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Disorders of the long arm of chromosome 11 (11q) are rare and involve various chromosomal regions. Patients with 11q disorders, including Jacobsen syndrome, often present with a susceptibility for bacterial and prolonged viral and fungal infections partially explained by hypogammaglobulinemia. Additional T lymphocyte or granular neutrophil dysfunction may also be present. In order to evaluate infectious burden and immunological function in patients with 11q disorders, we studied a cohort of 14 patients with 11q deletions and duplications. Clinically, 12 patients exhibited prolonged and repetitive respiratory tract infections, frequently requiring (prophylactic) antibiotic treatment (n = 7), ear-tube placement (n = 9), or use of inhalers (n = 5). Complicated varicella infections (n = 5), chronic eczema (n = 6), warts (n = 2), and chronic fungal infections (n = 4) were reported. Six patients were on immunoglobulin replacement therapy. We observed a high prevalence of low B lymphocyte counts (n = 8), decreased T lymphocyte counts (n = 5) and abnormal T lymphocyte function (n = 12). Granulocyte function was abnormal in 29% without a clinical phenotype. Immunodeficiency was found in patients with terminal and interstitial 11q deletions and in one patient with terminal 11q duplication. Genetically, FLI1 and ETS1 are seen as causative for the immunodeficiency, but these genes were deleted nor duplicated in 4 of our 14 patients. Alternative candidate genes on 11q may have a role in immune dysregulation. In conclusion, we present evidence that inborn errors of immunity are present in patients with 11q disorders leading to clinically relevant infections. Therefore, broad immunological screening and necessary treatment is of importance in this patient group., (© 2022. The Author(s).)

Rationale: Jacobsen syndrome is a rare chromosomal disorder caused by deletions in the long arm of human chromosome 11, resulting in multiple developmental defects including congenital heart defects. Combined studies in humans and genetically engineered mice implicate that loss of ETS1 (E26 transformation specific 1) is the cause of congenital heart defects in Jacobsen syndrome, but the underlying molecular and cellular mechanisms are unknown., Objective: To determine the role of ETS1 in heart development, specifically its roles in coronary endothelium and endocardium and the mechanisms by which loss of ETS1 causes coronary vascular defects and ventricular noncompaction., Methods and Results: ETS1 global and endothelial-specific knockout mice were used. Phenotypic assessments, RNA sequencing, and chromatin immunoprecipitation analysis were performed together with expression analysis, immunofluorescence and RNAscope in situ hybridization to uncover phenotypic and transcriptomic changes in response to loss of ETS1. Loss of ETS1 in endothelial cells causes ventricular noncompaction, reproducing the phenotype arising from global deletion of ETS1. Endothelial-specific deletion of ETS1 decreased the levels of Alk1 (activin receptor-like kinase 1), Cldn5 (claudin 5), Sox18 (SRY-box transcription factor 18), Robo4 (roundabout guidance receptor 4), Esm1 (endothelial cell specific molecule 1) and Kdr (kinase insert domain receptor), 6 important angiogenesis-relevant genes in endothelial cells, causing a coronary vasculature developmental defect in association with decreased compact zone cardiomyocyte proliferation. Downregulation of ALK1 expression in endocardium due to the loss of ETS1, along with the upregulation of TGF (transforming growth factor)-β1 and TGF-β3, occurred with increased TGFBR2/TGFBR1/SMAD2 signaling and increased extracellular matrix expression in the trabecular layer, in association with increased trabecular cardiomyocyte proliferation., Conclusions: These results demonstrate the importance of endothelial and endocardial ETS1 in cardiac development. Delineation of the gene regulatory network involving ETS1 in heart development will enhance our understanding of the molecular mechanisms underlying ventricular and coronary vascular developmental defects and will lead to improved approaches for the treatment of patients with congenital heart disease.

Jacobsen syndrome (JS) is caused by the terminal deletion at the long arm of chromosome 11. It is characterized by growth retardation, intellectual disability, facial dysmorphism, and other congenital abnormalities. The subband 11q24.1 has been confirmed to be the critical region for the typical features of JS. The patient in the current study is a 2-year-old male child with prominent craniofacial abnormalities and congenital heart disease. High-resolution single-nucleotide polymorphism arrays revealed breakage in chromosome 11q beginning at 11q24.2, with complete deletion of the distal portion. We collected all available reports describing patients with breakages at 11q24.1 or 11q24.2, and compared it with the typical features of JS. We found that the phenotype of cleft lip and palate (CLP) was present in both groups of patients with no overlap region in the deletion region (between 11q21-q23 and 11q24.2-qter), which indicated that other genes may be related to CLP in JS.

Jacobsen syndrome or JBS (OMIM #147791) is a contiguous gene syndrome caused by a deletion affecting the terminal q region of chromosome 11. The phenotype of patients with JBS is a specific syndromic phenotype predominately associated with hematological alterations. Complete and partial JBS are differentiated depending on which functional and causal genes are haploinsufficient in the patient. We describe the case of a 6-year-old Bulgarian boy in which it was possible to identify all of the major signs and symptoms listed by the Online Mendelian Inheritance in Man (OMIM) catalog using the Human Phenotype Ontology (HPO). Extensive blood and marrow tests revealed the existence of thrombocytopenia and leucopenia, specifically due to low levels of T and B cells and low levels of IgM. Genetic analysis using whole-genome single nucleotide polymorphisms (SNPs)/copy number variations (CNVs) microarray hybridization confirmed that the patient had the deletion arr[hg19]11q24.3q25(128,137,532-134,938,470)x1 in heterozygosis. This alteration was considered causal of partial JBS because the essential BSX and NRGN genes were not included, though 30 of the 96 HPO identifiers associated with this OMIM were identified in the patient. The deletion of the FLI-1 , ETS1 , JAM3 and THYN1 genes was considered to be directly associated with the immunodeficiency exhibited by the patient. Although immunodeficiency is widely accepted as a major sign of JBS, only constipation, bone marrow hypocellularity and recurrent respiratory infections have been included in the HPO as terms used to refer to the immunological defects in JBS. Exhaustive functional analysis and individual monitoring are required and should be mandatory for these patients.

