Chromosome 2q12.3-q13 copy number variants in patients with neurodevelopmental disorders: genotype-phenotype correlation and new hotspots.

Introduction: The complex structure of the chromosome 2q12.3-q13 region provides a high chance of recombination events between various low copy repeats (LCRs). Copy number variants (CNV) in this region are present in both healthy populations and individuals affected with developmental delay, autism and congenital anomalies.

Four children with postnatally diagnosed mosaic trisomy 12: Clinical features, literature review, and current diagnostic capabilities of genetic testing.

Children or adults with mosaic trisomy 12 diagnosed postnatally are extremely rare. Only a small number of patients with this mosaicism have been reported in the literature. The clinical manifestation of mosaic trisomy 12 is variable, ranging from mild developmental delay to severe congenital anomaly and neonatal death.

Partial 5p Deletion and Partial 5q Duplication in a Patient with Multiple Congenital Anomalies: A Two-Step Mechanism in Chromosomal Rearrangement Mediated by Non-Allelic Homologous Recombination.

We describe a 5-month-old female who presented with clinical features of 5p deletion syndrome, including high-pitched cry, microcephaly, micrognathia, bilateral preauricular tags, bifid uvula, abnormal palmar creases, bilateral hypoplastic nipples, feeding difficulties, and developmental delay. In addition, the patient also had a cardiac defect, proximal esophageal atresia, and distal tracheoesophageal fistula. aCGH of the patient revealed a 22.

Chromosome 12q13.13q13.13 microduplication and microdeletion: a case report and literature review.

Background: Duplications or deletions in the 12q13.13 region are rare. Only scattered cases with duplications and/or deletions in this region have been reported in the literature or in online databases.

The Genomic Landscape of PAX5, IKZF1, and CDKN2A/B Alterations in B-Cell Precursor Acute Lymphoblastic Leukemia.

We present a comprehensive comparison of PAX5,IKZF1, and CDKN2A/B abnormalities in 21 B-cell precursor acute lymphoblastic leukemia (B-ALL) patients studied by aCGH and gene-specific FISH assays. In our cohort of B-ALL patients, alterations of IKZF1, PAX5, and CDKN2A/B were detected by aCGH analysis in 43, 52, and 57% of samples, respectively. Deletions of IKZF1 were present in 9 samples, including 5 cases positive for both PAX5 and IKZF1 deletions, implying digenic impairment.

Selective antitumor activity of ibrutinib in EGFR-mutant non-small cell lung cancer cells.

Ibrutinib, which irreversibly inhibits Bruton tyrosine kinase, was evaluated for antitumor activity in a panel of non-small cell lung cancer (NSCLC) cell lines and found to selectively inhibit growth of NSCLC cells carrying mutations in the epidermal growth factor receptor (EGFR) gene, including T790M mutant and erlotinib-resistant H1975 cells. Ibrutinib induced dose-dependent inhibition of phosphor-EGFR at both Y1068 and Y1173 sites, suggesting ibrutinib functions as an EGFR inhibitor. Survival was analyzed by Kaplan-Meier estimation and log-rank test.

Lenalidomide in relapsed or refractory mantle cell lymphoma: overview and perspective.

Lenalidomide, a novel immunomodulatory agent, was approved by the US Food and Drug Administration for the treatment of myelodysplastic syndrome and relapsed multiple myeloma. Data from preclinical studies paved the way for clinical trials of lenalidomide in mantle cell lymphoma (MCL). Initial phase I and II clinical trials of lenalidomide alone and as part of combination regimens in patients with relapsed/refractory MCL have shown promising results.

Involvement of tumor-associated macrophage activation in vitro during development of a novel mantle cell lymphoma cell line, PF-1, derived from a typical patient with relapsed disease.

Human mantle cell lymphoma (MCL) cell lines are scarce and have been only sporadically described and validated, and only a few have been thoroughly molecularly or genetically characterized. We describe here the successful establishment of a new MCL line, PF-1, with typical MCL characteristics. Culturing primary MCL cells in vitro initially gave rise to an essential generative microenvironment "niche" involving macrophages required for MCL growth, and eventually produced the PF-1 MCL cell line.

