Prenatal ultrasonic characteristics and genetic analysis of fetuses with chromosome 22q11 microdeletion syndrome / 中华医学遗传学杂志

OBJECTIVE@#To analyze the prenatal ultrasonic characteristics and genetic features of 14 fetuses with chromosome 22q11 microdeletion syndrome (22q11DS).@*METHODS@#4989 fetuses were analyzed by using single nucleotide polymorphism array (SNP array) in the Fujian Maternal and Child Health Hospital from November 2016 to November 2019.@*RESULTS@#SNP array showed that 11 fetuses had classic 3 Mb microdeletion in 22q11 region, one fetus had 2.0 Mb microdeletion, and two fetuses had 1.0 Mb microdeletion. The 1.0 Mb microdeletion in 22q11 region contains SNAP29 and CRKL genes, which may increase the risk of congenital renal malformation and cardiovascular malformation.@*CONCLUSION@#Prenatal ultrasonic characteristics of fetuses with 22q11 microdeletion syndrome vary, and SNP array is a powerful tool to diagnose such diseases, which can provide accurate genetic diagnosis and enable prenatal diagnosis.

Prenatal diagnosis of a fetus with Phelan-McDermid syndrome and 21q21 microdeletion by multiple genetic techniques / 中华医学遗传学杂志

OBJECTIVE@#To carry out prenatal diagnose for a fetus with ultrasonography abnormalities using multiple genetic techniques.@*METHODS@#Routine G-banding chromosomal analysis and single nucleotide polymorphism array (SNP-array) were applied in conjunction for the prenatal diagnosis of the fetus. The result was confirmed by fluorescence in situ hybridization (FISH).@*RESULTS@#SNP-array detected that the fetus has carried a hemizygous 5.1 Mb deletion at 22q13.31q13.33, which is associated with Phelan-McDermid syndrome, and a hemizygous 4.5 Mb deletion at 21q21.1q21.2. FISH analysis of the fetus and its parents suggested that both deletions were de novo in origin.@*CONCLUSION@#The hemizygous deletions on 21q21.1q21.2 and 22q13.31q13.33 probably underlay the abnormal phenotype of the fetus. Genetic analysis can provide crucial information for the prenatal diagnosis and genetic counseling.

Cardiopatías congénitas asociadas a la microdeleción 22q11. 2, en un hospital pediátrico / Congenital heart defects associated with a 22q11. 2 microdeletion at a pediatric hospital

Introducción: El síndrome de deleción 22q11.2, también llamado síndrome Velo-Cardio-Facial (VCFS/del22q11.2) o síndrome de DiGeorge, es una entidad causada por una anomalía cromosómica, deleción en la región q11.2 (brazo largo) del cromosoma 22. Se trata de una enfermedad multisistémica de expresión variable que afecta el aparato cardiovascular, la inmunidad, las funciones endocrinológicas, la cavidad oral, el desarrollo neurocognitivo, con una expresión facial particular. La prevalencia estimada es de 1:2000/4000. Objetivos: Identificar y describir las cardiopatías congénitas más frecuentemente asociadas a pacientes con síndrome de microdeleción 22q11.2. Materiales y métodos: Estudio descriptivo, transversal y retrospectivo que analiza los pacientes con diagnóstico de microdeleción 22q11.2 atendidos en el Hospital Garrahan desde Octubre de 1998 hasta Febrero 2018. El criterio diagnóstico fueron signos clínicos compatibles y la presencia de la microdeleción 22q11.2 por técnica de FISH o MLPA. Resultados: Población: 321 pacientes, 151 Femeninos (47%) 170 Masculinos (53%). Rango etario: 0 a 197 meses (1 día a 16,4 años). Mediana de edad al diagnóstico clínico: 31 meses. El 74,4% (239/321) de los pacientes evaluados con microdeleción 22q11.2 tuvieron cardiopatías congénitas asociadas a facies peculiar. Las cardiopatías congénitas más frecuentemente asociadas fueron conotroncales. De los pacientes con cardiopatías congénitas el 68,6% requirió cirugía cardiovascular. Fallecieron 24 pacientes (10%) con cardiopatías congénitas asociadas y en el 93% la causa de muerte estuvo relacionada a la afección cardiológica. Conclusiones: Los pacientes con microdeleción 22q11.2 se asocian con un alto porcentaje de cardiopatías congénitas, la gran mayoría son complejas (conotroncales) y requieren resolución quirúrgica en los primeros años de vida. Es de vital importancia la evaluación multidisciplinaria de este grupo especial de pacientes con cardiopatía asociada a otras alteraciones extra cardíacas para el diagnóstico precoz y tratamiento oportuno (AU)