FEZ1-mediated axonal transport plays important roles in central nervous system development but its involvement in the peripheral nervous system is not well-characterized. FEZ1 is deleted in Jacobsen syndrome (JS), an 11q terminal deletion developmental disorder. JS patients display impaired psychomotor skills, including gross and fine motor delay, suggesting that FEZ1 deletion may be responsible for these phenotypes, given its association with the development of motor-related circuits. Supporting this hypothesis, our data show that FEZ1 is selectively expressed in the rat brain and spinal cord. Its levels progressively increase over the developmental course of human motor neurons (MN) derived from embryonic stem cells. Deletion of FEZ1 strongly impaired axon and dendrite development, and significantly delayed the transport of synaptic proteins into developing neurites. Concurring with these observations, Drosophila unc-76 mutants showed severe locomotion impairments, accompanied by a strong reduction of synaptic boutons at neuromuscular junctions. These abnormalities were ameliorated by pharmacological activation of UNC-51/ATG1, a FEZ1-activating kinase, with rapamycin and metformin. Collectively, the results highlight a role for FEZ1 in MN development and implicate its deletion as an underlying cause of motor impairments in JS patients., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Jacobsen syndrome (MIM #147791) is a rare multisystem genomic disorder involving craniofacial abnormalities, intellectual disability, other neurodevelopmental defects, and terminal truncation of chromosome 11q, typically deleting ~170 to >340 genes. We describe the first case of Jacobsen syndrome caused by congenital chromoanasynthesis, an extreme form of complex chromosomal rearrangement. Six duplications and five deletions occurred on one copy of chromosome 11q with microhomology signatures in the breakpoint junctions, indicating an all-at-once replication-based rearrangement mechanism in a gametocyte or early post-zygotic cell. Eighteen genes were deleted from the Jacobsen region, including KIRREL3, which is associated with intellectual disability., (© 2020 Wiley Periodicals LLC.)

Balanced rearrangements involving the KMT2A gene, located at 11q23, are among the most frequent chromosome aberrations in acute myeloid leukemia (AML). Because of numerous fusion partners, the mutational landscape and prognostic impact of specific 11q23/ KMT2A rearrangements are not fully understood. We analyzed clinical features of 172 adults with AML and recurrent 11q23/ KMT2A rearrangements, 141 of whom had outcome data available. We compared outcomes of these patients with outcomes of 1,097 patients without an 11q23/ KMT2A rearrangement categorized according to the 2017 European LeukemiaNet (ELN) classification. Using targeted next-generation sequencing, we investigated the mutational status of 81 leukemia/cancer-associated genes in 96 patients with 11q23/ KMT2A rearrangements with material for molecular studies available. Patients with 11q23/ KMT2A rearrangements had a low number of additional gene mutations (median, 1; range 0 to 6), which involved the RAS pathway ( KRAS , NRAS , and PTPN11 ) in 32% of patients. KRAS mutations occurred more often in patients with t(6;11)(q27;q23)/ KMT2A - AFDN compared with patients with the other 11q23/ KMT2A subsets. Specific gene mutations were too infrequent in patients with specific 11q23/ KMT2A rearrangements to assess their associations with outcomes. We demonstrate that younger (age <60 y) patients with t(9;11)(p22;q23)/ KMT2A - MLLT3 had better outcomes than patients with other 11q23/ KMT2A rearrangements and those without 11q23/ KMT2A rearrangements classified in the 2017 ELN intermediate-risk group. Conversely, outcomes of older patients (age ≥60 y) with t(9;11)(p22;q23) were poor and comparable to those of the ELN adverse-risk group patients. Our study shows that patients with an 11q23/ KMT2A rearrangement have distinct mutational patterns and outcomes depending on the fusion partner., Competing Interests: Competing interest statement: J.S.B. serves as a consultant/advisory board member for AbbVie, AstraZeneca, and KITE Pharma. The other authors declare no potential conflicts of interest.

Introduction: Jacobsen syndrome (JS) is caused by a deletion at the terminus of the long arm of chromosome 11. There are few reports of JS associated with cerebral white matter abnormalities (WMA), and the etiology, pathophysiology, and time-dependent changes in WMA with JS still remain unclear., Case Report: The patient was a 2-month-old female with several morphological anomalies, including trigonocephaly, ectropion, flat nasal bridge, low-set ears, and sparse eyebrows. Chromosome analysis (G-banding karyotyping) of 46,XX,del(11)(q23.3) led to the diagnosis of JS. Head MRI performed at age 9 months indicated diffuse WMA with hyperintense signals on T2-weighted imaging. MRI at age 2.5 years demonstrated a decrease in the WMA and progressive myelination., Discussion: These findings suggested that the WMA in the present patient were due to chronic white matter edema associated with a deletion in the 11q terminal region of HEPACAM/GlialCAM, a causative gene for megalencephalic leukoencephalopathy with subcortical cysts type 2B (MLC2B). As with some of MLC2B patients, the WMA in the present patient improved over time. The present report is the first to document dramatic changes in WMA in JS visualized by serial MRI examinations from the neonatal period through early childhood., Conclusion: The findings of the present study suggested that WMA in JS are due to chronic white matter edema associated with HEPACAM/GlialCAM deletion and show gradual improvement over time, as seen in some MLC2B patients., (Copyright © 2020 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Jacobsen syndrome (OMIM #147791) is a rare contiguous gene disorder caused by deletions in distal 11q. The clinical phenotype is variable and can include dysmorphic features, varying degrees of intellectual disability, behavioral problems including autism and attention deficit hyperactivity disorder, congenital heart defects, structural kidney defects, genitourinary problems, immunodeficiency, and a bleeding disorder due to impaired platelet production and function. Previous studies combining both human and animal systems have implicated several disease-causing genes in distal 11q that contribute to the Jacobsen syndrome phenotype. One gene, ETS1 , has been implicated in causing congenital heart defects, structural kidney defects, and immunodeficiency. We performed a comprehensive phenotypic analysis on a patient with congenital heart disease previously found to have a de novo frameshift mutation in ETS1 , resulting in the loss of the DNA-binding domain of the protein. Our results suggest that loss of Ets1 causes a "partial Jacobsen syndrome phenotype" including congenital heart disease, facial dysmorphism, intellectual disability, and attention deficit hyperactivity disorder., (© 2019 Tootleman et al.; Published by Cold Spring Harbor Laboratory Press.)

