A Val66Met polymorphism is associated with weaker somatosensory cortical activity in individuals with cerebral palsy.

Background: The brain-derived neurotrophic factor (BDNF) protein plays a prominent role in the capacity for neuroplastic change. However, a single nucleotide polymorphism at codon 66 of the BDNF gene results in significant reductions in neuroplastic change. Potentially, this polymorphism also contributes to the weaker somatosensory cortical activity that has been extensively reported in the neuroimaging literature on cerebral palsy (CP). Aims: The primary objective of this study was to use magnetoencephalography (MEG) to probe if BDNF genotype affects the strength of the somatosensory-evoked cortical activity seen within individuals with CP. Methods and procedures: and Procedures: Twenty individuals with CP and eighteen neurotypical controls participated. Standardized low resolution brain electromagnetic tomography (sLORETA) was used to image the somatosensory cortical activity evoked by stimulation of the tibial nerve. BDNF genotypes were determined from saliva samples. Outcomes and results: The somatosensory cortical activity was weaker in individuals with CP compared to healthy controls (P = 0.04). The individuals with a Val66Met or Met66Met BDNF polymorphism also showed a reduced response compared to the individuals without the polymorphism (P = 0.03), had higher GMFCS levels (P = 0.04), and decreased walking velocity (P = 0.05). Conclusions and implications: These results convey that BDNF genotype influences the strength of the somatosensory activity and mobility in individuals with CP. What this paper adds: Previous literature has extensively documented altered sensorimotor cortical activity in individuals with CP, which ultimately contributes to the clinical deficits in sensorimotor processing documented in this population. While some individuals with CP see vast improvements in their sensorimotor functioning following therapeutic intervention, others are clear non-responders. The underlying basis for this discrepancy is not well understood. Our study is the first to identify that a polymorphism at the gene that codes for brain derived neurotrophic factor (BDNF), a protein well-known to be involved in the capacity for neuroplastic change, may influence the altered sensorimotor cortical activity within this population. Potentially, individuals with CP that have a polymorphism at the BDNF gene may reflect those that have difficulties in achieving beneficial outcomes following intervention. Thus, these individuals may require different therapeutic approaches in order to stimulate neuroplastic change and get similar benefits from therapy as their neurotypical peers.

Frequency, variations, and prognostic implications of chromosome 14q32 deletions in chronic lymphocytic leukemia.

The clinical implications of deletions within chromosome 14q32 in CLL pathogenesis remain unclear. We examined the frequency of 14q32 deletions among CLL cases by karyotype and FISH, categorized the variation using genomic microarray, and assessed the prognostic impact by time-to-first-treatment (TTFT) analysis. A 14q32 abnormality was detected in 35 % (245/698) of cases, with the majority containing a 5' partial telomeric 14q32 deletion. These deletions within the IGH variable region (35/40) ranged from 236 kb to 1.4 Mb involving FAM30A, ADAM6, LINC00226, and LINC00221. The 214 kb minimum deleted region implicated in CLL pathogenesis encompassed LINC00221. Cases with a 14q32 deletion had a shorter median TTFT compared to cases with a sole deletion/nullisomy 13q, a good prognostic indicator, and longer than cases with a sole deletion of 11q or 17p, conferring an unfavorable prognosis. This investigation underscores the importance of comprehensive testing to apprehend the implications of 14q32 deletions in CLL.

The QT Interval in Patients With the Turner Syndrome.

Patients with the Turner syndrome (TS) often have longer QT intervals compared with age-matched peers although the significance of this remains unknown. We sought to determine the degree, frequency and impact of QTc prolongation in patients with TS. A chart review of all patients with an electrocardiogram (ECG) and genetically proven TS was performed. Medications at the time of the ECG were reviewed and QTc calculated. Medications were classified according to QTc risk using www.crediblemeds.com. ECG parameters were compared with an age, gender, and cardiac lesion-matched control group. Over the 10-year period of review, 112 TS patients with a mean age of 34 ± 25 years underwent 226 ECGs. At least 1 QTc prolonging medication was prescribed in 81 (74%) patients. Longer QTc interval correlated with absence of y chromosomal material (p = 0.01), older age (p <0.0001), increased number of QTc prolonging and nonprolonging medications (p <0.0001 each). During the 7.0 ± 5.1 years of follow-up, no patient had ventricular arrhythmia or unexplained sudden death. QTc was significantly shorter in matched controls using either Bazett or Hodges formula (424 ± 16 ms vs 448 ± 28 ms, p <0.0001; and 414.8 ± 16 ms vs 424.2 ± 20 ms; p = 0.0002, respectively). However, there was no difference in the frequency of QTc prolongation >460 msec (2.8% vs 2.6%, p = 0.9). In conclusion, despite frequent use of QT-prolonging medications, ventricular arrhythmias are rare in TS.

