Distal Deletion of Chromosome 11q Encompassing Jacobsen Syndrome without Platelet Abnormality

Terminal 11q deletion, known as Jacobsen syndrome (JBS), is a rare genetic disorder associated with numerous dysmorphic features. We studied two cases with multiple congenital anomalies that were cytogenetically detected with deletions on 11q encompassing JBS region: 46,XX,der(11) del(11)(q24). Array comparative genomic hybridization (aCGH) analysis confirmed partial deletion of 11.8–11.9 Mb at 11q24.1q25 (case 1) and 13.9–14 Mb deletion at 11q23.3q25 together with 7.3–7.6 Mb duplication at 12q24.32q24.33 (case 2). Dysmorphism because of the partial duplication of 12q was not overtly decipherable over the Jacobsen phenotype except for a triangular facial profile. Aberrant chromosome 11 was inherited from phenotypically normal father, carrier of balanced translocation 46,XY,t(11;12)(q23.3; q24.32). In the present study, both cases had phenotypes that were milder than the ones described in literature despite having large deletion size. Most prominent features in classical JBS is thrombocytopenia, which was absent in both these cases. Therefore, detailed functional analysis of terminal 11q region is warranted to elucidate etiology of JBS and their clinical presentation.

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Jacobsen syndrome and neonatal bleeding: report on two unrelated patients

Italian Journal of Pediatrics ◽

10.1186/s13052-021-01108-2 ◽

2021 ◽

Vol 47 (1) ◽

Author(s):

Gregorio Serra ◽

Luigi Memo ◽

Vincenzo Antona ◽

Giovanni Corsello ◽

Valentina Favero ◽

...

Keyword(s):

Developmental Delay ◽

De Novo ◽

Comparative Genomic ◽

Fish Analysis ◽

Variable Degree ◽

Jacobsen Syndrome ◽

Contiguous Gene ◽

Clinical Consequences ◽

11Q Deletion

Abstract Introduction In 1973, Petrea Jacobsen described the first patient showing dysmorphic features, developmental delay and congenital heart disease (atrial and ventricular septal defect) associated to a 11q deletion, inherited from the father. Since then, more than 200 patients have been reported, and the chromosomal critical region responsible for this contiguous gene disorder has been identified. Patients’ presentation We report on two unrelated newborns observed in Italy affected by Jacobsen syndrome (JBS, also known as 11q23 deletion). Both patients presented prenatal and postnatal bleeding, growth and developmental delay, craniofacial dysmorphisms, multiple congenital anomalies, and pancytopenia of variable degree. Array comparative genomic hybridization (aCGH) identified a terminal deletion at 11q24.1-q25 of 12.5 Mb and 11 Mb, in Patient 1 and 2, respectively. Fluorescent in situ hybridization (FISH) analysis of the parents documented a de novo origin of the deletion for Patient 1; parents of Patient 2 refused further genetic investigations. Conclusions Present newborns show the full phenotype of JBS including thrombocytopenia, according to their wide 11q deletion size. Bleeding was particularly severe in one of them, leading to a cerebral hemorrhage. Our report highlights the relevance of early diagnosis, genetic counselling and careful management and follow-up of JBS patients, which may avoid severe clinical consequences and lower the mortality risk. It may provide further insights and a better characterization of JBS, suggesting new elements of the genotype-phenotype correlations.

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A new case of intragenic deletion of the TCF4 gene without features of Pitt-Hopkins syndrome

Molecular and experimental biology in medicine ◽

10.33602/mebm.3.2.8 ◽

2020 ◽

Vol 3 (2) ◽

pp. 56-58

Author(s):

Leona Morozin Pohovski ◽

Adriana Bobinec ◽

Ana-Maria Measic ◽

Ivona Sansovic ◽

Ingeborg Barisic

Keyword(s):

