Analysis of genome copy number variations in fetuses with isolated ventricular septal defect and a literature review / 中华医学遗传学杂志

OBJECTIVE@#To assess the value of copy number variation sequencing (CNV-seq) for revealing the genetic etiology of fetuses with isolated ventricular septal defect (VSD).@*METHODS@#From December 2017 to December 2020, 69 fetuses with isolated VSD were identified at the First Affiliated Hospital of Zhengzhou University. Meanwhile, 839 similar prenatal cases were selected from public databases including Wanfang data, Wanfang Medicine, and China National Knowledge Infrastructure (CNKI) by using keywords such as "Ventricular septal defect", "Copy number variation", and "Prenatal". A total of 908 fetuses with isolated VSD were analyzed. CNV-seq was carried out for 69 fetuses.@*RESULTS@#Among the 908 fetuses, 33 (3.63%) were found to harbor pathogenic CNVs, which included 11 chromosomal aneuploidies (1.21%) and 22 pathogenic CNVs (2.42%). The pathogenic CNVs have involved 12 genetic syndromes, with those known to involve the heart development including 5 cases of 22q11.21 deletion syndrome, 2 cases of 4q terminal deletion syndrome, and 1 case of 9q subtelomere deletion syndrome. The outcome of pregnancies for 15 fetuses with pathogenic CNVs was known, of which 12 were terminated, and 3 had spontaneous closure of the ventricular septum after birth, but 1 of them had other abnormalities.@*CONCLUSION@#Fetuses with isolated VSD have a relatively high risk for chromosomal abnormalities, for which CNV-seq should be recommended.

Riesgo de Esquizofrenia y Síndrome Deleción 22Q11. 2 / RIsk of schizophrenia and 22q11. 2 deletion syndrome

INTRODUCCIÓN. La deleción 22q11.2 es una alteración cromosómica muy frecuente, en la cual un 60% de los afectados presenta patologías neuropsiquiátricas. Determinar si existe asociación entre el síndrome de deleción 22q11.2 (SD22q11.2) y patologías como la esquizofrenia (EQZ), ofrece una oportunidad para la intervención temprana, y seguimiento de personas con este síndrome. OBJETIVO. El objetivo del presente trabajo es determinar si existe mayor riesgo de EQZ en pacientes con síndrome deleción 22q11.2. MÉTODOS. Se realizó una búsqueda bibliográfica sistemática de publicaciones con fecha de 1990 a 2020. Las búsquedas se realizaron en PubMed y en la base de datos Cochrane. En total, se evaluaron 19 estudios, de los que se consideraron elegibles diez publicaciones para el análisis, lo que corresponde a 824 participantes. RESULTADOS. El riesgo de presentar EQZ en un individuo con SD22q11.2 es de 20-25%, en comparación al 1% de la población general. CONCLUSIONES. El riesgo para un individuo con SD22q11.2 de presentar EQZ se encuentra bien establecido. Considerar este riesgo podría ayudar a un adecuado seguimiento y una intervención temprana.

INTRODUCTION. 22q11.2 deletion syndrome is a very common chromosomal abnormality, in which 60% of those affected have neuropsychiatric disorders. Determining if there is an association between 22q11.2 deletion syndrome (22q11.2DS) and disorders such as schizophrenia (SCZ) offers an opportunity for early intervention and follow-up of people with this syndrome. OBJECTIVE. The objective of this study is to determine if there is a greater risk of SCZ in patients with 22q11.2 deletion syndrome. METHODS. A systematic review was performed for publications dated 1990 to 2020. The strategy was to search in PubMed and Cochrane databases for specific MeSH terms. In total, 19 studies were reviewed, of which 10 publications were eligible for analysis, corresponding to 824 participants. RESULTS. The risk of presenting SCZ in an individual with 22q11.2DS is 20-25%, compared to 1% in the general population.CONCLUSIONS. The risk of presenting SCZ in an individual with 22q11.2DS is well established. Considering this risk could help with adequate follow-up and early intervention.

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.