Vascular dissection in women with Turner syndrome.

BACKGROUND: The frequency of ascending aortic dissection in patients with Turner syndrome in the United States remains largely unknown with data surmised from published case reports or case series. Dissection of other vascular structures has only rarely been reported in this patient cohort. Recent European data identified aortic dissection to be a relatively rare event in a group of adult women with Turner syndrome. We sought to evaluate the prevalence of, and risk factors for, vascular dissection in women with Turner syndrome followed in the United States. METHOD: Retrospective review of all adult patients (age > 18 years) with Turner syndrome seen by any medical care provider within 2 medical systems covering a 5 state referral base was performed. Demographic, clinical, surgical and imaging variables of interest were recorded. RESULTS: Vascular dissection occurred in 16 (4.1%) of the 393 adult women and prophylactic aortic replacement occurred in 14 (3.5%). Only 35% of patients were under the care of a cardiologist with the remainder followed exclusively by other care providers. Vascular dissections occurred in the ascending & descending aorta as well as pulmonary artery and cerebral vessels. In addition to bicuspid aortic valve, and prior cardiac surgery, risk factors for vascular dissection included rural residence and lack of ongoing care by a cardiologist. CONCLUSION: Transition to adult cardiology subspecialty care is lacking in patients with Turner syndrome. Aortic dissection is not uncommon. Ongoing interaction with a cardiologist is essential to optimize cardiac outcomes in those with cardiac risk factors and may best be accomplished with centralized multidisciplinary clinics.

The recurrent TUBB3 Gly98Ser substitution is the first described to inconsistently result in CFEOM3.

Missense variants in TUBB3 have historically been associated with either congenital fibrosis of the extraocular muscles type 3 (CFEOM3) or malformations of cortical development (MCD). Until a recent report identified two amino acid substitutions in four patients that had clinical features of both disorders, pathogenic variants of TUBB3 were thought distinct to either respective disorder. Three recurrent de novo Gly71Arg TUBB3 substitutions and a single patient with a de novo Gly98Ser substitution blurred the MCD and CFEOM3 phenotypic distinctions. Here we report a second patient with a missense c.292G>A (p.Gly98Ser) substitution, but without CFEOM3, the first reported evidence that even the same TUBB3 substitution can produce a spectrum of TUBB3 syndrome phenotypes. Our patient presented with amblyopia, exotropia, optic disc pallor, and developmental delay. Neuroimaging identified hypoplasia of the corpus callosum, interdigitation of the frontal lobe gyri, and dysplasia or hypoplasia of the optic nerves, basal ganglia, brainstem, and cerebellum. This report identifies the TUBB3 Gly98Ser substitution to be recurrent but inconsistently including CFEOM3, and identifies the absence of joint contractures and the presence of optic disc abnormalities that may be genotype-specific to the TUBB3 Gly98Ser substitution.

MECOM rearrangement involving the MYC locus: Two additional patients with the rare translocation, t(3;8)(q26.2;q24), and molecular review.

A relatively small subset of myeloid neoplasms involve rearrangements of cytoband 3q26.2. Such rearrangements are often in response to therapy and carry a poor prognosis. The ectopic expression of MECOM is the result of such translocations. To date, thirty-three t(3;8)(q26.2;q24) cases have been reported; we contribute two patients with confirmed MECOM and MYC rearrangements. Both patients presented with pancytopenia and were diagnosed with myelodysplastic/myeloproliferative disorders. In addition to translocation t(3;8), Patient 1 possessed a derivative chromosome 5, while Patient 2 possessed monosomy 7; neither patient's clonal abnormalities resolved in follow-up studies. Of the previous 33 cases, one exhibited 5q loss, while monosomy 7 was found in fifteen. These findings contribute to the small number of reported cases with t(3;8) translocations. We also speculate about the molecular mechanisms associated with this translocation.