Genetic Disorder ◽

Protein Isoforms ◽

Comparative Genomic ◽

Bhlh Transcription Factor ◽

Balanced Translocation ◽

Genomic Alterations ◽

Coding Sequence ◽

Psychomotor Delay ◽

Severe Intellectual Disability ◽

First Case

Different genomic alterations affecting the TCF4 gene are usually associated with Pitt-Hopkins syndrome (PTHS). This syndrome is a rare neurodevelopmental genetic disorder characterized by distinctive facial features, abnormal breathing, psychomotor delay and severe intellectual disability (ID). The genomic alterations include whole or partial gene deletion; balanced translocation disrupting the coding sequence of the gene; and intragenic variants. The TCF4 gene encodes a basic helix-loop-helix (bHLH) transcription factor 4. Using alternative promoters, TCF4 can be transcribed from a number of alternative initial exons, allowing for translation of variable protein isoforms containing different functional domains. Full-length TCF4 has two activation domains (AD1 and AD2) that are thought to modulate transcriptional activity, a NLS domain (nuclear localization signal) that controls subcellular localization and bHLH domain. Typical PTHS patients have aberration localized between exons 9 and 18 of the gene. On the other hand, variants affecting the first protein coding exons give rise to mild non-syndromic ID. We present a ten-year-old girl with psychomotor delay and mild ID without the typical features of PTHS. Genetic investigation using array-based comparative genomic hybridization, revealed a 73.45 kb deletion within the TCF4 gene. The deletion encompassing only exon 6 (NM_001083962). This deletion was not detected in both parents. Cytogenetic analysis excluded balanced translocation disrupting the coding sequence of the gene. To the best of our knowledge, this is the first case described in literature involving only exon 6. The findings in our patients support the notion that position of the alteration in TCF4 is relevant to the phenotype. Reporting our case we want to contribute to the phenotype-genotype correlation in patients with intragenomic deletion of TCF4 gene.

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Report of Jacobsen syndrome with a mild facial dysmorphism, severe hearing impairment and thrombocytopenia

Acta medica Lituanica ◽

10.6001/actamedica.v19i1.2303 ◽

2012 ◽

Vol 19 (1) ◽

pp. 1-6

Author(s):

Vaidas DIRSĖ ◽

Loreta CIMBALISTIENĖ ◽

Jūratė KASNAUSKIENĖ ◽

Vaidutis KUČINSKAS

Keyword(s):

Cytogenetic Analysis ◽

Array Cgh ◽

Phenotypic Expression ◽

Facial Dysmorphism ◽

Balanced Translocation ◽

Jacobsen Syndrome ◽

Molecular Cytogenetic ◽

Wide Range ◽

Precise Analysis ◽

11Q Deletion

Background. Jacobsen syndrome is a rare syndrome with variable phenotypic expression depending on the breakpoints and the size of 11q deletion. There is presented a wide range of phenotypes of varying severity. Detailed molecular cytogenetic analysis leads to better knowledge of genetic causes of this syndrome. Materials and methods. Molecular cytogenetic analysis using subtelomeric FISH and array CGH was performed for a patient with Jacobsen syndrome. Results. Subtelomeric FISH detected an unbalanced translocation 46,XY,der(11)t(11;13)(q24.2;p11.2) of our patient. Array CGH analysis revealed a 13.95 Mb terminal deletion of the 11q23.3 region (breakpoint positions 120, 505, 418–134, 452, 384, NCBI build 36). FISH and GTG banding analysis identified a balanced translocation 46,XX,t(11;13) (q24.2;p11.2) of patient’s mother. Conclusions. The results of this case report suggest the need of combining both molecular cytogenetic methods: array CGH and FISH for precise analysis of patients with Jacobsen syndrome.

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AN OVERVIEW OF LESS KNOWN JACOBSEN SYNDROMEAN OVERVIEW OF LESS KNOWN JACOBSEN SYNDROME

International Journal of Advanced Research ◽

10.21474/ijar01/13197 ◽

2021 ◽

Vol 9 (07) ◽

pp. 947-953

Author(s):

Sushma Kumari ◽

◽

Hanna Hedleen ◽

Keyword(s):