Congenital Heart Disease Revealing Familial 22q11 Deletion Syndrome

Abstract Congenital heart defects are the most common birth defects and the leading cause of mortality in the first year of life. It is well known that the 22q11 deletion syndrome (22q11DS) is the most common microdeletion syndrome in humans and that congenial heart diseases (CHDs) are one of the most common phenotypic manifestations. However, it should be noted that the 22q11 deletion was also found in a significant number of patients with isolated CHD. The 22q11DS phenotype may include cardiovascular anomalies, palatal abnormalities, nasal voice, immune deficiency, endocrine dysfunctions, a varying degree of cognitive deficits and intellectual disabilities, velopharyngeal insufficiency, and characteristic craniofacial dysmorphism. This condition affects about 1 in 4,000 live births, making 22q11DS the most common microdeletion syndrome in humans. Here we describe the cases of three children who were referred to the clinical hospital center with the diagnosis of CHD, but with no direct signs of 22q11DS. Investigation of familial data led us to suspect that the mothers could be carriers of 22q11DS. The multiplex ligation-dependent probe amplification (MLPA) testing confirmed that the patients and mothers exhibited 3 Mb 22q11 deletions, which justified the clinical signs in the mothers and the CHD in children. In the presence of a few characteristics that are common of a spectrum of some known syndromes, a familial examination can provide clues to a definitive diagnosis, as well as to the prevention of diseases and genetic counseling of these patients.

Síndrome de DiGeorge/velocardiofacial: reporte de un caso / DiGeorge/velocardiofacial syndrome: a case report

El síndrome de DiGeorge, también conocido como síndrome velocardiofacial o síndrome de deleción 22q11, se caracteriza por la ausencia congénita del timo y la glándula paratiroides. La tríada clásica de este trastorno es cardiopatía congénita, endocrinopatía con hipocalcemia e inmunodeficiencia primaria. Sin embargo, el síndrome puede exhibir múltiples alteraciones y manifestaciones clínicas pleiotrópicas que, a menudo, resultan en dismorfismo facial y alteraciones en el paladar. Clínicamente se evidencia mayor susceptibilidad a infecciones respiratorias o gastrointestinales recurrentes y, en los casos de aplasia tímica, se requiere tratamiento con antibióticos profilácticos y trasplante tímico, mientras que en los demás se hace manejo expectante. En este manuscrito se presenta el caso de un paciente masculino de 18 meses de edad, remitido al servicio de genética por presentar diversas alteraciones fenotípicas. Se describe el proceso mediante el cual se llegó al diagnóstico de síndrome de DiGeorge, a su manejo y pronóstico, y se hace una breve revisión de la literatura

DiGeorge syndrome, also known as velocardiofacial syndrome or 22q11 deletion syndrome, is characterized by the congenital absence of the thymus and the parathyroid gland. The classic triad of this disorder is congenital heart disease, endocrinopathy with hypocalcemia and primary immunodeficiency. However, the syndrome may exhibit multiple pleotropic abnormalities and clinical manifestations that often result in facial dysmorphism and changes in the palate. Clinically, a high susceptibility to recurrent respiratory or gastrointestinal infections is observed. In cases of thymic aplasia, treatment with prophylactic antibiotics and thymic transplantation is necessary, while in others, expectant management is used. This manuscript presents the case of an 18-month old male patient, referred to the genetics service due to several phenotypic alterations. The process by which the Di- George syndrome diagnosis, management and prognosis was reached, as well as a brief review of the literature, are presented.

Aplicación de Hibridación In Situ Fluorescente (FISH) en pacientes con sospecha clínica de Síndrome de Deleción 22q11. 2 (SD22q11. 2) / Applying Fluorescent in situ hy-bridiza on (FISH) in patients with suspected clinical signs of 22q11. 2 dele on syndrome (DS22q11. 2)