This report presents two families with interstitial 11q24.2q24.3 deletion, associated with malformations, hematologic features, and typical facial dysmorphism, observed in Jacobsen syndrome (JS), except for intellectual disability (ID). The smallest 700 Kb deletion contains only two genes: FLI1 and ETS1, and a long noncoding RNA, SENCR, narrowing the minimal critical region for some features of JS. Consistent with recent literature, it adds supplemental data to confirm the crucial role of FLI1 and ETS1 in JS, namely FLI1 in thrombocytopenia and ETS1 in cardiopathy and immune deficiency. It also supports that combined ETS1 and FLI1 haploinsufficiency explains dysmorphic features, notably ears, and nose anomalies. Moreover, it raises the possibility that SENCR, a long noncoding RNA, could be responsible for limb defects, because of its early role in endothelial cell commitment and function. Considering ID and autism spectrum disorder, which are some of the main features of JS, a participation of ETS1, FLI1, or SENCR cannot be excluded. But, considering the normal neurodevelopment of our patients, their role would be either minor or with an important variability in penetrance. Furthermore, according to literature, ARHGAP32 and KIRREL3 seem to be the strongest candidate genes in the 11q24 region for other Jacobsen patients., (© 2019 Wiley Periodicals, Inc.)

Jacobsen syndrome refers to a congenital anomaly caused by deletion at 11q23.3-qter. We here describe two siblings with the same 11q23.3-qter deletion. Both parents were healthy with a normal karyotype. Cytogenetic microarray analysis revealed no mosaicism in either parent but the mother showed uniparental disomy encompassing the deleted region found in the two siblings. The pattern of X chromosome inactivation was almost completely skewed in the mother. These data suggested that the mother was a carrier of the 11q23.3-qter deletion but that this had been rescued by disomy formation during early embryogenesis except for her germinal cells., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Ets-1 is a member of the Ets family of transcription factors and has critical roles in multiple biological functions. Structural kidney defects occur at an increased frequency in Jacobsen syndrome (OMIM #147791), a rare chromosomal disorder caused by deletions in distal 11q, implicating at least one causal gene in distal 11q. In this study, we define an 8.1 Mb "critical region" for kidney defects in Jacobsen syndrome, which spans ~50 genes. We demonstrate that gene-targeted deletion of Ets-1 in mice results in some of the most common congenital kidney defects occurring in Jacobsen syndrome, including: duplicated kidney, hypoplastic kidney, and dilated renal pelvis and calyces. Taken together, our results implicate Ets-1 in normal mammalian kidney development and, potentially, in the pathogenesis of some of the most common types of human structural kidney defects., (© 2018 Wiley Periodicals, Inc.)

A 7-year-old boy was diagnosed and treated for familial exudative vitreoretinopathy. Genetic testing revealed a 16p13.11 microdeletion and unbalanced translocation causing 11q deletion syndrome. This is the first report describing retinal findings associated with this combination of genetic alterations. Patients with 11q deletion syndrome or 16p13 microdeletions should undergo ophthalmologic examination. [J Pediatr Ophthalmol Strabismus. 2017;54:e71-e74.]., (Copyright 2017, SLACK Incorporated.)

Jacobsen syndrome is a rare chromosomal disorder caused by distal deletions in the long arm of chromosome 11. All patients with Jacobsen syndrome have Paris-Trousseau syndrome, a bleeding disorder that causes neonatal thrombocytopenia, and persistent platelet dysfunction. Despite that, to date there are no reported cases of hemorrhagic strokes occurring in patients with Jacobsen syndrome. In the last 6 years at least six cases of brain hemorrhages in patients with Jacobsen syndrome have occurred. In this report, we perform a retrospective review of these six cases. The analysis indicates that the etiology of brain hemorrhages in Jacobsen syndrome is likely multifactorial. A likely cause (or causes) was identified in three of the cases, and additional potential risk factors were identified. Based on these findings, clinical recommendations are provided that should aid in the identification of those individuals with Jacobsen syndrome that are at increased risk for brain hemorrhages, and will hopefully decrease the occurrence of this devastating complication in people with Jacobsen syndrome.© 2017 Wiley Periodicals, Inc., (© 2017 Wiley Periodicals, Inc.)

Objective: We present molecular cytogenetic characterization of Jacobsen syndrome (11q23.3-q25 deletion) in a fetus associated with double outlet right ventricle (DORV), hypoplastic left heart syndrome (HLHS), and ductus venosus (DV) agenesis on prenatal ultrasound., Case Report: A 26-year-old woman underwent prenatal ultrasound examination at 22 weeks of gestation, which revealed intrauterine growth restriction, short femurs, DORV, HLHS, DV agenesis, single umbilical artery, and curly fourth toe of the left foot. The parents elected to terminate the pregnancy, and a 500-g female fetus was delivered at 23 weeks of gestation with facial dysmorphism, bilateral camptodactyly, and hammertoes. The parental karyotypes were normal. Cytogenetic analysis of the cord blood and umbilical cord revealed a karyotype of 46,XX,del(11)(q23). Array comparative genomic hybridization analysis of the DNA extracted from the umbilical cord revealed a 14.38-Mb deletion of 11q23.3-q25 encompassing BSX, ETS1, FLI1, and ARHGAP32. Metaphase fluorescence in situ hybridization analysis using the probes RP11-209L12 (11q25) and RP11-25M7 (11q11) showed a distal 11q deletion in the aberrant chromosome 11 in 17/17 cells examined., Conclusion: Prenatal diagnosis of DORV, HLHS, DV agenesis associated with intrauterine growth restriction and short limbs should include a differential diagnosis of Jacobsen syndrome., (Copyright © 2017 Taiwan Association of Obstetrics & Gynecology. Published by Elsevier B.V. All rights reserved.)