Introduction: 22q11.2 deletion syndrome, also called velocardiofacial syndrome (VCFS/del22q11.2) or DiGeorge syndrome, is a condition caused by chromosomal abnormality, a deletion in the q11.2 region (long arm) of chromosome 22. VCFS is a multisystem disease of variable expression that affects the cardiovascular, immune, and endocrine systems, the oral cavity, neurocognitive development, and is associated with specific facial features. The estimated prevalence is 1:2000/4000. Objectives: To identify and describe the most common congenital heart defects associated with 22q11.2 micro-deletion syndrome. Materials and methods: Descriptive, cross-sectional, and retrospective study analyzing patients diagnosed with a 22q11.2 microdeletion seen at Garrahan Hospital from October 1998 to February 2018. Diagnostic criteria were compatible clinical signs and the presence of a 22q11.2 microdeletion identified by FISH or MLPA. Results: Population: 321 patients, 151 female (47%) and 170 Male (53%). Age range: 0 to 197 months (1 day to 16.4 years). Median age at clinical diagnosis: 31 months. Overall, 74.4% (239/321) of patients with a 22q11.2 microdeletion had congenital heart defects associated with a peculiar facies. The most commonly associated congenital heart defects were conotruncal. Of the patients with congenital heart defects, 68.6% required cardiovascular surgery. Of the patients with congenital heart defects 24 patients died (10%) and in 93% the cause of death was related to the heart disease (p 0.002). Conclusions: A high percentage of patients with a 22q11.2 microdeletion have congenital heart defects, which are complex (conotruncal) in the majority, requiring surgical treatment in the first years of life. Multidisciplinary evaluation of this special group of patients with heart defects associated with other extracardiac disorders is essential for an early diagnosis and timely treatment (AU)

Genomic imbalances in syndromic congenital heart disease / Desequilíbrios genômicos na cardiopatia congênita sindrômica

Abstract Objective: To identify pathogenic genomic imbalances in patients presenting congenital heart disease (CHD) with extra cardiac anomalies and exclusion of 22q11.2 deletion syndrome (22q11.2 DS). Methods: 78 patients negative for the 22q11.2 deletion, previously screened by fluorescence in situ hybridization (FISH) and/or multiplex ligation probe amplification (MLPA) were tested by chromosomal microarray analysis (CMA). Results: Clinically significant copy number variations (CNVs ≥300 kb) were identified in 10% (8/78) of cases. In addition, potentially relevant CNVs were detected in two cases (993 kb duplication in 15q21.1 and 706 kb duplication in 2p22.3). Genes inside the CNV regions found in this study, such as IRX4, BMPR1A, SORBS2, ID2, ROCK2, E2F6, GATA4, SOX7, SEMAD6D, FBN1, and LTPB1 are known to participate in cardiac development and could be candidate genes for CHD. Conclusion: These data showed that patients presenting CHD with extra cardiac anomalies and exclusion of 22q11.2 DS should be investigated by CMA. The present study emphasizes the possible role of CNVs in CHD.