El SD22q11.2 está asociado a síndromes de DiGeorge, velocardiofacial, facioconotruncal y Cayler, reconocidos con la misma etiología: microdeleción 22q11.2. El fenotipo es variable y presenta cardiopatía conotruncal (CC), dismorfias faciales, anomalías palatinas, inmunodeficiencias y trastornos del neurodesarrollo. Las manifestaciones endocrinológicas que predominan son talla baja, hipocalcemia neonatal asociada a hipoparatiroidismo y disfunción tiroidea. El 90% de los afectados presenta una deleción típica de 3-Mb, mientras que el resto tiene deleciones de menor tamaño o deleción localizada más distal a la región crítica . El objetivo del trabajo es identificar en una cohorte de 63 pacientes con sospecha clínica de SD22q11.2, la presencia de la microdeleción 22q11.2 empleando como método diagnóstico la técnica de FISH y describir brevemente las características clínicas más prevalentes que presentan los pacientes con resultado de FISH positivo y negativo. La microdeleción 22q11.2 se identificó en el 38% (24/63) de los pacientes estudiados. Las características clínicas más prevalentes en este grupo fueron las cardiopatías congénitas conotruncales (95,6%), microcefalia (50%), inmunodeficiencias (50%), hipocalcemia (48,8%), anomalías del paladar (45,8%), retraso del desarrollo y déficit cognitivo (41,5%). En nuestro hospital, el algoritmo diagnóstico para la detección de la microdeleción 22q11.2 es el cariotipo de alta resolución y el estudio por la técnica de FISH.

DS22q11.2 is associated with a wide spectrum of clinical disorders (DiGeorge, velocardiofacial, facioconotrunal and Cayler syndromes) known to arise from the same etiology 22q11.2 microdeletion The phenotype is variable and includes conotruncal cardiac defect (CCD), facial phenotype, palate anomalies, inmunodeficiency and developmental disorders. The endocrine manifestations are short stature (ST), neonatal hypocalcemia due to hypoparathyroidism, and thyroid dysfunction. In 90% of patients with 22q11.1 deletion a common 3-Mb deletion has been found, whereas the rest of cases share a smaller deletion or more distal atypical deletions. The aim of the present study was to identify the 22q11.2 microdeletion by FISH in 63 patients from the Genetic and Endocrinology Division between 2002 and 2017 who had more than one clinical feature of DS22q11. 2. High resolution karyotype and fluorescent in situ hybridization (FISH) were performed with different commercial probes. The 22q11.2 microdeletion was demonstrated in 24/63 patients (38%). The more relevant clinical features in this group were: conotruncal cardiac defect (95.6%), microcephaly (50%), immunodeficiency (50%), hypocalcaemia (48.8%) palate anomalies (45.8%), development delay and cognitive deficit (41.5%). In our hospital, the diagnostic algorithm for the detection of the 22q11.2 microdeletion is the high resolution karyotype and the study by the FISH technique.

Consideraciones anestésicas en pacientes con microdeleción del cromosoma 22q11 / Anesthetic issues in patients mycrodeletion syndrome produced by the deletion of chromosome 22q11

The syndrome produced by the deletion of chromosome 22q11 corresponds to a pattern of anomalies that occurs when a specific region of chromosome 22 is lost, specifically called 22q11.2. This microdeletion corresponds to the most frequent chromosomal alteration in humans, which has a prevalence of 1 per 4,000 live births. This includes a great variety of phenotypes, many of them subclinical, among which the Di George syndrome and the Velocardiofacial syndrome stand out. The main cause of mortality is of cardiac origin. Embryologically, this microdeletion is associated with alterations in the differentiation and migration of the pharyngeal system, with consequent craniofacial, cardiac, airway, thymus and parathyroid alterations, among others. In this sense, these patients present a higher risk of complications such as inmunodeficiency, hypocalcemia and hemorrhagic risk. From the surgical and anesthetic point of view, they can present cardiopathies of greater complexity of correction, which in some cases is also related to anatomical airway alterations which can constitute an important challenge when operating this type of patients. Considering the above, there is an increase in perioperative risk which could increase mortality. The objective of this review is to present the characteristics and behavior of this group of patients in the correction of their heart diseases, so that they are known by the anesthesiologists who work in the cardiovascular area.