Jacobsen syndrome (JS) is a contiguous gene syndrome caused by partial deletion of the long arm of chromosome 11. The syndrome is rare and there are very few observations regarding the pubertal period of the affected individuals. We report the case of a 22-year-old female, with JS, monitored since the age of three months. She presented intrauterine growth retardation, failure to thrive and feeding difficulties from the first year of the life, and she learned to walk at the age of four years. Phenotypically, the case is characterized by distinctive facial and limb abnormalities. She shows spasticity and profound delay in gross and fine motor skills. Additionally, she has severe learning difficulties, non-verbally communicates, and displays hetero-aggressive and auto-aggressive behavior. The evolution of puberty was characterized by hypogenitalism and primary amenorrhea. Thrombocytopenia and IgM deficiency became apparent also at puberty. Array comparative genomic hybridization (aCGH) analysis confirmed a deletion of 16.3 Mb on 11q23.3-q23.4. We report this case as the first documented case of JS in Romania, as well as for clinical particularities (long period of survival and late appearance of hematological and immunological disorders).

Antibody deficiency is common finding in patients with Jacobsen syndrome (JS). In addition, there have been few reports of T-cell defects in this condition, possibly because most of the reported patients have not been specifically evaluated for T-cell function. In this article, we present a child with an 11q deletion and combined immunodeficiency and we perform a literature overview on immunodeficiency in JS. Our patient presented with recurrent bacterial and prolonged viral infections involving the respiratory system, as well as other classic features of the syndrome. In addition to low IgM, IgG4, and B-cells, also low recent thymic emigrants, helper and naïve T-cells were found. We propose that patients with Jacobsen syndrome need thorough immunological evaluations as T-cell dysfunction might be more prevalent than previously reported. Patients with infections consistent with T-cell defects should be classified as having combined immunodeficiency. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

We describe a 19-month-old male presenting with right stenotic megaureter, anemia and thrombocytopenia, cardiac and ophthalmologic abnormalities. Analysis with array-based comparative genomic hybridization (aCGH) revealed an interstitial deletion of about 2.4 Mb of chromosome 11q24.2q24.3. We compared the phenotype of our patient with that of recently reported patients studied by aCGH, who showed an overlapping deletion. We also analysed the gene content of the deleted region in order to investigate the possible involvement of specific genes in the clinical phenotype.

The 11q terminal deletion disorder is a rare genetic disorder associated with numerous clinical features. A few case reports have been made about de novo interstitial deletion of chromosome 11q. However, due to the heterogeneity in size and position of the deletions, a clear genotype-phenotype correlation is not easily made. Here we report a case interstitial 20.5-Mb deletion at chromosome 11q13.4q21, as confirmed by array comparative genomic hybridization. Dysmorphic features such as coarse facial features, congenital laryngomalacia, oblique inguinal hernia, high-arched palate, and camptodactyly were observed in the subject. The present case broadens the spectrum of clinical findings observed in individuals with 11q interstitial deletion.

Jacobsen syndrome (JBS) is a rare congenital disorder caused by a terminal deletion of the long arm of chromosome 11. A subset of patients exhibit social behavioural problems that meet the diagnostic criteria for autism spectrum disorder (ASD); however, the underlying molecular pathogenesis remains poorly understood. PX-RICS is located in the chromosomal region commonly deleted in JBS patients with autistic-like behaviour. Here we report that PX-RICS-deficient mice exhibit ASD-like social behaviours and ASD-related comorbidities. PX-RICS-deficient neurons show reduced surface γ-aminobutyric acid type A receptor (GABAAR) levels and impaired GABAAR-mediated synaptic transmission. PX-RICS, GABARAP and 14-3-3ζ/θ form an adaptor complex that interconnects GABAAR and dynein/dynactin, thereby facilitating GABAAR surface expression. ASD-like behavioural abnormalities in PX-RICS-deficient mice are ameliorated by enhancing inhibitory synaptic transmission with a GABAAR agonist. Our findings demonstrate a critical role of PX-RICS in cognition and suggest a causal link between PX-RICS deletion and ASD-like behaviour in JBS patients.

Jacobsen syndrome (JS) is characterized by intellectual disability and higher risk for autism spectrum disorders (ASD). All patients with JS are carriers of contiguous de novo deletions of 11q24.2-25, but the causative genes remain unknown. Within the critical interval, we hypothesized that haploinsufficiency of the neuronal cell adhesion molecule Neurotrimin (NTM) might increase the risk for ASD and could affect brain structure volumes. We searched for deleterious mutations affecting NTM in 1256 ASD patients and 1287 controls, using SNP arrays, and by direct sequencing of 250 ASD patients and 180 controls. We compared our results to those obtained from independent cohorts of ASD patients and controls. We identified two patients with Copy Number Variants (CNV) encompassing NTM, one with a large de novo deletion, and a clinical phenotype of JS (including macrocephaly), and a second with a paternally inherited duplication, not consistent with JS. Interestingly, no similar CNVs were observed in controls. We did not observe enrichment for deleterious NTM mutations in our cohort. We then explored if the macrocephaly in the patient with JS was associated with a homogeneous increase of brain structures volumes using automatic segmentation. Compared to subjects without NTM micro-rearrangements (n=188), the patient had an increased volume of the sub-cortical structures but a decrease of the occipital gray matter. Finally our explorations could not incriminate NTM as a susceptibility gene for ASD, but provides new information on the impact of the 11q24.2-25 deletion on brain anatomy., (© 2015 Wiley Periodicals, Inc.)

In this issue of Blood, Stevenson et al describe a family with a homozygous missense mutation in FLI1 that is associated with a platelet phenotype identical to the one observed in Paris-Trousseau syndrome, supporting existing evidence that FLI1 is directly involved in the mechanism of thrombocytopenia observed in this disease.