Resumo Objetivo: Identificar desequilíbrios genômicos patogênicos em pacientes que apresentam cardiopatias congênitas (CC) e anomalias extracardíacas e exclusão da síndrome de deleção 22q11.2 (SD22q11.2). Métodos: Foram avaliados por microarray cromossômico (CMA) 78 pacientes negativos para a deleção 22q11.2, previamente testados por hibridação in situ com fluorescência (FISH) e/ou amplificação de múltiplas sondas dependentes de ligação (MLPA). Resultados: Foram identificadas variações do número de cópias de DNA (CNVs) clinicamente significativas (≥ 300 kb) em 10% (8/78) dos casos, além de CNVs potencialmente relevantes em dois casos (duplicação de 993 kb em 15q21.1 e duplicação de 706 kb em 2p22.3). Genes envolvidos como IRX4, BMPR1A, SORBS2, ID2, ROCK2, E2F6, GATA4, SOX7, SEMAD6D, FBN1 e LTPB1 são conhecidos por atuar no desenvolvimento cardíaco e podem ser genes candidatos a CC. Conclusão: Esses dados mostram que pacientes que apresentam CC, com anomalias extracardíacas e exclusão da SD22q11.2, devem ser investigados por CMA. Ainda, este estudo enfatiza a possível função das CNVs nas CC.

Characterization of a rare short arm heteromorphism of chromosome 22 in a girl with down-syndrome like facies.

Chromosomal heteromorphisms are described as interindividual variation of chromosomes without phenotypic consequence. Chromosomal polymorphisms detected include most regions of heterochromatin of chromosomes 1, 9, 16 and Y and the short arms of all acrocentric chromosomes. Here, we report a girl with Down‑syndrome such as facies and tremendously enlarged short arm of a chromosome 22. Fluorescence in situ hybridization (FISH) with a probe specific for all acrocentric short arms revealed that the enlargement p arms of the chromosome 22 in question contained exclusively heterochromatic material derived from an acrocentric short arm. Parental studies identified a maternal origin of this heteromorphism. Cryptic trisomy 21 of the Down‑syndrome critical region was excluded by a corresponding FISH‑probe. Here, we report, to the best of our knowledge, largest ever seen chromosome 22 short arm, being ~×1.5 larger than the normal long arm.

Unexpected Inheritance of a Balanced Homologous translocation t(22q;22q) from father to a phenotypically normal daughter.

Rearrangements between homologous chromosomes are extremely rare and manifest mainly as monosomic or trisomic offsprings. There are remarkably few reports of balanced homologous chromosomal translocation t (22q; 22q) and only two cases of transmission of this balanced homohologous rearrangement from mother to normal daughter are reported. Robersonian translocation carriers in non‑homologous chromosomes have the ability to have an unaffected child. However, it is not possible to have an unaffected child in cases with Robersonian translocations in homologous chromosomes. Carriers of homologous chromosome 22 translocations with maternal uniparental disomy do not have any impact on their phenotype. We are presenting a family with a history of multiple first trimester miscarriages and an unexpected inheritance of balanced homologous translocation of chromosome 22 with paternal uniparental disomy. There are no data available regarding the impact of paternal UPD 22 on the phenotype. We claim this to be the first report explaining that paternal UPD 22 does not impact the phenotype.

Phenotypic correlations in a patient with ring chromosome 22.

Ring chromosome 22, a rare cytogenetic anomaly, has been described in over 60 cases in the medical literature. The aim of this report was to present a case carrying ring chromosome 22, and her family. It is a case report of a patient presented at Medical Faculty of Çukurova University in Turkey. An 8-year-old girl with ring chromosome 22 and her family were evaluated cytogenetically and clinically. A chromosome analysis of the proband revealed a de novo 46, XX, r(22)(p11.2;q13) karyotype. Our subject demonstrated the prominent features of this syndrome including profound mental retardation, language impairment, dysmorphic features, lack of speech, hyperactivity, and behavioral disorders. There is lack of consistency between the physical abnormalities that we observed in our subject and those observed for such patients in the literature. The wide range of manifestations observed in patients with this cytogenetic alteration is probably due to size differences in the deleted region.