El síndrome de microdeleción 22q11 corresponde a un patrón de anomalías que se produce al perderse una región específica del cromosoma 22, específicamente llamada 22q11.2. Esta microdeleción corresponde a la alteración genética más frecuente en humanos la cual tiene una prevalencia de 1 cada 4.000 recién nacidos vivos. Incluye una gran variedad de fenotipos, muchos de ellos subclínicos, entre los que destaca el síndrome Di George y el síndrome Velocardiofacial. La principal causa de mortalidad es de origen cardíaco. Embriológicamente la microdeleción se asocia a alteraciones en diferenciación y migración del aparato faríngeo, con las consiguientes alteraciones cráneo-faciales, cardíacas, de vía aérea, timo y paratiroides, entre otras. En ese sentido, presentan mayor frecuencia de complicaciones tales como infecciones, hipocalcemia y riesgo hemorrágico. Desde el punto de vista quirúrgico y anestésico pueden presentar cardiopatías de mayor complejidad de corrección, asociado o no a alteraciones anatómicas en vía aérea lo que puede constituir un importante desafío al momento de intervenir. Lo anterior aumenta el riesgo perioperatorio, lo que podría derivar en aumento de la mortalidad. El objetivo de esta revisión es presentar las características y comportamiento de este grupo de pacientes en la corrección de sus cardiopatías, de modo que sean un aporte para los anestesiólogos que se desempeñan en el área cardiovascular.

Delayed diagnosis of 22q11 deletion syndrome due to late onset hypocalcemia in a 11-year-old girl with imperforated anus

Neonatal hypocalcemia and congenital heart defects has been known as the first clinical manifestation of the chromosome 22q11.2 deletion syndrome (22q11DS). However, because of its wide clinical spectrum, diagnosis of 22q11DS can be delayed in children without classic symptoms. We report the case of a girl with the history of imperforate anus but without neonatal hypocalcemia or major cardiac anomaly, who was diagnosed for 22q11DS at the age of 11 after the onset of overt hypocalcemia. She was born uneventfully from phenotypically normal Korean parents. Imperforate anus and partial cleft palate were found at birth, which were surgically repaired thereafter. There was no history of neonatal hypocalcemia, and karyotyping by GTG banding was normal. At the age of 11, hypocalcemia (serum calcium, 5.0 mg/dL) and decreased parathyroid hormone level (10.8 pg/mL) was noted when she visited our Emergency Department for fever and vomiting. The 22q11DS was suspected because of her mild mental retardation and velopharyngeal insufficiency, and a microdeletion on chromosome 22q11.2 was confirmed by fluorescence in situ hybridization. The 22q11DS should be considered in the differential diagnosis of hypocalcemia at any age because of its wide clinical spectrum.

Síndrome de deleción 22q11: bases embriológicas y algoritmo diagnóstico / 22q11 deletion syndrome: embryology and diagnostic algorithm

Resumen El síndrome de deleción 22q11 consiste en una agrupación variable de características fenotípicas secundarias a la pérdida del material genético localizado en la banda 22q11.2. El espectro de deleción del 22q11 abarca varios síndromes, antes considerados independientes pero hoy relacionados con la misma etiología, con anomalías superpuestas incluyendo el síndrome de DiGeorge y el síndrome velocardiofacial, entre otros. Se trata de un síndrome pleiotrópico incluyendo: alteraciones en los sistemas cardiaco e inmunológico, dificultades en el aprendizaje y malformaciones del paladar entre las afecciones más comunes. Se hizo una revisión de: la base embriológica de las malformaciones congénitas cardiacas, la epidemiología, la genética, la fisiopatología y los aspectos clínicos en el manejo de esta enfermedad. Dado que esta enfermedad rara es potencialmente una causa importante pero ignorada de morbimortalidad en Colombia, se propone también una estrategia para su búsqueda activa y se discuten aspectos relacionados con su diagnóstico.

Abstract The 22q11 deletion syndrome is characterized by a variable group of phenotypic features secondary to the loss of genetic material located on the band 22q11.2. Its spectrum covers multiple syndromes, previously considered independent but nowadays related to the same etiology with overlapping anomalies, including DiGeorge and velocardiofacial syndromes. It presents alterations in the immune and cardiac systems, neurodevelopment and palatal defects amongst the most common problems. This article is a review of the embryologic basis for the congenital heart defects, epidemiology, genetics, pathophysiology and clinical aspects of this disease. This is a rare disease but is a potentially underdiagnosed cause of morbidity and mortality in Colombia, for which a strategy for its active search is also proposed and diagnostic aspects are discussed.