Hemizygous deletion of a variable region on chromosome 11q containing FLI1 causes an inherited platelet-related bleeding disorder in Paris-Trousseau thrombocytopenia and Jacobsen syndrome. These multisystem disorders are also characterized by heart anomalies, changes in facial structure, and intellectual disability. We have identified a consanguineous family with autosomal recessive inheritance of a bleeding disorder that mimics Paris-Trousseau thrombocytopenia but has no other features of the 11q23 deletion syndrome. Affected individuals in this family have moderate thrombocytopenia; absent collagen-induced platelet aggregation; and large, fused α-granules in 1% to 5% of circulating platelets. This phenotype was caused by a FLI1 homozygous c.970C>T-point mutation that predicts an arginine-to-tryptophan substitution in the conserved ETS DNA-binding domain of FLI1. This mutation caused a transcription defect at the promoter of known FLI1 target genes GP6, GP9, and ITGA2B, as measured by luciferase assay in HEK293 cells, and decreased the expression of these target proteins in affected members of the family as measured by Western blotting of platelet lysates. This kindred suggests abnormalities in FLI1 as causative of Paris-Trousseau thrombocytopenia and confirms the important role of FLI1 in normal platelet development., (© 2015 by The American Society of Hematology.)

Objective: To detect chromosomal imbalance in a fetus with complex congenital heart disease, and to correlate the genotype with the phenotype., Methods: Routine G-banding was carried out to analyze the karyotypes of the fetus and its parents, and single nucleotide polymorphisms array (SNP-array) was used for delineating fine genomic aberrations. The detected aberrations were confirmed with multiplex ligation-dependent probe amplification (MLPA)., Results: The fetus and its parents all showed a normal karyotype, while array-SNP has detected a 13.87 Mb duplication at 4p16.3-p15.33 and a 15.65 Mb deletion at 11q23.3-q25 in the fetus. The results were confirmed by the MLPA assay., Conclusion: The partial trisomy 4p (Wolf-Hirschhorn syndrome) and partial monosomy 11q (Jacobsen syndrome) probably underlie the complex heart defects detected in the fetus. Analysis of the karyotypes of its parents offered no help for the determination of the aberrant type and recurrent risk. Compared with routine karyotype analysis, aberrant regions can be identified with array-SNP with greater resolution and accuracy. This has provided useful information for prenatal diagnosis and genetic counseling.

E26 transformation-specific 1 (ETS1) and friend leukemia integration 1 (FLI1) are members of the ETS family of transcription factors, of which there are 28 in humans. Both genes are hemizygous in Jacobsen syndrome, an 11q contiguous gene deletion disorder involving thrombocytopenia, facial dysmorphism, growth and mental retardation, malformation of the heart and other organs, and hearing impairment associated with recurrent ear infections. To determine whether any of these defects are because of hemizygosity for ETS1 and FLI1, we characterized the phenotype of mice heterozygous for mutant alleles of Ets1 and Fli1. Fli1(+/-) mice displayed mild thrombocytopenia, as did Ets1(+/-)Fli1(+/-) animals. Fli1(+/-) and Ets1(+/-)Fli1(+/-) mice also displayed craniofacial abnormalities, including a small middle ear cavity, short nasal bone, and malformed interface between the nasal bone process and cartilaginous nasal septum. They exhibited hearing impairment, otitis media, fusions of ossicles to the middle ear wall, and deformed stapes. Hearing impairment was more penetrant and stapes malformations were more severe in Ets1(+/-)Fli1(+/-) mice than in Fli1(+/-) mice, indicating partial functional redundancy of these transcription factors during auditory development. Our findings indicate that the short nose, otitis media, and hearing impairment in Jacobsen syndrome are likely because of hemizygosity for ETS1 and FLI1., (Copyright © 2015 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Purpose: Jacobsen syndrome, also called the 11q terminal deletion disorder, is a contiguous gene disorder caused by the deletion of the end of the long arm of chromosome 11. Intellectual skills range from low average to severe/profound intellectual disability and usually correlate with deletion size. Comprehensive genotype/phenotype evaluations are limited, and little is known about specific behavioral characteristics associated with 11q terminal deletion disorder., Methods: In this prospective study, 17 patients with 11q terminal deletion disorder underwent cognitive and behavioral assessments. Deletion sizes were determined by array comparative genomic hybridization., Results: Deletion sizes ranged from 8.7 to 14.5 Mb across the patients. We found that 8 of 17 patients (47%) exhibited behavioral characteristics consistent with an autism spectrum disorder diagnosis. There was no correlation between deletion size and the presence of autism spectrum disorder, implicating at least one predisposing gene in the distal 8.7 Mb of 11q. The findings from three additional patients with autistic features and "atypical" distal 11q deletions led to the identification of an autism "critical region" in distal 11q containing four annotated genes including ARHGAP32 (also known as RICS), a gene encoding rho GTPase activating protein., Conclusion: Results from this study support early autism spectrum disorder screening for patients with 11q terminal deletion disorder and provide further molecular insights into the pathogenesis of autism spectrum disorder.

Subtelomeric deletions represent an important class of abnormalities to be considered when investigating genetic links to intellectual disability (ID). One subtelomeric deletion found on the long arm of chromosome 11q produces a characteristic phenotype that includes ID and is often referred to as Jacobsen syndrome (JBS). Previously, researchers found an inverse relationship between IQ and deletion size. While useful, IQ does not provide a comprehensive picture of the cognitive-behavioral strengths and weaknesses in JBS, nor does it reveal how the profiles evolve as these individuals age. One purpose of this study was to confirm the relationship between IQ or adaptive behavior (DQ) and deletion size. We also examined cognitive-behavioral profiles of children with JBS and the extent to which they changed over time. Initially, at T1, we examined 10 children, ages 5-20 years, diagnosed with JBS. Cognitive ability was assessed with the Stanford-Binet (4th Edition). Adaptive behavoir was evaluated with the Vineland Adaptive Behavior Scales (VABS). Eight children were reassessed 2 years later (T2). Results show a negative but non-significant correlation between IQ and deletion size. There was no statistically significant relationship between DQ and deletion size. As for our second aim, IQ and DQ scores were stable from T1 to T2. Cognitive profiles were not significantly different from T1 to T2. However, there were significant changes in adaptive behavior domain scores from T1 to T2. Lack of a significant relationship between cognitive-behavioral measures and deletion size, as well as changes in cognitive-behavioral profiles are discussed., (© 2014 Wiley Periodicals, Inc.)