High-risk cytogenetics in multiple myeloma: Further scrutiny of deletions within the IGH gene region enhances risk stratification.

Multiple myeloma is a clonal malignancy of plasma cells in the bone marrow. Risk stratification is partly based on cytogenetic findings that include abnormalities of the IGH locus as determined by fluorescence in situ hybridization (FISH), such as rearrangements that result in either standard-risk or high-risk gene fusions. IGH deletions have been evaluated as a group in multiple myeloma patients with respect to cumulative outcomes but have provided limited guidance. Whether these deletions have the potential to result in gene fusions and thus further stratify patients is unknown. We identified 229 IGH deletions in patients referred for plasma cell dyscrasia genetic testing over 5.5 years. Follow-up was conducted on 208 of the deletions with dual fusion FISH probes for standard-risk (IGH-CCND1) and high-risk IGH gene fusions (IGH-FGFR3, IGH-MAF, IGH-MAFB). Of all deletions identified with follow-up, 44 (21%) resulted in a gene fusion as detected by FISH, 15 (7%) of which were fusion partners associated with high-risk multiple myeloma. All fusion-positive 3'-IGH deletions (6 fusions) resulted in high-risk IGH-FGFR3 fusions. Of the 15 high-risk fusion-positive cases, eight were without other high-risk cytogenetic findings. This study is the first to evaluate the presence of IGH gene fusions upon identification of IGH deletions and to characterize the deletion locus. Importantly, these findings indicate that follow-up FISH studies with dual fusion probes should be standard of care when IGH deletions are identified in multiple myeloma.

Valve-Sparing Root and Total Arch Replacement for Cutis Laxa Aortopathy.

Aortic aneurysms requiring surgery in early childhood are rare. Herein we describe the case of a three-year-old with massive aneurysmal aortic dilation secondary to the rare and often lethal genetic disorder, cutis laxa. Initial thoracic aortic aneurysm gene panel was negative. Parents of the child were not known to be consanguineous, but high-density SNP array revealed several regions of homozygosity. This prompted targeted sequence analysis that identified a novel homozygous missense mutation in the gene for cutis laxa, EFEMP2. The patient underwent aortic valve-sparing aortic root and ascending aorta replacement and total aortic arch replacement, with continuous, moderately hypothermic cardiopulmonary bypass, using a dual cannulation technique. He was discharged well on the third postoperative day and remains free of aneurysmal disease at two-year follow-up.

Copy number variant discrepancy resolution using the ClinGen dosage sensitivity map results in updated clinical interpretations in ClinVar.

Conflict resolution in genomic variant interpretation is a critical step toward improving patient care. Evaluating interpretation discrepancies in copy number variants (CNVs) typically involves assessing overlapping genomic content with focus on genes/regions that may be subject to dosage sensitivity (haploinsufficiency (HI) and/or triplosensitivity (TS)). CNVs containing dosage sensitive genes/regions are generally interpreted as "likely pathogenic" (LP) or "pathogenic" (P), and CNVs involving the same known dosage sensitive gene(s) should receive the same clinical interpretation. We compared the Clinical Genome Resource (ClinGen) Dosage Map, a publicly available resource documenting known HI and TS genes/regions, against germline, clinical CNV interpretations within the ClinVar database. We identified 251 CNVs overlapping known dosage sensitive genes/regions but not classified as LP or P; these were sent back to their original submitting laboratories for re-evaluation. Of 246 CNVs re-evaluated, an updated clinical classification was warranted in 157 cases (63.8%); no change was made to the current classification in 79 cases (32.1%); and 10 cases (4.1%) resulted in other types of updates to ClinVar records. This effort will add curated interpretation data into the public domain and allow laboratories to focus attention on more complex discrepancies.

Lymphomas with pseudo-double-hit BCL6-MYC translocations due to t(3;8)(q27;q24) are associated with a germinal center immunophenotype, extranodal involvement, and frequent BCL2 translocations.