In vitro and in vivo therapeutic efficacy of carfilzomib in mantle cell lymphoma: targeting the immunoproteasome.

Mantle cell lymphoma (MCL) remains incurable due to its inevitable pattern of relapse after treatment with current existing therapies. However, the promise of a cure for MCL lies in the burgeoning area of novel agents. In this study, we elucidated the therapeutic effect and mechanism of carfilzomib, a novel long-acting second-generation proteasome inhibitor, in MCL cells.

Immunomodulation therapy with lenalidomide in follicular, transformed and diffuse large B cell lymphoma: current data on safety and efficacy.

Lenalidomide is an immunomodulatory agent which has been approved for multiple myeloma. Lenalidomide is also effective in and tolerated well by patients with follicular lymphoma, diffuse large B-cell lymphoma, and transformed large cell lymphoma. This review summarizes the results of current preclinical and clinical studies of lenalidomide, alone or in combination with the monoclonal antibody rituximab, as a therapeutic option for these three lymphoma types.

Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma.

Background: Bruton's tyrosine kinase (BTK) is a mediator of the B-cell-receptor signaling pathway implicated in the pathogenesis of B-cell cancers. In a phase 1 study, ibrutinib, a BTK inhibitor, showed antitumor activity in several types of non-Hodgkin's lymphoma, including mantle-cell lymphoma.

Methods: In this phase 2 study, we investigated oral ibrutinib, at a daily dose of 560 mg, in 111 patients with relapsed or refractory mantle-cell lymphoma.

Small noncoding differentially methylated copy-number variants, including lncRNA genes, cause a lethal lung developmental disorder.

An unanticipated and tremendous amount of the noncoding sequence of the human genome is transcribed. Long noncoding RNAs (lncRNAs) constitute a significant fraction of non-protein-coding transcripts; however, their functions remain enigmatic. We demonstrate that deletions of a small noncoding differentially methylated region at 16q24.

Novel selective inhibitors of nuclear export CRM1 antagonists for therapy in mantle cell lymphoma.

Overexpression of the cellular nuclear exportin 1, more commonly called chromosomal region maintenance 1 (CRM1), has been associated with malignant progression and mortality. Therefore, activation of nuclear export can play a significant etiologic role in some forms of human neoplasia and serve as a novel target for the treatment of these cancers. Mantle cell lymphoma (MCL) is an aggressive histotype of B-cell non-Hodgkin lymphoma that remains incurable.

Rare DNA copy number variants in cardiovascular malformations with extracardiac abnormalities.

Clinically significant cardiovascular malformations (CVMs) occur in 5-8 per 1000 live births. Recurrent copy number variations (CNVs) are among the known causes of syndromic CVMs, accounting for an important fraction of cases. We hypothesized that many additional rare CNVs also cause CVMs and can be detected in patients with CVMs plus extracardiac anomalies (ECAs).

Use of array CGH to detect exonic copy number variants throughout the genome in autism families detects a novel deletion in TMLHE.

Autism is a neurodevelopmental disorder with increasing evidence of heterogeneous genetic etiology including de novo and inherited copy number variants (CNVs). We performed array comparative genomic hybridization using a custom Agilent 1 M oligonucleotide array intended to cover 197 332 unique exons in RefSeq genes; 98% were covered by at least one probe and 95% were covered by three or more probes with the focus on detecting relatively small CNVs that would implicate a single protein-coding gene. The study group included 99 trios from the Simons Simplex Collection.

Observation and prediction of recurrent human translocations mediated by NAHR between nonhomologous chromosomes.

Four unrelated families with the same unbalanced translocation der(4)t(4;11)(p16.2;p15.4) were analyzed.

Insertional translocation detected using FISH confirmation of array-comparative genomic hybridization (aCGH) results.

