22q11 Microdeletion Research Articles

The 22q11 deletion syndrome poses a multidisciplinary challenge for pediatricians and child psychiatrists as shown by a case report

Microdeletion 22q11.2 (22q11DS) is the most frequent chromosomal deletion known in man. The deletion syndrome subsumes different phenotypes, including Di George syndrome, characterized by thymic hypoplasia, congenital heart disease and facial dysmorphism, while velocardiofacial syndrome is described with added cleft palate and learning disabilities. In the last 15 years there has been an increasing recognition of associations with neuropsychiatric disorders. Researches revealed that people with this microdeletion are at high risk of developing attention-deficit/hyperactivity disorder, schizophrenic psychosis, depressive disorders, intellectual impairment, seizures and motoric abnormalities. Recent studies supported the association of schizophrenia and 22q11DS. However the pathogenetic implications for schizophrenia are still controversial. Both the neurobiology of 22q11 deletion syndrome and the relationship between abnormalities in brain anatomy and behaviour remain unclear. We report on the clinical case of an 18-year-old girl with a genetic confirmed Microdeletion 22q11.2 which developed psychotic symptoms. Additionally, this article gives a systematic review regarding optional psychiatric disorders in 22q11 deletion syndromes.

Right aortic arch detected in fetal life

To evaluate the prenatal distribution, associated conditions and outcome of the different types of right aortic arch (RAA) detected in fetal life. This was a retrospective review of all cases of RAA detected prenatally between 1998 and 2005 in two tertiary referral centers. In the study period 71 cases of RAA were detected; 26 (37%) had RAA with aberrant left subclavian artery, 23 (32%) had RAA with mirror-image branching, 20 (28%) had RAA of unknown type and two (3%) had double aortic arch. While 20/26 cases with RAA and aberrant left subclavian artery were isolated findings, all 23 cases with RAA and mirror-image branching were associated with cardiac defects, namely tetralogy of Fallot (43%) or pulmonary atresia with ventricular septal defect (22%). Of the 20 cases with RAA, 19 of unknown type were associated with heterotaxy syndromes and had additional cardiac malformations and ambiguities of the situs. The two cases with DAA were isolated findings. Seven cases in our series (10%) had a microdeletion 22q11 and these were significantly associated with extracardiac malformations. The outcome in our series depended solely on the associated cardiac and extracardiac malformations, with the exception of one infant with isolated DAA, in whom a surgical correction was warranted. RAA detected in fetal life is associated frequently with other cardiac/non-cardiac malformations, heterotaxy syndromes and microdeletions 22q11. The associated conditions vary depending on the branching type of the brachiocephalic vessels and the presence of extracardiac malformations.

Right aortic arch in the fetus

To examine our experience of the detection of a right aortic arch in the fetus over an 8-year period. Between February 1998 and December 2005, all patients prospectively diagnosed with a right aortic arch at our center were identified from our database and the videotape reviewed. In addition, the videotapes of 300 normal and 110 abnormal arbitrarily selected fetal echocardiograms, as well as 123 cases of tetralogy of Fallot and nine of a common arterial trunk were reviewed. Data including indication for fetal echocardiography, gestational age at diagnosis, karyotype, nuchal translucency measurement and outcome were collected. A right aortic arch was diagnosed prospectively in 55 fetuses and in a further 20 on retrospective videotape review. There were 21 examples of isolated aortic arch and four thought to have a double arch. A right arch was found in association with additional intracardiac malformations in 50 cases. The detection rate of a right aortic arch increased over the study period. The majority of patients were referred for a suspicion of congenital heart disease on obstetric scanning. Mean gestational age at diagnosis was 21 weeks. The karyotype including 22q11 status was known in 45/75 cases. There were 23 confirmed karyotypic anomalies, 12 of which were 22q11 deletions, occurring in 2/25 of the isolated group and 10/48 of the complex group, with a further two complex cases that were likely to have had 22q11 microdeletions. There were 29 pregnancy interruptions, four intrauterine deaths, 31 live births, four neonatal deaths and three patients lost to follow-up. The remaining four pregnancies are continuing. Of the four with suspected double arch, three were confirmed postnatally. The diagnosis of a right-sided aortic arch can be made by fetal echocardiography, either as an isolated lesion or in association with other cardiac malformations, from as early as 12 weeks' gestation. It can be difficult to distinguish from a double arch. Its increasing incidence over time in our series probably indicates that the diagnosis was previously overlooked. Karyotyping in the absence of other abnormal findings may be unnecessary in every case, but establishment of 22q11 microdeletion status in those cases with other anomalies is important.