High-grade B-cell lymphomas with MYC, BCL2, and/or BCL6 rearrangements, "double-hit" or "triple-hit" lymphomas (DTHL), are aggressive neoplasms associated with a poor prognosis. A t(3;8)(q27;q24) rarely occurs in B-cell lymphomas that results in a unique "pseudo-double-hit" BCL6-MYC fusion, indistinguishable by interphase fluorescence in situ hybridization (FISH) from more conventional DTHL with independent MYC and BCL6 translocations. Reports of t(3;8)(q27;q24) lymphomas are sparse, and to better characterize their pathologic, cytogenetic, and clinical features, 6 new cases from 2 institutions and 19 previously published cases were reviewed. All new cases displayed aggressive morphologic features, and most previously published cases were classified as aggressive lymphomas. Collectively, all t(3;8)(q27;q24) cases had a germinal center (GC) phenotype, and most had complex karyotypes (22/24, 92%), including frequent concomitant BCL2 rearrangements (17/24, 71%). When compared to two large published DTHL cohorts, t(3;8)(q27;q24) lymphomas less often expressed BCL2 (P < .01), had a greater likelihood of extranodal involvement (P < .01), and more frequently appeared triple-hit by FISH analysis (P < .01). Despite presenting with aggressive clinicopathologic features, 100% (6/6) of t(3;8;)(q27;q24) patients achieved complete remission after intensive induction regimens, and 2- and 3-year overall survival rates were 63% (10/16) and 57% (8/14), respectively. These findings suggest that lymphomas with t(3;8)(q27;q24) may represent a subset of GC B-cell lymphomas distinct from conventional DTHL. Our results further highlight the value of routine karyotype assessment in aggressive B-cell lymphomas, and the importance of recognizing the t(3;8)(q27;q24) so that its clinical significance can be more fully explored.

ALK-positive Large B-cell Lymphoma: A Clinicopathologic Study of 26 Cases With Review of Additional 108 Cases in the Literature.

Anaplastic lymphoma kinase-positive large B-cell lymphoma (ALK LBCL) is a rare, aggressive subtype of diffuse large B-cell lymphoma with characteristic ALK rearrangements. Diagnosis of ALK LBCL can be challenging because of its rarity, unique morphologic characteristics, and unusual immunophenotypic features, which significantly overlap with other hematologic and nonhematologic neoplasms. The purpose of this study is to further explore the clinicopathologic features of ALK LBCL to ensure the awareness and accurate diagnosis of this entity. We retrospectively reviewed the data from 26 cases in our institutions and additional 108 cases from the literature. ALK LBCL typically occurred in the lymph nodes of young and middle-aged, immunocompetent patients. The medium age was 35 years with a male to female ratio of 3.5:1. Vast majority of cases showed immunoblastic and/or plasmablastic morphology. All cases expressed ALK protein with a cytoplasmic granular pattern in most of them. Common B-cell markers (CD20, CD79a, and PAX5) were typically negative, but the tumor cells mostly expressed 2 B-cell transcriptional factors, BOB1 and OCT2. The 5-year overall survival (OS) was 34%, and the median survival was 1.83 years. In patients with stage III/IV disease, the 5-year OS was only 8%. Moreover, patients below 35 years of age had a significantly better OS than those aged 35 years or above.

Karyotypic abnormalities associated with Epstein-Barr virus status in classical Hodgkin lymphoma.

Classical Hodgkin lymphoma (CHL) is morphologically characterized by scattered malignant Hodgkin/Reed-Sternberg (HRS) cells that are far outnumbered by surrounding reactive hematolymphoid cells. Approximately half of all cases of CHL are associated with infection by Epstein-Barr virus (EBV), an oncogenic herpesvirus that expresses a number of proteins thought to contribute to transformation. While a small number of published studies have attempted to identify recurrent cytogenetic abnormalities in CHL, no large case series have explored karyotypic differences between EBV-positive and EBV-negative tumors. Here, we report a two-institution retrospective investigation of cytogenetic features characterizing CHL. In our cohort, cases of EBV-negative CHL were characterized by more complex routine karyotypes than their EBV-positive counterparts (24.6 versus 15.6 independent aberrations per case, P = 0.009). The increased complexity of EBV-negative cases was driven by a number of features suggestive of genomic instability, including a larger number of independent chromosomal breakpoints (P = 0.03) and apparently aneuploid autosomes (P = 0.008). Compelling but nonsignificant trends also suggest a larger modal number and increased marker chromosomes in EBV-negative cases (P = 0.13 and 0.06, respectively). While some of these differences are related to histologic subtype, others appear independent of histology. Finally, a significant subset of EBV-positive tumors has a surprisingly simple karyotype relative to what is normally seen in CHL, an observation suggesting considerable biological and genetic diversity in this disease.