Abordaje inmunológico del síndrome por deleción 22q11 / Immunological approaches to 22q11 deletion syndrome

El síndrome por deleción 22q11 (SD22q11) es el síndrome por deleción cromosómica más frecuente en humanos y se caracteriza por la tríada clínica que incluye cardiopatía congénita, hipocalcemia e inmunodeficiencia primaria. El 85-90% de los pacientes tienen microdeleciones en el cromosoma 22q11.2. Tomando como punto cardinal la cardiopatía congénita, se diseñó una estrategia para tamización y diagnóstico de SD22q11 con énfasis en la evaluación inmune. Es imprescindible realizar una historia clínica detallada y, posteriormente, un análisis cuantitativo y funcional de las subpoblaciones de linfocitos en sangre periférica para clasificarlo en SD22q11 completo (<1%) o parcial (95-99%) e instaurar las pautas de tratamiento en aspectos como: aislamiento del paciente, vacunación, profilaxis contra microorganismos oportunistas, uso de productos sanguíneos irradiados y reconstitución inmunológica. Sin embargo, el abordaje del paciente debe ser multidisciplinario para detectar y prevenir complicaciones a largo plazo que pueden ser graves, especialmente en los pacientes con SD22q11 completo.

In humans, 22q11 deletion syndrome (22q11DS) is considered the most common chromosome deletion syndrome. It is characterised by a clinical triad that includes congenital heart disease, hypocalcaemia and primary immunodeficiency. Approximately 85-90% of patients with this syndrome exhibit microdeletions in chromosome 22q11.2. Using congenital heart disease as a starting point, we designed a strategy for the screening and diagnosis of 22q11DS with an emphasis on immunological evaluation. A detailed clinical history and the subsequent quantitative and functional analyses of the lymphocyte subpopulations in the peripheral blood is crucial to classify as complete (<1%) or partial (95-99%) the disease and to guide clinicians in terms of patient isolation, vaccination, prophylaxis for opportunistic infections, use of irradiated blood products and immunological reconstitution. However, multidisciplinary care is necessary to detect and prevent long-term complications that could be severe, particularly in cases of complete 22q11DS.

¿Ausencia previa de circulación del virus de Chikungunya en Tuchín, Córdoba, Colombia? / Previous absence of circulation of the Chikungunya virus in Tuchín, Córdoba, Colombia?

El síndrome por deleción 22q11 (SD22q11) es el síndrome por deleción cromosómica más frecuente en humanos y se caracteriza por la tríada clínica que incluye cardiopatía congénita, hipocalcemia e inmunodeficiencia primaria. El 85-90% de los pacientes tienen microdeleciones en el cromosoma 22q11.2. Tomando como punto cardinal la cardiopatía congénita, se diseñó una estrategia para tamización y diagnóstico de SD22q11 con énfasis en la evaluación inmune. Es imprescindible realizar una historia clínica detallada y, posteriormente, un análisis cuantitativo y funcional de las subpoblaciones de linfocitos en sangre periférica para clasificarlo en SD22q11 completo (<1%) o parcial (95-99%) e instaurar las pautas de tratamiento en aspectos como: aislamiento del paciente, vacunación, profilaxis contra microorganismos oportunistas, uso de productos sanguíneos irradiados y reconstitución inmunológica. Sin embargo, el abordaje del paciente debe ser multidisciplinario para detectar y prevenir complicaciones a largo plazo que pueden ser graves, especialmente en los pacientes con SD22q11 completo.