A microdeletion 22q11.2 can resemble Shprintzen–Goldberg omphalocele syndrome

American Journal of Medical Genetics Part AVolume 140A, Issue 24 p. 2838-2839 Correspondence A microdeletion 22q11.2 can resemble Shprintzen–Goldberg omphalocele syndrome† Sibylle Strenge, Corresponding Author Sibylle Strenge [email protected] Faculty of Medicine, Institute of Human Genetics, University of Leipzig, Leipzig, GermanyInstitute of Human Genetics, Medical Faculty, University of Leipzig, Philipp-Rosenthal-Str. 55, D-04103 Leipzig, Germany.Search for more papers by this authorAnnegret Kujat, Annegret Kujat Faculty of Medicine, Institute of Human Genetics, University of Leipzig, Leipzig, GermanySearch for more papers by this authorLeopoldo Zelante, Leopoldo Zelante Medical Genetics Service IRCCS “CSS” Hospital, San Giovanni Rotondo, Foggia, ItalySearch for more papers by this authorUrsula G. Froster, Ursula G. Froster Faculty of Medicine, Institute of Human Genetics, University of Leipzig, Leipzig, GermanySearch for more papers by this author Sibylle Strenge, Corresponding Author Sibylle Strenge [email protected] Faculty of Medicine, Institute of Human Genetics, University of Leipzig, Leipzig, GermanyInstitute of Human Genetics, Medical Faculty, University of Leipzig, Philipp-Rosenthal-Str. 55, D-04103 Leipzig, Germany.Search for more papers by this authorAnnegret Kujat, Annegret Kujat Faculty of Medicine, Institute of Human Genetics, University of Leipzig, Leipzig, GermanySearch for more papers by this authorLeopoldo Zelante, Leopoldo Zelante Medical Genetics Service IRCCS “CSS” Hospital, San Giovanni Rotondo, Foggia, ItalySearch for more papers by this authorUrsula G. Froster, Ursula G. Froster Faculty of Medicine, Institute of Human Genetics, University of Leipzig, Leipzig, GermanySearch for more papers by this author First published: 13 November 2006 https://doi.org/10.1002/ajmg.a.31534Citations: 3 † How to cite this article: Strenge S, Kujat A, Zelante L, Froster UG. 2006. A microdeletion 22q11.2 can resemble Shprintzen–Goldberg omphalocele syndrome. Am J Med Genet Part A 140A:2838–2839. Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL No abstract is available for this article.Citing Literature Volume140A, Issue2415 December 2006Pages 2838-2839 RelatedInformation

Microdeletion and microduplication 22q11.2 screening in 295 patients with clinical features of DiGeorge/Velocardiofacial syndrome

The 22q11.2 region is susceptible to chromosomal rearrangements, leading to various types of congenital malformation and mental retardation. The most common anomaly is 22q11.2 microdeletion, associated with DiGeorge/Velocardiofacial syndrome (DG/VCFS). Recently the microduplication 22q11.2 syndrome has been identified. Some clinical features in patients with this new chromosomal disorder present a substantial overlap with DG/VCFS. The aim of this hospital-based study was to evaluate the incidence of deletions and duplications on 22q11.2 in patients with DG/VCFS features. We investigated a group of 295 patients with widely variable manifestations associated with DG/VCFS. Along with the clinical diagnoses different anomalies were noted such as conotruncal cardiac anomaly, velopharyngeal insufficiency, characteristic facial dysmorphic features, language impairment, developmental delay/learning difficulties, and immunologic anomalies or thymic hypoplasia. Laboratory studies included conventional cytogenetic and FISH testing. Metaphase and interphase cells were analyzed for the presence of 22q11.2 microdeletion or microduplication. There were 12 patients who carried 22q11.2 microdeletion and no microduplication in the region was identified. Other chromosomal anomalies were reported in five patients with an overlapped DG/VCFS phenotype. All patients with 22q11.2 microdeletion showed a characteristic phenotype of DG/VCFS. We did not identify 22q11.2 microduplication, suggesting that this is a rare event in patients with DG/VCFS features.