The first patient with tandem duplication of 6q14q16: Molecular and phenotypic characterization.

Duplications of the long arm of chromosome 6 have been previously reported in a limited number of patients; however, most reported duplications encompass regions of chromosome 6 distal to band q21. Duplications restricted to the proximal portion of 6q are rare. We report an 8-year-old male with a 16.4 megabase (Mb) tandem duplication of chromosome 6q14.1q16.1 (chr6:78950191-95395865; hg19) who exhibited dysmorphic facial features, seizures, global developmental delay, intellectual disability, autism spectrum disorder, sensorineural hearing loss, and immune deficiency. This patient refines and potentially expands the current, poorly-characterized phenotype associated with duplication of this proximal 6q region. We recommend a low threshold for a hearing evaluation beyond newborn screening and for pursuing an immune work-up in patients with similar 6q duplications. © 2016 Wiley Periodicals, Inc.

A formalin-free method for stabilizing cells for nucleic acid amplification, hybridization and next-generation sequencing.

BACKGROUND: Formalin has been widely used by pathology laboratories. Its carcinogenicity has led researchers to explore formalin substitutes. Streck Cell Preservative (SCP) is a formalin-free preservative that can preserve cellular antigens. This study was undertaken to investigate the effects of cell preservation using SCP on nucleic acid amplification, hybridization, and next-generation sequencing (NGS) as compared to control frozen cells and cells fixed in the traditional cell and tissue fixative, 10 % neutral buffered formalin (NBF). FINDINGS: The breast cancer cell line, SKBR-3, was used as a model system. Prior to nucleic acid extraction and fluorescence in situ hybridization (FISH), cells were fixed in SCP or NBF overnight at room temperature with frozen cells in parallel. Analysis showed that similar DNA extraction yields and amplification profiles determined by PCR in SCP preserved cells and control frozen cells, whereas NBF preserved cells had decreased DNA yield and impaired PCR amplification. Molecular cytogenetic studies by FISH technique indicated that the ratios of ERBB2 (HER-2/neu) signals to the chromosome 17 centromere (CEP17) were comparable for frozen cells and SCP preserved cells. The fluorescence images of both SCP fixed and control frozen cells were also clear and comparable. On the contrary, the same analysis was unsuccessful with NBF preserved cells due to poor hybridization quality. Our data also demonstrated that SCP had negligible effect on NGS testing. CONCLUSION: We conclude that SCP can be used as an alternative to NBF as a preservative for maintaining the integrity of nucleic acids for nucleic acid amplification, sequencing and FISH analysis.

Myhre syndrome: Clinical features and restrictive cardiopulmonary complications.

Myhre syndrome, a connective tissue disorder characterized by deafness, restricted joint movement, compact body habitus, and distinctive craniofacial and skeletal features, is caused by heterozygous mutations in SMAD4. Cardiac manifestations reported to date have included patent ductus arteriosus, septal defects, aortic coarctation and pericarditis. We present five previously unreported patients with Myhre syndrome. Despite varied clinical phenotypes all had significant cardiac and/or pulmonary pathology and abnormal wound healing. Included herein is the first report of cardiac transplantation in patients with Myhre syndrome. A progressive and markedly abnormal fibroproliferative response to surgical intervention is a newly delineated complication that occurred in all patients and contributes to our understanding of the natural history of this disorder. We recommend routine cardiopulmonary surveillance for patients with Myhre syndrome. Surgical intervention should be approached with extreme caution and with as little invasion as possible as the propensity to develop fibrosis/scar tissue is dramatic and can cause significant morbidity and mortality.