Partial Tetrasomy of Chromosome 22q11.1 Resulting from a Supernumerary Isodicentric Marker Chromosome in a Boy with Cat-eye Syndrome

The 22q11 region has been implicated in chromosomal rearrangements that result in altered gene dosage, leading to three different congenital malformation syndromes: DiGeorge syndrome, cat-eye syndrome (CES), and der(22) syndrome. Although DiGeorge syndrome is a common genomic disorder on 22q11, CES is quite rare, and there has been no report of Korean CES cases with molecular cytogenetic confirmation. In this study, we present the phenotypic and genetic characteristics of a 3-month-old boy with CES. Clinical findings included micropthalmia, multiple colobomata, and renal and genital anomalies. Cytogenetic analyses showed the presence of a supernumerary marker chromosome, which was identified as a bisatellited and isodicentric chromosome derived from an acrocentric chromosome. The results of array comparative genomic hybridization and fluorescence in situ hybridization studies confirmed the karyotype as 47,XY,+mar.ish idic(22)(q11.1) (D22S43+).arr 22q11.1(15,500,000-15,900,000)x4, resulting in a partial tetrasomy of 22q11.1. To the best of our knowledge, this is the first report in Korea of CES confirmed by cytogenetic and molecular cytogenetic analyses.

Two Cases of Acute Myeloid Leukemia with t(16;21)(p11;q22) and TLS/FUS-ERG Fusion Transcripts / 대한진단검사의학회지

Many AML-associated chromosomal abnormalities, such as t(8;21), t(15;17), inv(16), t(9;11), t(9;22) and t(6;9) are well known. The chromosomal aberration of t(16;21)(p11;q22) in AML is rare and it is known to be associated with poor prognosis, young age (median age, 22 yr), and involvement of various subtypes of the French-American-British classification. We report here 2 AML patients with t(16;21)(p11;q22), proved by conventional cytogenetics and/or reverse transcription (RT)-PCR. Erythrophagocytosis by leukemic blasts was observed in both of the cases. One patient was a 24 yr-old male with acute myelomonocytic leukemia. His karyotype was 46,XY,t(16;21)(p11;q22),del(18)(p11.2) and RT-PCR revealed the TLS/FUS-ERG fusion transcripts. Although he received allogeneic peripheral blood stem cell transplantation after the first remission, he died 9 months after the initial diagnosis due to relapse of the disease and graft-versus-host disease. The other patient was a 72 yr-old male with acute myeloid leukemia without maturation. His karyotype was 45,XY,-16,add(21)(q22) and the presence of t(16;21)(p11;q22) was detected by RT-PCR. He was transferred to another hospital with no more follow-up. We suggest that the presence of t(16;21)(p11;q22) and/or TLS/FUS-ERG fusion transcripts has to be considered in cases of AML with erythrophagocytosis.

Genetic landscape of the people of India: a canvas for disease gene exploration.

Analyses of frequency profiles of markers on disease or drug-response related genes in diverse populations are important for the dissection of common diseases. We report the results of analyses of data on 405 SNPs from 75 such genes and a 5.2 Mb chromosome, 22 genomic region in 1871 individuals from diverse 55 endogamous Indian populations. These include 32 large (>10 million individuals) and 23 isolated populations, representing a large fraction of the people of India. We observe high levels of genetic divergence between groups of populations that cluster largely on the basis of ethnicity and language. Indian populations not only overlap with the diversity of HapMap populations, but also contain population groups that are genetically distinct. These data and results are useful for addressing stratification and study design issues in complex traits especially for heterogeneous populations.