Abstract ATM gene alteration is a frequent event in pathogenesis of chronic lymphocytic leukemia (CLL) and occurs as monoallelic loss in the form of 11q23 deletion, with and without mutation in the remaining ATM allele. ATM is a principal DNA damage response gene and biallelic ATM alterations lead to ATM functional loss and chemoresistance. The introduction of new therapies, such as intensive chemoimmunotherapy and inhibition of B-cell receptor (BCR) signaling, has changed clinical responses for the majority of CLL tumors including those with 11q deletion, but it remains to be determined whether these strategies can prevent clonal evolution of tumors with biallelic ATM alterations. In this review we discuss ATM function and the consequences of its loss during CLL pathogenesis, differences in clinical behavior of tumors with monoallelic and biallelic ATM alterations, and we outline possible approaches for targeting the ATM null CLL phenotype.

Background: Interstitial deletions of chromosome 11 long arm are rarely observed and the associated phenotype ranges from normal to severe, depending on the position and size of the deletion and on the presence of unmasked recessive genes on the normal homologous. To our knowledge 32 cases are reported in literature with three family cases. Phenotype-genotype correlation is not very clear and the most common features are characteristic facial dysmorphisms, palate anomalies and developmental delay. Growth retardation is not typical and other major malformations are reported in some cases., Case Presentation: We described a child with 11q interstitial deletion diagnosed at birth with hypotonia and minor dysmorphisms using standard cytogenetic techniques; array CGH was subsequently performed to define the deletion at a molecular level., Conclusions: This case gave us the opportunity to attempt a genotype-phenotype correlation reviewing the literature and to describe a rehabilitative program that improved the development perspectives of this child.

We describe a family with recurrent 11q23-qter deletion Jacobsen syndrome in two affected brothers, with unique mosaic deletion 'rescue' through development of uniparental disomy (UPD) in the mother and one of the brothers. Inheritance studies show that the deleted chromosome is of maternal origin in both boys, and microarray shows a break near the ASAM gene. Parental lymphocyte chromosomes were normal. However, the mother is homozygous in lymphocytes for all loci within the deleted region in her sons, and presumably has UPD for this region. In addition, she is mosaic for the 11q deletion seen in her sons at a level of 20-30% in skin fibroblasts. We hypothesize that one of her #11 chromosomes shows fragility, that breakage at 11q23 occurred with telomeric loss in some cells, but 'rescue' from the deletion occurred in most cells by the development of mitotic UPD. She apparently carries the 11q deletion in her germ line resulting in recurrence of the syndrome. The older son is mosaic for the 11q cell line (70-88%, remainder 46,XY), and segmental UPD11 'rescue' apparently also occurred in his cytogenetically normal cells. This is a novel phenomenon restoring disomy to an individual with a chromosomal deletion., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Jacobsen syndrome (11q-) is a rare chromosomal disorder caused by deletions in distal11q. Many of the most common and severe congenital heart defects that occur in the general population occur in 11q-. Previous studies have demonstrated that gene-targeted deletion in mice of ETS-1, a cardiac transcription factor in distal 11q, causes ventricular septal defects with 100% penetrance. It is unclear whether deletion of other genes in distal 11q contributes to the full spectrum of congenital heart defects that occur in 11q-. Three patients with congenital heart defects have been identified that carry a translocation or paracentric inversion with a breakpoint in distal 11q disrupting one of two functionally related genes, OPCML and Neurotrimin. OPCML and Neurotrimin are two members of the IgLON subfamily of cell adhesion molecules. In this study, we report the generation and cardiac phenotype of single and double heterozygous gene-targeted OPCML and Neurotrimin knockout mice. No cardiac phenotype was detected, consistent with a single gene model as the cause of the congenital heart defects in 11q-., (© 2014 Wiley Periodicals, Inc.)

Jacobsen syndrome (JS) is a disorder of developmental delay, growth retardation, thrombocytopenia, dysmorphic features, and cardiac abnormalities, among other congenital anomalies. JS is caused by contiguous gene deletion in distal chromosome 11q, generally varying in size from 7 to 20 Mb. Periventricular nodular heterotopia (PVNH) is a neuronal migration disorder in which neurons are abnormally located in nodules along the edges of the lateral ventricles. PVNH can also be seen with other congenital anomalies, including a recurrent association with distal limb defects. Transverse limb defects have previously been reported in two patients with JS. We report on a patient with a 3.162 Mb interstitial deletion at chromosome region 11q24 overlapping the region commonly affected in JS. The patient had PVNH and a transverse limb reduction defect, with minimal typical findings of JS. This is the first report of PVNH associated with a microdeletion at chromosome 11q and may represent an expansion of the phenotypic spectrum associated with JS. This is the third report of transverse limb reduction defects in association with JS, supporting a widening of the skeletal phenotypic spectrum in JS to include more severe limb anomalies. ETS1 is proposed as a candidate gene for involvement in limb anomalies in JS., (© 2013 Wiley Periodicals, Inc.)

Here we describe clinical and cytogenetic data on a female child whom had been referred to our laboratory suspected to have Turner syndrome since she had webbed neck. Cytogenetic analysis revealed that she had deletion at 11q23.2 to 11q terminal so her karyotype was ascertained as 46,XX,del(11)(q23.2). Her parents had normal karyotypes. In addition to many clinical features of del(11q ) syndrome the case had poor vision which is not common for this syndrome. Clinical features of this case and a few published cases will be reviewed briefly.