Chromosome 22 microdeletion by F.I.S.H. in isolated congenital heart disease

To analyze the frequency of del22q11.2 in non-syndromic CHDs using classical cytogenetics and Fluorescence In Situ Hybridization (FISH) technique in Indian population. 105 prospective cases which included 6 families with isolated, non-syndromic cardiac defects were analyzed clinically by a cardiologist and a geneticist. The cases were then subjected to karyotypic (classical cytogenetics) as well as FISH analysis. The efficacy of FISH technique was compared with inference drawn from classical cytogenetics. Karyotypic analysis of all the 105 patients revealed a normal chromosomal complement. Microdeletion 22q11.2 was observed in six patients (5.71%) by FISH studies. FISH studies were also performed on the parents of these six patients who revealed a normal chromosome 22. No correlation was found between clinical features (mild or unspecific) with 22q11.2 microdeletion. The testing for microdeletion 22q11.2 in isolated non-syndromic patients using FISH technique is mandatory even when mild/unspecific extracardiac abnormalities are seen in the patients.

OP04.03: Timing of presentation and outcome of fetuses suspected of having coarctation of the aorta

Methods: Over the last 10 years, 1901 cases of CHD have been diagnosed and managed at the two institutions. Only 17 confirmed cases of pAVSD (0.8%) have been detected in the same period and represent the study population. The following variables were assessed: indication to fetal echocardiography, diagnostic features, associated cardiac, extra-cardiac and chromosomal anomalies, feto-neonatal outcome. Results: The key features leading to the diagnosis were the lost of the offset appearance of the AV plane and the ostium primum atrial septal defect. Twelve cases were diagnosed before 23 weeks of gestation, 5 after. Only three cases were referred for a suspect of CHD, the majority because of extra-cardiac anomalies (4) and known Down syndrome (4). Aortic coarctation was associated in 2 cases, chromosomal anomalies in 9 cases [42% – trisomy 21 (6), trisomy 18, 22q11 microdeletion and unbalanced translocation (1 each)], extra-cardiac anomalies in 6 cases (35%), non-chromsomal syndromes in 3 cases (Ellis van Creveld, Noonan, to be defined). Conclusion: pAVSD is rarely detected in utero due to the subtle modification of the 4-chamber view. The diagnosis is made only if fetal echocardiography is performed by experts in cases referred for various reasons.

Diagnostic yield of various genetic approaches in patients with unexplained developmental delay or mental retardation

The underlying cause of mental retardation remains unknown in up to 80% of patients. As chromosomal aberrations are the most common known cause of mental retardation, several new methods based on FISH, PCR, and array techniques have been developed over recent years to increase detection rate of subtle aneusomies initially of the gene rich subtelomeric regions, but nowadays also genome wide. As the reported detection rates vary widely between different reports and in order to compare the diagnostic yield of various investigations, we analyzed the diagnostic yield of conventional karyotyping, subtelomeric screening, molecular karyotyping, X-inactivation studies, and dysmorphological evaluation with targeted laboratory testing in unselected patients referred for developmental delay or mental retardation to our cytogenetic laboratory (n = 600) and to our genetic clinic (n = 570). In the cytogenetic group, 15% of patients showed a disease-related aberration, while various targeted analyses after dysmorphological investigation led to a diagnosis in about 20% in the genetic clinic group. When adding the patients with a cytogenetic aberration to the patient group seen in genetic clinic, an etiological diagnosis was established in about 40% of the combined study group. A conventional cytogenetic diagnosis was present in 16% of combined patients and a microdeletion syndrome was diagnosed in 5.3%, while subtelomeric screening revealed only 1.3% of causes. Molecular karyotyping with a 10 K SNP array in addition revealed 5% of underlying causes, but 29% of all diagnoses would have been detectable by molecular karyotyping. In those patients without a clear diagnosis, 5.6% of mothers of affected boys showed significant (>95%) skewing of X-inactivation suggesting X-linked mental retardation. The most common diagnoses with a frequency of more than 0.5% were Down syndrome (9.2%), common microdeletion 22q11.2 (2.4%), Williams-Beuren syndrome (1.3%), Fragile-X syndrome (1.2%), Cohen syndrome (0.7%), and monosomy 1p36.3 (0.6%). From our data, we suggest the following diagnostic procedure in patients with unexplained developmental delay or mental retardation: (1) Clinical/dysmorphological investigation with respective targeted analyses; (2) In the remaining patients without an etiological diagnosis, we suggest conventional karyotyping, X-inactivation screening in mothers of boys, and molecular karyotyping, if available. If molecular karyotyping is not available, subtelomeric screening should be performed.