Primary Pulmonary Ewing's Sarcoma/Primitive Neuroectodermal Tumor in a 67-year-old Man

Extraskeletal Ewing's sarcoma (EES) is a branch of neuroectodermal tumor (PNET), which is very rare soft tissue sarcoma. We report a case of EES/PNET arising is the lung of a 67-yr-old man. Computed tomography, bone scintigraphy, and positron emission tomography confirmed the mass to have a primary pulmonary origin. The mass showed positive reactivity in the Periodic Acid Schiff (PAS) stain and MIC-2 immunoreactivity in immunohistochemical stain. Fluorescence in situ hybridization (FISH) was performed, which revealed an EWSR1 (Ewing sarcoma breakpoint region 1) 22q12 rearrangement. The diagnosis was confirmed both pathologically and genetically. The mass lesion was resected, and the patient is currently undergoing chemotherapy.

DiGeorge syndrome associated with solitary median maxillary central incisor.

DiGeorge syndrome is a primary immunodeficiency disease characterized by dysgenesis of the thymus and parathyroid glands, conotruncal cardiac anomalies, and other dysmorphic features. Although most patients have a common microscopic deletion in chromosome 22q11.2, marked clinical variability exists. A solitary median maxillary central incisor (SMMCI) is a rare dental anomaly which may be an isolated occurrence or associated with congenital nasal airway abnormalities or holoprosencephaly. We report a patient with DiGeorge syndrome who was diagnosed at nearly 1 month of age and was later found to have a solitary median central incisor. Initially, the patient presented with recurrent episodes of respiratory distress attributed to partial airway obstruction, one of the phenotypic features of SMMCI. A fluorescence in situ hybridization study showed a chromosome 22q11.2 deletion.

Congenital glaucoma associated with 22p+ variant in a dysmorphic child.

A case of congenital glaucoma with developmental delay and several dysmorphic features showing 22p+ chromosomal variant is reported.

Prenatal diagnosis of partial trisomy 21 associated with maternal balanced translocation 46xx der 21 t(21q;22q) with pericentric inversion of chromosome 9.

This communication reports prenatal diagnosis of partial trisomy 21 resulting from balanced translocation (21q;22q) in a 36-year-old gravida 7, para 1 woman. The lady had only one living child and there was history of recurrent spontaneous first trimester abortions. Triple test was abnormal in the present conception. In addition, the woman had pericentric inversion of chromosome 9, a finding scarcely reported previously with carrier status in Indian literature. A few cytogeneticists consider this as a normal variant. However, many reports in the recent literature link pericentric inversion of chromosome 9 with infertility, recurrent abortions and a number of other abnormal conditions. A review of the relevant literature pertinent to the case is provided.

Heterogeneidad de la presentación clínica del síndrome de microdeleción del cromosoma 22 región q11 / Clinical heterogenity of the chromosome 22q11 microdeletion syndrome

Background: DiGeorge anomaly, velocardiofacial syndrome and conotruncal anomaly face syndrome are part of a group of congenital malformations of the chromosome 22q11 microdeletion syndrome, since they share certain phenotypic features as well as a common genetic abnormality. The malformations include mild facial dysmorphic features, conotruncal heart defects, thymic and parathyroid hypoplasia or aplasia and cleft palate. Aim: To describe the initial clinical presentation of children with clinical and molecular diagnosis of 22q11 microdeletion. Patients and methods: Ten children (seven male) with the phenotypic features of 22q11 microdeletion syndrome are reported. Microdeletion was detected in peripheral Iymphocytes by fluorescent in situ hybridisation (FISH) with the TUPLE-1 DNA probe. Results: Two children had abnormal karyotypes, one of them had a visible deletion and another child had an unbalanced translocation inherited from his mother who had a balanced translocation between chromosomes 14 and 22. Two of the 10 patients had an anterior laryngeal web, a malformation infrequently described in this syndrome. Five patients had the diagnosis of DiGeorge anomaly, had a more serious clinical presentation and a higher early mortality. Conclusions: The high frequency of the 22q11 microdeletion syndrome, estimated at 1:5.000 newborns, and its variable presentations requires a high level of awareness for its early diagnosis and appropriate management of associated complications

Association between EcoRI fragment-length polymorphism of the immunoglobulin lambda variable 8 (IGLV8) gene family with rheumatoid arthritis and systemic lupus erythematosus