Insertional translocations (ITs) are rare events that require at least three breaks in the chromosomes involved and thus qualify as complex chromosomal rearrangements (CCR). In the current study, we identified 40 ITs from approximately 18,000 clinical cases (1:500) using array-comparative genomic hybridization (aCGH) in conjunction with fluorescence in situ hybridization (FISH) confirmation of the aCGH findings, and parental follow-up studies. Both submicroscopic and microscopically visible IT events were detected.

Redefined genomic architecture in 15q24 directed by patient deletion/duplication breakpoint mapping.

We report four new patients with a submicroscopic deletion in 15q24 manifesting developmental delay, short stature, hypotonia, digital abnormalities, joint laxity, genital abnormalities, and characteristic facial features. These clinical features are shared with six recently reported patients with a 15q24 microdeletion, supporting the notion that this is a recognizable syndrome. We describe a case of an ~2.

Genomic and genic deletions of the FOX gene cluster on 16q24.1 and inactivating mutations of FOXF1 cause alveolar capillary dysplasia and other malformations.

Alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV) is a rare, neonatally lethal developmental disorder of the lung with defining histologic abnormalities typically associated with multiple congenital anomalies (MCA). Using array CGH analysis, we have identified six overlapping microdeletions encompassing the FOX transcription factor gene cluster in chromosome 16q24.1q24.

Microarray-based comparative genomic hybridization using sex-matched reference DNA provides greater sensitivity for detection of sex chromosome imbalances than array-comparative genomic hybridization with sex-mismatched reference DNA.

In array-comparative genomic hybridization (array-CGH) experiments, the measurement of DNA copy number of sex chromosomal regions depends on the sex of the patient and the reference DNAs used. We evaluated the ability of bacterial artificial chromosomes/P1-derived artificial and oligonucleotide array-CGH analyses to detect constitutional sex chromosome imbalances using sex-mismatched reference DNAs. Twenty-two samples with imbalances involving either the X or Y chromosome, including deletions, duplications, triplications, derivative or isodicentric chromosomes, and aneuploidy, were analyzed.

Interstitial deletion of 6q25.2-q25.3: a novel microdeletion syndrome associated with microcephaly, developmental delay, dysmorphic features and hearing loss.

Interstitial deletions of 6q are rare. We report a detailed clinical and molecular characterization of four patients with interstitial deletion involving 6q25. All of our patients presented with microcephaly, developmental delay, dysmorphic features and hearing loss, whereas two of them had agenesis of the corpus callosum.

Branchiootorenal syndrome and oculoauriculovertebral spectrum features associated with duplication of SIX1, SIX6, and OTX2 resulting from a complex chromosomal rearrangement.

We report on a 26-month-old boy with developmental delay and multiple congenital anomalies, including many features suggestive of either branchiootorenal syndrome (BOR) or oculoauriculovertebral spectrum (OAVS). Chromosomal microarray analysis (CMA) initially revealed a copy-number gain with a single BAC clone (RP11-79M1) mapping to 14q23.1.

Mosaicism for r(X) and der(X)del(X)(p11.23)dup(X)(p11.21p11.22) provides insight into the possible mechanism of rearrangement.

We report a patient with a unique and complex cytogenetic abnormality involving mosaicism for a small ring X and deleted Xp derivative chromosome with tandem duplication at the break point. The patient presented with failure to thrive, muscular hypotonia, and minor facial anatomic anomalies, all concerning for Turner syndrome. Brain MRI revealed mild thinning of the corpus callosum, an apparent decrease in ventricular white matter volume, and an asymmetric myelination pattern.

De novo and complex imbalanced chromosomal rearrangements revealed by array CGH in a patient with an abnormal phenotype and apparently "balanced" paracentric inversion of 14(q21q23).

Paracentric inversions are one of the common chromosomal rearrangements typically associated with a normal phenotype. However, if dosage-sensitive genes are disrupted by the breakpoints, an abnormal phenotype could result. Detection of paracentric inversions often relies on careful high resolution banding, which has limited sensitivity.