A case of 3q29 microdeletion with novel features and a review of cytogenetically visible terminal 3q deletions

A further case of 3q29 deletion, in a 13-year-old boy, is described and compared with previous reports. Our case shares a number of dysmorphic and neurodevelopmental features with previously reported individuals with 3q29 microdeletion and is the second reported case with deceleration in head growth--which may be a useful diagnostic clue. Novel features, which may expand the phenotype, include nasal voice, six lumbar vertebrae, lower limb contractures and cerebral sigmoid venous thrombosis. Additionally, cases with cytogenetically visible terminal 3q deletions are reviewed.

The spectrum of parathyroid gland dysfunction associated with the microdeletion 22q11

Clinical features associated with microdeletion of chromosome 22q11 (del(22)(q11)) are highly variable. Increased awareness of this condition is needed among specialists such as endocrinologists to reduce diagnostic delay and improve clinical care. The purpose of this study was to describe the phenotype of patients with del(22)(q11), focusing on parathyroid gland dysfunction. Charts of 19 patients, including one kindred of three, known to have del(22)(q11) diagnosed by fluorescence in situ hybridization (FISH) were reviewed from the register of the department of Medical Genetics. Major clinical features including hypoparathyroidism phenotype were collected. Parathyroid dysfunction was present in 8 out of 16 patients (50%). Six patients were diagnosed with overt hypoparathyroidism. Hypocalcemia manifested as laryngeal stridor within the first days of life (n = 3), seizures in infancy (n = 1) and adolescence (n = 2). The connection between hypoparathyroidism and diagnosis of del(22)(q11) was belated at the median age of 18 years. One patient had presented with transient neonatal hypoparathyroidism, and one patient had latent hypoparathyroidism. Within the kindred family, the phenotype variability including that of parathyroid dysfunction was as marked as between unrelated individuals. Standard karyotype failed to detect the deletion in 15 out of 19 cases. Abnormal parathyroid function in the del(22)(q11) ranges from severe neonatal hypocalcemia to latent hypoparathyroidism. Del(22)(q11) should be considered as a potential cause of hypocalcemia even in young adult. When suspected, the diagnosis requires investigation by FISH. Furthermore, long-term calcemia follow-up is needed in normocalcemic patients with del(22)(q11) because of the possible evolution to hypocalcemic hypoparathyroidism.

Prenatal diagnosis and outcome for fetuses with congenital absence of the pulmonary valve

To analyze fetal echocardiographic findings of absent pulmonary valve syndrome (APVS), its association with chromosomal and extracardiac anomalies including nuchal translucency (NT) and the outcome after diagnosis. Data of 14 fetuses with confirmed APVS retrospectively collected in two tertiary referral centers between 1998 and 2004 were analyzed. The variables examined were: reason for referral, gestational age at diagnosis and associated abnormalities, including first trimester NT thickness. Cardiac evaluation included measurement of cardiothoracic ratio, diameter of pulmonary arteries and Doppler flow in the pulmonary trunk. Information was retrieved from clinical files, recorded videotapes and stored images. Karyotyping including examination for the 22q11 deletion was performed in all cases. Mean gestational age at diagnosis was 28 weeks, with 5/14 (36%) diagnosed before 22 weeks. In 13/14 (93%) there was an associated ventricular septal defect (subaortic in 12 fetuses and inlet-type in one) and all 13 had tetralogy of Fallot. Enlargement of the central pulmonary arteries and cardiomegaly were present in all cases diagnosed after 22 weeks. Of the five fetuses in which APVS was detected before 22 weeks, four (80%) had a normal pulmonary trunk diameter, two (40%) had normal pulmonary branches and three (60%) had normal cardiac size. The arterial duct was absent in 11/14 (79%). A correlation between presence of the arterial duct and the size of the central pulmonary arteries or cardiomegaly could not be established. Increased NT was observed in 4/10 cases (40%) for which this information was available. 22q11 microdeletion was diagnosed in three fetuses (21%). There were five terminations of pregnancy, one intrauterine death, five neonatal deaths and one infant death. Of the six neonates with respiratory distress, only one (17%) survived and of the eight babies in whom there was an intention to treat, two survived (25%). APVS can be accurately diagnosed by fetal echocardiography but screening ultrasound in the mid-second trimester is likely to have a low detection rate, probably due to the incomplete expression of the disease at this point. Many fetuses with APVS have an increased NT in the first trimester and this may help an earlier recognition of the defect. The most common associated karyotype anomaly is 22q11 microdeletion. Enlargement of the central pulmonary arteries is mainly related to the gestational age at diagnosis. Our results confirm that the outlook for these patients is extremely poor.