The human immunoglobulin lambda variable 8 (IGLV8) subgroup is a gene family containing three members, one of them included in a monomorphic 3.7-kb EcoRI genomic fragment located at the major lambda variable locus on chromosome 22q11.1 (gene IGLV8a, EMBL accession No. Z73650) at 100 percent frequency in the normal urban population. The second is a polymorphic RFLP allele included in a 6.0-kb EcoRI fragment at 10 percent frequency, and the third is located in a monomorphic 8.0-kb EcoRI fragment at 100 percent frequency, the last being translocated to chromosome 8q11.2 and considered to be an orphan gene. Our Southern blot-EcoRI-RFLP studies in normal individuals and in patients with rheumatoid arthritis (RA) or with systemic lupus erythematosus (SLE), using a specific probe for the IGLV8 gene family (probe pVL8, EMBL accession No. X75424), have revealed the two monomorphic genomic fragments containing the IGLV8 genes, i.e., the 3.7-kb fragment from chromosome 22q11.1 and the 8.0-kb fragment from 8q11.2, both occurring at 100 percent frequency (103 normal individuals, 48 RA and 28 SLE patients analyzed), but absence of the 6.0-kb IGLV8 polymorphic RFLP allele in all RA or SLE patients. As expected, the frequency of the 6.0-kb allele among the normal individuals was 10 percent. These findings suggest an association between the absence of the 6.0-kb EcoRI fragment and rheumatoid arthritis and systemic lupus erythematosus

Deleción en el cromosoma 22 (22q. 11.2). Etiología de cardiopatías congénitas troncoconales / Deletion within chromosome 22 (22q 11.2). Etiology of conotruncal heart malformations

El estudio y tratamiento de las cardiopatías congénitas ha mostrado en los últimos 50 años un progreso acelerado. El ecocardiograma permite observar casi todas las características de las cardiopatías y el cateterismo tiene un carácter primordialmente terapéutico. La cirugía cardiaca es cada vez más temprana y con intenciones correctivas. Hoy en día hay una mayor sobrevida de estos pacientes que llegan a la vida adulta y por razones naturales procrean. Un aspecto que no había tenido este desarrollo es el conocimiento de la etiología de algunas cardiopatías. Con las técnicas de estudio molecular de los cromosomas se encontró la deleción de la región 11.2 en el brazo largo del cromosoma 22, en pacientes que comparten cardiopatía troncoconal y características fenotípicas como facies con puente de la nariz ancho, punta nasal recortada, anomalía en la forma e implantación de los pabellones auriculares y paladar alto, entre otros. Con la finalidad de saber cuales de nuestros pacientes tienen tal deleción, reunimos a aquellos con aspectos fenotípicos asociados a cardiopatías troncoconales. En los primeros dos pacientes a los cuales se les realizó estudio cromosómico de inmunofluorescencia in situ se comprobó deleción en la región 11.2 en el cromosoma 22. La importancia de estos resultados reside en que un porcentaje significativo de los pacientes que acuden a nuestra Institución tienen alteraciones troncoconales, el comprobar en algunos de ellos su etiología permite establecer la indicación del asesoramiento genético y el tratamiento adecuado a nivel cardiológico y del desarrollo psicológico.

Hallazgo de una deleción en el brazo largo del Cromosoma 22, en un paciente con problemas de lenguaje y de conducta / Discovery of a delection in the large arm of Chromosome 22, in a patiene with lenguage problems and behavior

Se presenta el estudio citogenético de un paciente masculino de 6 años de edad sin historia familiar de retardo mental ni consanguinidad, con serios problemas de lenguaje. En el estudio citogenético en sangre periférica se encontró una deleción terminal en el brazo largo del Cromosoma 22 a nivel 22q-->qter. Se presenta revisión de literatura y se discute la importancia de la realización del cariotipo en pacientes que, aunque no evidencian razgos clínicos característicos de alguna patología, sí manifiestan alternaciones que obligan a sospecharla