non‐receptor PTP and interacts with a number of important components of growth and apoptosis pathways. It is also involved in the inhibition of Fas‐induced apoptosis.

[Rapid-FISH--fast and reliable method of detecting common numerical chromosomal aberrations in prenatal diagnosis].

Mutations in nucleotide excision repair (NER) genes are the cause of xeroderma pigmentosum, a genetic syndrome with proneness to basal cell carcinoma (BCC) of the skin. Single nucleotide polymorphisms (SNPs) may affect the effectiveness of DNA repair and hence influence individual susceptibility to a variety of neoplasms. The aim of this study was to find associations between SNPs in selected NER genes and sporadic BCC development.