Syndrome identification based on 2D analysis software

Clinical evaluation of children with developmental delay continues to present a challenge to the clinicians. In many cases, the face provides important information to diagnose a condition. However, database support with respect to facial traits is limited at present. Computer-based analyses of 2D and 3D representations of faces have been developed, but it is unclear how well a larger number of conditions can be handled by such systems. We have therefore analysed 2D pictures of patients each being affected with one of 10 syndromes (fragile X syndrome; Cornelia de Lange syndrome; Williams-Beuren syndrome; Prader-Willi syndrome; Mucopolysaccharidosis type III; Cri-du-chat syndrome; Smith-Lemli-Opitz syndrome; Sotos syndrome; Microdeletion 22q11.2; Noonan syndrome). We can show that a classification accuracy of >75% can be achieved for a computer-based diagnosis among the 10 syndromes, which is about the same accuracy achieved for five syndromes in a previous study. Pairwise discrimination of syndromes ranges from 80 to 99%. Furthermore, we can demonstrate that the criteria used by the computer decisions match clinical observations in many cases. These findings indicate that computer-based picture analysis might be a helpful addition to existing database systems, which are meant to assist in syndrome diagnosis, especially as data acquisition is straightforward and involves off-the-shelf digital camera equipment.

Antiphospholipid Antibodies Syndrome Associated with Hyperhomocysteinemia Related to MTHFR Gene C677T and A1298C Heterozygous Mutations in a Young Man with Idiopathic Hypoparathyroidism (DiGeorge Syndrome)

Antiphospholipid syndrome (APS, or Hughes' syndrome) is a systemic autoimmune disorder characterized by antiphospholipid antibody positivity, which may lead to arterial and/or venous thrombosis. Hyperhomocysteinemia (HHcy), variously associated with 5,10-methylene tetrahydrofolate reductase (MTHFR) gene point mutations, is also implicated in thromboembolic events. The association of APS and HHcy has already been described but has never been reported in patients with DiGeorge syndrome (DGS), the most common contiguous-gene deletion syndrome (22q11.2) in humans, whose phenotype conversely includes bleeding disorders. In this report, we present the case of a 19-yr-old patient with a past medical history of learning disability and obesity affected with idiopathic hypoparathyroidism, metabolic syndrome, and diffuse vasculitis disorders. He was referred to our endocrinology clinic for the management of severe hypocalcemia. At the time of presentation he had been taking antiepileptic drugs for 2 wk and displayed facial dysmorphism (short neck, micrognathia, a small mouth, hypoplastic nasal alae, eye hypertelorism, and low-set simple ears). DGS was suspected and confirmed by both fluorescence in situ hybridization analysis and single nucleotide polymorphism-array analysis, which revealed contiguous gene microdeletion of the chromosome 22q11.2 in the minimal DiGeorge critical region, specifically at the gene locus D22S75 (N25). APS, revealed by anti-beta-2-glycoprotein and anti-prothrombin antibodies positivity, and moderate HHcy related to heterozygous C677T and A1298C point mutations of the MTHFR gene were identified as a possible cause of thrombotic disorder responsible for the widespread presence of cutaneous and cerebral lesions.