De Novo ◽

Psychomotor Retardation ◽

Clinical Findings ◽

Physical Growth ◽

Facial Dysmorphism ◽

Chromosome 11 ◽

Balanced Translocation ◽

Nasal Bridge ◽

Jacobsen Syndrome ◽

Intellectual Deficit

Jacobsen syndrome is catastrophic in 1 out of every 5 cases, with children usually dying within the first 2 years of life due to heart complications. Jacobsen syndrome is a contiguous gene syndrome caused by partial deletion of the long arm of chromosome 11. The prevalence has been estimated at 1/100,000 births, with a female/male ratio 2:1. The most common clinical features include pre- and postnatal physical growth retardation, psychomotor retardation, and characteristic facial dysmorphism (skull deformities, hypertelorism, ptosis, coloboma, downslanting palpebral fissures, epicanthal folds, broad nasal bridge, short nose, v-shaped mouth, small ears, low set posteriorly rotated ears). Abnormal platelet function, thrombocytopenia or pancytopenia are usually present at birth. Patients commonly have malformations of the heart, kidney, gastrointestinal tract, genitalia, central nervous system and skeleton. Ocular, hearing, immunological and hormonal problems may be also present. The deletion size ranges from 07 to 20 Mb, with the proximal breakpoint within or telomeric to subband 11q 23.3 and the deletion extending usually to the telomere. The deletion is de novo in 85% of reported cases, and in 15% of cases it results from an unbalanced segregation of a familial balanced translocation or from other chromosome rearrangements. Diagnosis is based on clinical findings (intellectual deficit, facial dysmorphic features and thrombocytopenia) and confirmed by cytogenetics analysis.

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Familial 3-Way Balanced Translocation Causes 1q43→qter Loss and 10q25.2→qter Gain in a Severely Affected Male Toddler

Cytogenetic and Genome Research ◽

10.1159/000498998 ◽

2019 ◽

Vol 157 (4) ◽

pp. 231-238

Author(s):

Carlos Córdova-Fletes ◽

Eliakym Arámbula-Meraz ◽

Ana Itzel Zarazúa-Niño ◽

Jesús Madueña-Molina ◽

Marbella Elizabeth Sáinz-Barraza ◽

...

Keyword(s):

Genetic Counseling ◽

Microarray Analysis ◽

Rare Events ◽

Chromosomal Rearrangements ◽

Balanced Translocation ◽

Cardiac Defects ◽

Recurrent Miscarriages ◽

Complex Chromosomal Rearrangements ◽

Key Features ◽

Normal Father

Constitutional complex chromosomal rearrangements (CCRs) are rare events that typically involve 2 or more chromosomes with at least 3 breakpoints and can result in normal or abnormal phenotypes depending on whether they disturb the euchromatic neighborhood. Here, we report an unusual balanced CCR involving chromosomes 1, 9, and 10 that causes an unbalanced karyotype in a severely affected toddler. The CCR was initially reported as a maternal 2-way translocation but was reclassified as a 3-way translocation after a microarray analysis of the propositus revealed the involvement of another chromosome not identified by G-banding in his phenotypically normal mother. FISH assays on maternal metaphase cells confirmed that the 1qter region of der(1) was translocated to der(10), whereas the 10qter segment was translocated to der(9), which in turn donated a segment to der(1). Subsequently, this CCR was also identified in her phenotypically normal father (the patient's grandfather). Thus, the patient inherited the previously unreported pathogenic combination of der(1) with a loss of 1q43→qter (including AKT3, ZBTB18, HNRNPU, and SMYD3) and der(9) with a gain of 10q25.2→qter (including FGFR2), leading to a compound phenotype with key features of the 1q43→qter deletion and distal 10q trisomy syndromes. Our observations suggest that the loss of SMYD3 accounts for cardiac defects in a subset of patients. Moreover, due to recurrent miscarriages in this family, our findings allowed improved genetic counseling.

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Renal Dysplasia and Progressive Renal Failure in a Newborn with Interstitial Chromosome 4 Deletion 4q25-28.3: A New Phenotype?

Journal of Pediatric Genetics ◽

10.1055/s-0039-1701043 ◽

2020 ◽

Author(s):

Cláudia Teles-Silva ◽

Francisca Martins ◽

Sandra Costa ◽

Paulo Soares ◽

Gustavo Rocha ◽

...