Jacobsen syndrome (JS), a rare disorder with multiple dysmorphic features, is caused by the terminal deletion of chromosome 11q. Typical features include mild to moderate psychomotor retardation, trigonocephaly, facial dysmorphism, cardiac defects, and thrombocytopenia, though none of these features are invariably present. The estimated occurrence of JS is about 1/100,000 births. The female/male ratio is 2:1. The patient admitted to our clinic at 3.5 years of age with a cardiac murmur and facial anomalies. Facial anomalies included trigonocephaly with bulging forehead, hypertelorism, telecanthus, downward slanting palpebral fissures, and a carp-shaped mouth. The patient also had strabismus. An echocardiogram demonstrated perimembranous aneurysmatic ventricular septal defect and a secundum atrial defect. The patient was <3rd percentile for height and weight and showed some developmental delay. Magnetic resonance imaging (MRI) showed hyperintensive gliotic signal changes in periventricular cerebral white matter, and leukodystrophy was suspected. Chromosomal analysis of the patient showed terminal deletion of chromosome 11. The karyotype was designated 46, XX, del(11) (q24.1). A review of published reports shows that the severity of the observed clinical abnormalities in patients with JS is not clearly correlated with the extent of the deletion. Most of the patients with JS had short stature, and some of them had documented growth hormone deficiency, or central or primary hypothyroidism. In patients with the classical phenotype, the diagnosis is suspected on the basis of clinical findings: intellectual disability, facial dysmorphic features and thrombocytopenia. The diagnosis must be confirmed by cytogenetic analysis. For patients who survive the neonatal period and infancy, the life expectancy remains unknown. In this report, we describe a patient with the clinical features of JS without thrombocytopenia. To our knowledge, this is the first case reported from Turkey.

We report on a child with Jacobsen syndrome (JBS, OMIM 147791) and abnormalities consistent with Beckwith-Wiedemann syndrome (BWS, OMIM 130650). The constitutional karyotype was apparently normal, but FISH analysis with probes specific for the short and long arms of chromosome 11 found 11qter deletion with 11pter trisomy in 80% of the cells studied. Array-CGH identified breakpoints in the 11p15.3 and 11q24.1 regions consistent with Jacobsen and Beckwith-Wiedemann syndromes. We suggest that this chromosome imbalance results from a pericentric inversion of chromosome 11 inherited from the father, with mosaicism resulting from meiotic recombination of a paternal inversion followed by mitotic recombination during the first embryonic divisions. This hypothesis is supported by the results of microsatellite marker analysis. Three previous cases of pericentric inversion and recombination of chromosome 11 have been reported. Our case is unusual in that it combines the Jacobsen and Beckwith-Wiedemann syndromes with mosaicism., (Copyright © 2013 Wiley Periodicals, Inc.)

The joint application of clinical and genetic investigation to patients with inherited thrombocytopenias, as well as the availability of new methods for studying megakaryopoiesis, has greatly expanded the knowledge of these disorders in the last few years with regard to their etiology, pathogenesis and clinical aspects. In particular, new diseases have been described, as deriving from mutations in the genes FLNA, TUBB1, ITGA2/ITGB3, ANKRD26, CYCS, and ABCG5 or ABCG8. Moreover, forms previously considered separate entities were found to be different clinical aspects of a single disease. For instance, identification of MYH9 as the gene whose mutations cause the May-Hegglin anomaly led to the recognition that Sebastian platelet syndrome, Epstein syndrome, and Fechtner syndrome derive from mutations of the same gene and describe overlapping disorders. Despite these advances, knowledge of hereditary thrombocytopenias is still far from satisfactory because for approximately half of the patients it is not possible to formulate a definite diagnosis in that their illnesses has not yet been described. In this review, we provide a systematic description of hereditary thrombocytopenias as we know them today, giving special attention to genetic aspects.

Jacobsen syndrome (JS) is a rare contiguous gene disorder characterized by a deletion within the distal part of the long arm of chromosome 11 ranging in size from 7 to 20 Mb. The clinical findings include characteristic dysmorphic features, growth and psychomotor delays and developmental anomalies involving the brain, eyes, heart, kidneys, immune, hematologic, endocrine, and gastrointestinal systems. The majority of cases are due to a terminal deletion of 11q; however interstitial deletions have also been reported. We report on a child with clinical manifestations consistent with JS who had a 2.899 Mb interstitial deletion at 11q24.2-q24.3 which is the smallest interstitial deletion reported so far to our knowledge. This deletion includes the KIRREL3 gene, and given our patient's history of neurocognitive delay and autism spectrum disorder, it raises the possibility that this gene is a candidate for the social and expressive language delay observed in our patient., (Copyright © 2012 Wiley Periodicals, Inc.)

Introduction: The thrombocytopenia of the Paris-Trousseau (TCPT) type is a contiguous gene syndrome characterized by mild bleeding tendency, variable thrombocytopenia (THC), abnormal giant alpha-granules in platelets and dysmegakaryopoiesis: it derives from a constitutional deletion of chromosome 11 leading to the loss of FLI1, a transcription factor involved in megakaryocyte differentiation and maturation., Case Report: A women with an acquired, isolated THC developing over 10 yr showed morphological features typical of TCPT in platelets and bone marrow (BM). Twenty years after the onset of THC, the other hematological parameters are still normal and the patient is well., Results: Clonal hemopoiesis was shown and chromosome analyses performed on BM revealed a clone with 45 chromosomes and a complex unbalanced translocation involving chromosomes 2, 3, and 11. The anomaly was present in the majority of bone marrow cells but only in a few peripheral blood elements. A microarray-based comparative genomic hybridization defined the deleted region of chromosome 11 including the FLI1 locus that was missing., Conclusion: Although our patient presented with nearly all the characteristics of TCPT, her illness was acquired instead of being inherited and the most appropriate diagnosis is that of the unilineage dysplasia 'refractory THC.' This observation suggests that appropriate cytogenetic investigations should be always considered in patients with acquired THC of unknown origin., (© 2012 John Wiley & Sons A/S.)

Jacobsen syndrome (JBS) is a rare chromosomal disorder caused by terminal deletion of the long arm of chromosome 11. We report on four prenatally diagnosed patients with JBS with variable prenatal and postnatal phenotypes and 11q deletions of varying sizes. Precise characterization of the deleted region in three patients was performed by SNP arrays. The severity of both the prenatal and postnatal phenotypes did not correlate with the size of the haploinsufficient region. Despite the large difference in the deletion size (nearly 6 Mb), both of the live-born patients had similar phenotypes corresponding to JBS. However, one of the most prominent features of JBS, thrombocytopenia, was only present in the live-born boy. The girl, who had a significantly longer deletion spanning all four genes suspected of being causative of JBS-related thrombocytopenia (FLI1, ETS1, NFRKB, and JAM3), did not manifest a platelet phenotype. Therefore, our findings do not support the traditional view of deletion size correlation in JBS or the causative role of FLI1, ETS1, NFRKB, and JAM3 deletion per se for the development of disease-related thrombocytopenia., (Copyright © 2012 Wiley Periodicals, Inc.)