Breakpoint Associated with a novel 2.3 Mb deletion in the VCFS region of 22q11 and the role of Alu (SINE) in recurring microdeletions

BackgroundChromosome 22q11.2 region is highly susceptible to rearrangement, specifically deletions that give rise to a variety of genomic disorders including velocardiofacial or DiGeorge syndrome. Individuals with this 22q11 microdeletion syndrome are at a greatly increased risk to develop schizophrenia.MethodsGenotype analysis was carried out on the DNA from a patient with the 22q11 microdeletion using genetic markers and custom primer sets to define the deletion. Bioinformatic analysis was performed for molecular characterization of the deletion breakpoint sequences in this patient.ResultsThis 22q11 deletion patient was established to have a novel 2.3 Mb deletion with a proximal breakpoint located between genetic markers RH48663 and RH48348 and a distal breakpoint between markers D22S1138 and SHGC-145314. Molecular characterization of the sequences at the breakpoints revealed a 270 bp shared sequence of the breakpoint regions (SSBR) common to both ends that share >90% sequence similarity to each other and also to short interspersed nuclear elements/Alu elements.ConclusionThis Alu sequence like SSBR is commonly in the proximity of all known deletion breakpoints of 22q11 region and also in the low copy repeat regions (LCRs). This sequence may represent a preferred sequence in the breakpoint regions or LCRs for intra-chromosomal homologous recombination mechanisms resulting in common 22q11 deletion.

Coexistence of Peripheral Primitive Neuroectodermal Tumor and Tetralogy of Fallot

We describe a little girl with tetralogy of Fallot (TOF) who was found to have a huge peripheral primitive neuroectodermal tumor (pPNET) when she developed progressive difficulty in standing and crawling at the age of 11 months. The tumor was located in the left paraspinal region (T4-T12), with intraspinal extension causing severe compression. Nine days after surgical decompression with laminectomy, chemotherapy was initiated with alternative courses of vincristine, doxorubicin, cyclophosphamide, etoposide, and ifosfamide every 3 weeks. The muscle power in her legs recovered substantially after 2 courses of chemotherapy. Although peripheral blood for cytogenetic study revealed no chromosome abnormality, recent cytogenetic analysis has revealed a high frequency of reciprocal translocation t(11;22)(q24;q12) detected in pPNET and a strong association between TOF and chromosome 22q11 microdeletion (del 22q11). Both genetic defects involve chromosome 22q in the close region. This case report illustrates the necessity of investigating for cytogenetic change in chromosome 22 and close follow-up due to the possibility of subsequent development of malignancies in patients with TOF.

Prospective study of 22q11 deletion analysis in fetuses with excess nuchal translucency

The purpose of this study was to determine the frequency of 22q11 deletions (DiGeorge, velocardiofacial syndromes) in chromosomally normal fetuses with excess nuchal translucency. We evaluated chorionic villus sampling (CVS) samples submitted with an indication of excess nuchal translucency. If chromosome analysis was normal, permission was obtained to perform 22q11 microdeletion fluorescence in situ hybridization analysis. By Fisher exact test, the null hypothesis that there is no association between excess nuchal translucency and 22q11 deletions was tested. Among 239 CVS samples from fetuses with excess nuchal translucency, 93 (39%) were chromosomally abnormal. Of the remaining 146 specimens, 80 CVS samples were chromosomally normal, had documentation of nuchal translucency > 3.0 mm, and were included in the study at the referring obstetrician's request. None of the 80 fetuses with an increased nuchal translucency and normal karyotype demonstrated a 22q11 microdeletion. By Fisher exact test, the probability of 80 fetuses with excess nuchal translucency having no deletions of chromosome 22 was not significantly different than the expected rate of 0.18% (P value = 1). Routine 22q11 microdeletion analysis for fetuses with excess nuchal translucency is not indicated. Instead, we recommend storing an extra unbanded slide from the cultured CVS material to permit 22q11 FISH analysis should a cardiac malformation be identified later by fetal echocardiography.

Clinical and molecular characterization of a new syndrome: the case of 3q29 microdeletion syndrome

Clinical and molecular characterization of a new syndrome: the case of 3q29 microdeletion syndrome

22q11 microdeletion studies in the heart tissue of an abortus involving a familial form of congenital heart disease

Microdeletion of chromosome 22 is responsible for DiGeorge syndrome, Velo Cardio Facial syndrome, and conotruncal defects. Here, we report on a case of microdeletion 22q11.2 in the heart tissue of a miscarried fetus in a family whose two children had died due to complex congenital heart disease. Fluorescence in situ hybridization (FISH) analysis in the couple revealed that the mother was mosaic for microdeletion of chromosome 22q11.2 in 10% of her peripheral lymphocytes. Prenatal diagnosis was offered to her in her third pregnancy. On routine ultrasonography at 10 weeks, the overall view of the heart was normal. However, before any further tests could be performed, she miscarried at 16 weeks. FISH studies on the heart tissue of the abortus revealed 22q11.2 microdeletion with two different cell lines. This suggests the importance of performing FISH studies when there is a history of congenital heart disease, even though ultrasonography shows a normal view of the heart.