22q11 deletion syndrome (SD22q11) is the most common chromosomal deletion syndrome in humans and is characterised by the clinical triad of congenital heart disease, hypocalcaemia and primary immunodeficiency. 85-90% of patients have microdeletions on chromosome 22q11.2. Taking congenital heart disease as a cardinal point, a strategy for screening and diagnosis of SD22q11 was designed with emphasis on immune assessment. A detailed clinical history and subsequent quantitative and functional analysis of peripheral blood lymphocyte subpopulations is essential to classify the patient as having complete (<1%) or partial (95-99%) SD22q11 and to establish treatment guidelines such as patient isolation, vaccination, prophylaxis against opportunistic microorganisms, use of irradiated blood products and immune reconstitution. However, the patient's approach must be multidisciplinary to detect and prevent long-term complications that can be severe, especially in patients with complete SD22q11.

Genetic Syndromes associated with Congenital Heart Disease

Recent research has demonstrated that genetic alterations or variations contribute considerably to the development of congenital heart disease. Many kinds of genetic tests are commercially available, and more are currently under development. Congenital heart disease is frequently accompanied by genetic syndromes showing both cardiac and extra-cardiac anomalies. Congenital heart disease is the leading cause of birth defects, and is an important cause of morbidity and mortality during infancy and childhood. This review introduces common genetic syndromes showing various types of congenital heart disease, including Down syndrome, Turner syndrome, 22q11 deletion syndrome, Williams syndrome, and Noonan syndrome. Although surgical techniques and perioperative care have improved substantially, patients with genetic syndromes may be at an increased risk of death or major complications associated with surgery. Therefore, risk management based on an accurate genetic diagnosis is necessary in order to effectively plan the surgical and medical management and follow-up for these patients. In addition, multidisciplinary approaches and care for the combined extra-cardiac anomalies may help to reduce mortality and morbidity accompanied with congenital heart disease.

Monosomy 22 Mosaicism Associated Thrombocytopenia Presenting as Behcet's Disease / 임상소아혈액종양

We describe an 18 year old female with monosomy 22 mosaicism and thrombocytopenia. She had some unique facial appearance such as small eyes and thin lip, similar to those with 22q11 deletion syndrome and thrombocytopenia with slightly increased mean platelet volume and recurrent orogenital ulcers presented as Behcet's disease. There are very few published case reports and a great variability of phenotypic presentations among the anomalies of the patients with monosomy 22 mosaicism. We report this case with a brief review of the literature suggesting that thrombocytopenia can be a new component manifestation of monosomy 22 mosaicism.

Monosomy 22 Mosaicism Associated Thrombocytopenia Presenting as Behcet's Disease / 임상소아혈액종양

We describe an 18 year old female with monosomy 22 mosaicism and thrombocytopenia. She had some unique facial appearance such as small eyes and thin lip, similar to those with 22q11 deletion syndrome and thrombocytopenia with slightly increased mean platelet volume and recurrent orogenital ulcers presented as Behcet's disease. There are very few published case reports and a great variability of phenotypic presentations among the anomalies of the patients with monosomy 22 mosaicism. We report this case with a brief review of the literature suggesting that thrombocytopenia can be a new component manifestation of monosomy 22 mosaicism.

A Case Report of Schizophrenia Patient with 22q11 Deletion Syndrome / 신경정신의학

It has been well known that 22q deletion syndrome (22qDS), encompasses several genetic syndromes associated with microdeletions at chromosome 22q11.2 became relatively generally identified in the 1990s through the availability of specialized chromosomal studies, and it includes such syndromes as velocardiofacial syndrome (VCFS), DiGeorge syndrome (DGS), Shprintzen syndrome, CATCH 22. The syndrome is characterized by distinctive dysmorphology, congenital heart disease, athymia, parathyroid disease, other congenital diseases, learning difficulties and various psychiatric illnesses. This syndrome is a common genetic condition often accompanied by mild cognitive impairment. Learning difficulties and anger outburst are also common in adolescence with this syndrome. In addition, a prevalence of major psychiatric disorders in adults' individuals are high, especially schizophrenia, schizoaffective disorder, bipolar disorder and other psychiatric illnesses, including simple or social phobia, depression, obsessive-compulsive disorder. We report a patient with facial dysmorphology, cleft lip and palate, ventricular septal defect, borderline IQ, poor impulse control and psychotic symptoms who was diagnosed schizophrenia and 22qDS by FISH analysis which finds 22q11.2 microdeletion.