RUNX1 gene alterations are associated with acquired and inherited hematologic malignancies that include familial platelet disorder/acute myeloid leukemia, primary or secondary acute myeloid leukemia, and chronic myelomonocytic leukemia. Recently, we reported that RUNX1-mediated silencing of nonmuscle myosin heavy chain IIB (MYH10) was required for megakaryocyte ploidization and maturation. Here we demonstrate that runx1 deletion in mice induces the persistence of MYH10 in platelets, and a similar persistence was observed in platelets of patients with constitutional (familial platelet disorder/acute myeloid leukemia) or acquired (chronic myelomonocytic leukemia) RUNX1 mutations. MYH10 was also detected in platelets of patients with the Paris-Trousseau syndrome, a thrombocytopenia related to the deletion of the transcription factor FLI1 that forms a complex with RUNX1 to regulate megakaryopoiesis, whereas MYH10 persistence was not observed in other inherited forms of thrombocytopenia. We propose MYH10 detection as a new and simple tool to identify inherited platelet disorders and myeloid neoplasms with abnormalities in RUNX1 and its associated proteins.

We report a neonate with pure deletion of distal 11q (11q23.3-->qter) and Jacobsen syndrome. The patient had growth restriction, petechiae, thrombocytopenia, dilation of renal pelvis, congenital heart defects, and seizures. Array comparative genomic hybridization revealed a 15.8-Mb deletion from 11q23.3 to 11q25 without genomic imbalances in other chromosomes. Cytogenetic analysis revealed a karyotype of 46,XX,der(7)(7pter-->7q32),der(11)(11pter--> 11q23.3::7q32-->7qter). The parental karyotypes were normal. This is the first report of pure distal 11q deletion without additional genomic imbalances in a patient with Jacobsen syndrome and a de novo unbalanced reciprocal translocation.

A woman with psychomotor developmental delay, congenital glaucoma, and distinctive facial features, and a short neck was diagnosed with Jacobsen syndrome (JBS) at age 40 years. A previously reported balanced translocation between chromosome 11 and 22 instead showed an unbalanced translocation by a microarray-based comparative hybridization analysis with the final karyotype of 46,XX,der(11)t(11;22)(q23.3;q11.21),del(22)(q11.21) dn. The breakpoint of chromosome 11 was determined to be at TECTA and not near the apolipoprotein gene cluster site or the fragile site (FRA11B), which are commonly seen in patients with t(11;22) and patients with typical 11q deletions, respectively. Although the phenotypic features of the patient, including psychomotor developmental delay, distinctive features, and mild thrombocytopenia, were consistent with JBS, congenital glaucoma, which is an uncommon finding of JBS, was the most prominent condition during her natural history., (Copyright © 2011 Wiley Periodicals, Inc.)

We report here three children with a der(11)t(11;16), two sibs (patients 1 and 2) having inherited a recombinant chromosome from a maternal t(11;16)(q24.3;q23.2) and a third unrelated child with a de novo der(11)t(11;16)(q25;q22.1), leading to partial monosomy 11q and trisomy 16q. Fluorescent in situ hybridization (FISH) using bacterial artificial chromosome (BAC) clones and array-CGH were performed to determine the breakpoints involved in the familial and the de novo rearrangements. The partial 11 monosomy extended from 11q24.3 to 11qter and measured 6.17-6.21 Mb in Patients 1 and 2 while the size of the partial 11q25->qter monosomy was estimated at 1.97-2.11 Mb for Patient 3. The partial 16 trisomy extended from 16q23.2 to 16qter and measured 8.93-8.95 Mb in Patients 1 and 2 while the size of the partial 16q22.1->qter trisomy was 20.82 Mb for Patient 3. Intraventricular hemorrhage and transitional thrombocytopenia were found in both sibs but not in the third patient. The FLI1 gene, which is the most relevant gene for thrombocytopenia in Jacobsen syndrome, was neither deleted in family A nor in Patient 3. We suggest that a positional effect could affect the FLI1 expression for these two sibs. Deafness of our three patients confirmed the association of this anomaly to 11q monosomy and tended to confirm the hypothetic role of DFNB20 in Jacobsen syndrome hearing loss. Both sibs shared most of the features commonly observed in Jacobsen syndrome, but not the third patient. This confirmed that terminal 11q trisomy spanning 1 to 1.97-2.11 Mb is not associated with a typical Jacobsen syndrome., (Copyright © 2011 Wiley-Liss, Inc.)

Jacobsen syndrome (JBS) is a haploinsufficiency syndrome caused by partial deletion of the long arm of chromosome 11. It is characterized by developmental delay (DD)/mental retardation (MR), physical growth retardation, facial dysmorphism, visceral malformations and thrombocytopenia. We report two JBS patients from China out of a total of 451 patients with unexplained DD/MR. The genotypes of these patients were compared with earlier reported patients in North America and Europe. Both patients presented with severe DD, microcephaly and facial dysmorphism; one patient had a low birth weight, congenital heart disease and structural brain abnormalities. Neither patient was thrombocytopenic at the time of diagnosis. The two deletions were 4.1 and 12.8 Mb. The 4.1 Mb deletion is the smallest of all pathogenic regions earlier reported in JBS. Therefore, the critical region underlying DD/MR might be located in the distal portion of the chromosomal segment within 4.1 Mb of the telomere. Candidate genes for DD/MR in this region include SNX19, THYN1, OPCML, NCAPD3 and NTM. One of the critical regions for craniofacial abnormalities may be within 130.3-134.4 Mb in chromosome 11q. Further analysis of Chinese JBS patients would elucidate the relation of phenotype to genotype further.