Minitransplant Using Repeated Unrelated Donor Lymphocyte Infusions as a Treatment of Immunodeficiency in Complete DiGeorge Syndrome.

Complete DiGeorge syndrome (DGS) is a congenital disorder characterized by developmental defects of the heart, parathyroid glands and thymus associated with T-cell deficiency. Peripheral expansion of mature donor T cells thus represents a rational therapy. We present an infant with complete DGS treated with unrelated donor lymphocyte infusion (DLI). A Caucasian boy with multiple anomalies including choanal and esophageal atresia, congenital heart defects, retinal coloboma, tracheobronchomalacia, and gastroesofageal reflux was diagnosed with complete DGS at the age of 2 months. Lymphocyte subsets showed absence of T cells (0.0021x106/mL T cells, 1.9x106/mL lymphocytes at diagnosis) with no response to mitogens and absence of thymus. Microdeletion 22q11 was not found. During first 7 months of age he required long-term ventilation. At the same time, he suffered recurrent infections and sepsis. He had no sibling and no fully matched unrelated donor was available. At the age of six months the first dose of DLI (1x106/kg CD3+; 2x105/kg CD34+) was administered from an unrelated donor (mismatched for B and Cw alleles) with no conditioning regimen and no graft versus host disease (GVHD) prophylaxis. Although several units of blood products were not irradiated by mistake (9 in total, 8 times prior the 1st DLI), there was no proof of their engraftment. On day +10 after first DLI the boy developed severe isolated skin acute GVHD (stage 3–4) complicated with sepsis, cardiopulmonary instability and capillary leak syndrome, treated with antithymocyte globulin (rATG), cyclosporin A (CsA) and corticosteroids with a complete resolution of GVHD. Ventilation support was terminated at the age of 7 months. On day +36 after 1st DLI he was given the 2nd DLI (0.9x106/kg CD3+) from the same donor with no conditioning and with GVHD prophylaxis consisting of continued CsA. Severe documented complications were EBV infection 4 weeks after application (peripheral expansion of CD8+ donor cells started, treated with CsA withdrawal and 2 doses of rituximab). Isolated cholestatic liver GVHD manifested 1 month after second DLI, progressed to stage 4 over 3 weeks, successfully treated with corticosteroids, CsA and rATG. Since day+19 after 1st DLI, the donor genotype was documented in FACS-sorted T cells. Response to mitogens appeared and is now comparable to healthy controls. We used 7-color flow cytometry in subsequent specimens (three at the time of this abstract submission) to specify the developmental stage of the engrafted T cells. Central memory (CD27posCD45RAneg) stages dominate in the peripheral blood CD4 and CD8 cells (64 to 81% and 52 to 95%, respectively), which was higher than in control blood. Effector memory cells are increased in CD4 subset but decreased in CD8, whereas naive cells are decreased or normal. The patient, age 13 months, is now 6 months after 2nd DLI still on immunosupression (CsA and steroids), slowly started to gain his developmental milestones. We believe that infusions of small doses of DLI from an unrelated donor represent an adequate therapy for complete DiGeorge syndrome. Supported by NI 7410-3, MSM0021620812

Transcriptional and behavioral interaction between 22q11.2 orthologs modulates schizophrenia-related phenotypes in mice

Microdeletions of 22q11.2 represent one of the highest known genetic risk factors for schizophrenia. It is likely that more than one gene contributes to the marked risk associated with this locus. Two of the candidate risk genes encode the enzymes proline dehydrogenase (PRODH) and catechol-O-methyltransferase (COMT), which modulate the levels of a putative neuromodulator (L-proline) and the neurotransmitter dopamine, respectively. Mice that model the state of PRODH deficiency observed in humans with schizophrenia show increased neurotransmitter release at glutamatergic synapses as well as deficits in associative learning and response to psychomimetic drugs. Transcriptional profiling and pharmacological manipulations identified a transcriptional and behavioral interaction between the Prodh and Comt genes that is likely to represent a homeostatic response to enhanced dopaminergic signaling in the frontal cortex. This interaction modulates a number of schizophrenia-related phenotypes, providing a framework for understanding the high disease risk associated with this locus, the expression of the phenotype, or both.