Keyword(s):

Renal Failure ◽

Clinical Presentation ◽

Renal Dysplasia ◽

Large Deletion ◽

Comparative Genomic ◽

Chromosome 4 ◽

Clinical Progression ◽

Cystic Kidneys ◽

Progressive Renal Failure ◽

Subcutaneous Edema

AbstractThe deletion of the long arm of chromosome 4 is rare, presenting with a variable phenotype depending on the chromosomic area affected. A term newborn with prenatal diagnosis of anhydramnios, dysplastic cystic kidneys, and cardiomegaly was born with generalized subcutaneous edema, several dysmorphic features, and progressive renal failure requiring dialysis. The infant continued to deteriorate and died at 52 days of age. Autopsy confirmed bilateral renal dysplasia with cysts. Array-comparative genomic hybridization (CGH) identified a large deletion on 4q25-q28.3, which is not yet described in association with renal disease. The clinical progression could be expected due to the severity of the perinatal clinical presentation.

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Antenatal diagnosis of deletion chromosome 11(q23-qter) (Jacobsen syndrome)

Clinical Dysmorphology ◽

10.1097/mcd.0b013e3281e668bf ◽

2007 ◽

Vol 16 (3) ◽

pp. 177-179 ◽

Cited By ~ 6

Author(s):

Patricia Foley ◽

Fionnuala McAuliffe ◽

Marice Mullarkey ◽

William Reardon

Keyword(s):

Antenatal Diagnosis ◽

Chromosome 11 ◽

Jacobsen Syndrome

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Fluorescence In Situ Hybridization (FISH) Using a Subtelomeric 11q Probe as a New Diagnostic Tool for Congenital Thrombocytopenia Caused by Deletions in 11q.

Blood ◽

10.1182/blood.v104.11.3035.3035 ◽

2004 ◽

Vol 104 (11) ◽

pp. 3035-3035

Author(s):

Dorothea Gadzicki ◽

Gudrun Michaelsen ◽

Cornelia Rudolph ◽

Doris Steinemann ◽

Christoph M. Happel ◽

...

Keyword(s):

In Situ Hybridization ◽

Fluorescence In Situ Hybridization ◽

Diagnostic Tool ◽

Partial Trisomy ◽

Comparative Genomic ◽

Facial Dysmorphism ◽

Chromosome 11 ◽

Partial Monosomy ◽

Structural Aberrations

Abstract Neonatal thrombocytopenia occurs in about 1% of all newborns. Inherited forms like 11q- or Jacobsen syndrome are rare. However, they may remain undetected with karyotyping because the deleted regions in 11q often involve small subtelomeric regions. Here we report on the detection of deletions in 11q in two newborns with normal routine karyotypes who were shown to carry subtelomeric deletions in 11q by means of fluorescence in situ hybridization (FISH) using a subtelomeric 11q probe (Abbott, Diagnostics, Wiesbaden, Germany). Both children showed thrombocytopenia (18.000/μl and 26.000/μl, respectively) and dysmegakaryopoiesis (absence of normal megakaryocytes and presence of micromegakaryocytes) associated with facial dysmorphism, cardiac defects and psychomotoric retardation. In the second case, the mother and the grandmother also showed mild thrombocytopenia. In both patients, FISH analyses on peripheral blood and bone marrow showed the loss of the telomere-associated region of 11q distal of the MLL gene. In the first patient, the deletion of 11q resulted from an unbalanced complex rearrangement with duplication of 11p. As the source of this chromosomal aberration, a paternal pericentric inversion of chromosome 11 was identified. The partial monosomy 11q and the partial trisomy 11p in the first patient were confirmed by comparative genomic hybridization (CGH) analysis. Array/matrix CGH assisted in determining the breakpoints at 11p15.1 and 11q24.1. No structural aberrations of 11q were found in the mother of the second patient, but further investigations are under way. These findings give further evidence that small subtelomeric deletions of 11q and probably mutations of genes located therein cause thrombocytopenia. Since it can be very difficult to detect these deletions by karyotyping, FISH using a subtelomeric 11q probe seems to be an extremely useful new diagnostic tool. This new method should be applied in children with congenital thrombocytopenia, in particular if they have additional complex dysmorphic features.

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Therapy Personalization Using Predictive Simulation Approach with Ex-Vivo Clinical Validations

Blood ◽

10.1182/blood.v124.21.2232.2232 ◽

2014 ◽

Vol 124 (21) ◽

pp. 2232-2232

Author(s):

Nicole A Doudican ◽

Ravi Vij ◽

Mark A Fiala ◽

Justin King ◽

Shireen Vali ◽

...

Keyword(s):

New York ◽

Ex Vivo ◽

Patient Simulation ◽

Comparative Genomic ◽

Beta Catenin ◽

Genomic Profile ◽

Chromosome 11 ◽

New York University ◽

Predictive Simulation ◽

Profile Information

Abstract Background The epitome of cancer treatment personalization is N=1 segmentation where a custom therapy is designed for every patient. Because most cancer aberrations are not actionable mutations and tumors can have more than one actionable mutation, this one biomarker/one drug approach to cancer personalization has inherent limitations due to its over simplification. Personalization 2.0 methodology creates a patient simulation avatar incorporating a patient’s genomic profile information holistically. Methods Bone marrow samples from two myeloma patients (P1 and P2) refractory to most recent treatment was collected, and P1’s sample was sorted into CD138+ and CD138- cells. The patient cells were analyzed for chromosomal alterations using Comparative Genomic Hybridization (aCGH) arrays by GenPath Diagnostics and cytogenetic chromosome analysis by Washington University School of Medicine and New York University (NYU), respectively. Using this information, a predictive simulation avatar model of each patient was created by Cellworks based on genomic profile of patients. A digital functional library of over 80 FDA-approved drugs and agents currently in clinical trials were simulated individually and in combination using the two patient avatars to create a personalized treatment for each patient. The findings were prospectively validated using patient cells ex vivo as assessed by MTT assay at New York University. Results P1 aberrations included trisomy of CCND1 and deletion of TP53 along with single copy losses in different arms of chromosomes 1, 6, 8, 12, 13, 14, 16, 17 and 22 and gains in different arms and regions of chromosomes X, 1, 4, 7, 9, 17, 3, 5, 11, 15 and 19, indicating the presence of hyperdiploid clones. Using this information, 897 gene perturbations were included to model this patient simulation avatar. Simulation predicted high beta-catenin (CTNNB1) activity with increased hedgehog and NOTCH pathways that were inherent causes of Bortezomib resistance. Significant activation of STAT3 and STAT5 due to amplification of IL6 pathway, JAK2 and JAK3 was noted. Amplifications of MET, IGFR and FGFR converged at ERK and AKT signaling loops. Along with deletion of TP53, this profile had amplification of many anti-apoptotic genes including survivin, MCL1 and XIAP. Modeling predicted sensitivity to the JAK inhibitor Tofacitinib, a drug approved for rheumatoid arthritis. This was prospectively validated ex vivo, and the experimental data correlated with the prediction showing a reduction in viability. P2 aberrations include losses in chromosomes X and 9 and a chromosome 11:14 translocation that is a common occurrence in MM. This translocation results in an amplification of CCND1 expression. The genomic aberrations reported include knockdown of tumor suppressors RXRA, TGFBR1, TJP2 and TSC1. TSC1 regulates the mTOR pathway, and its deletion causes an aberrant activation of mTOR and its downstream targets. Reduced expression of RXRA and TJP2 both in different manners leads to increase in AP1 activation. NFkB is also activated due to RXRA reduction. TGFBR1 reduction decreases the expression of cell cycle inhibitors via SMAD2/3 down-regulation. In this patient avatar, modeling predicted sensitivity to a combination of Sirolimus and Trametinib. Ex vivo validation confirmed this prediction of additive synergy of these two drug agents in the context of this patient. Conclusions This study demonstrates and validates the personalization of treatment through two patient cases based on creating predictive simulation avatar models using genomic profile information. This modeling holistically incorporates all genomic aberration information and is not limited to associating drugs to actionable mutations. Disclosures Doudican: Cellworks: Research Funding. Vali:Cellworks: Employment. Basu:Cellworks: Employment. Kumar:cellworks: Employment. Singh:Cellworks: Employment. Sultana:Cellworks: Employment. Abbasi:Cellworks: Employment, Equity Ownership.

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