染色体22q11.2微缺失综合征的临床诊断

22q11.2缺失综合征(22q11.2 deletion syndrome,22q11.2 DS)主要包括了以临床特征定义的DiGeorge综合征(DiGeorge syndrome,DGS)、腭-心-面综合征(velocardiofacial syndrome,VCFS)和圆锥动脉干-异常面容综合征(conotruncal anomaly face syndrome,CAFS)等,上述综合征均具有共同的遗传学基础,即22q11微缺失的比例均较高,分别为88%、85%和100%.     

22q11微缺失综合征的产前诊断

22q11微缺失综合征的临床表型变异范围广泛,其典型的临床表现是心脏畸形,面容异常,胸腺发育不全,腭裂和低钙血症.进行产前诊断的人群主要是:曾经有22q11微缺失综合征孕产史的夫妇,自身是22q11微缺失患者的夫妇和宫内监测到妊娠胎儿有心脏锥干畸形者.产前诊断的方法主要有:常规染色体核型分析,荧光原位杂交,多重PCR,实时定量PCR和微阵列-比较基因组杂交.     

CATCH22综合征与染色体22q11缺失

CATCH22综合征是以先天性心脏畸形、异常面容、低钙血症、胸腺发育不良等为特征的遗传性疾病，与人类22号染色体长臂1区1带（22q11）的1.5—3Mb缺失有关，22q11区域中某些基因有可能是致病关键基因，22q11微缺失的检测有助于TCATCH22综合征产前和产后的诊断，减少患病儿出生率，提高人口质量。     

CATCH22综合征与染色体22q11缺失

CATCH22综合征是以先天性心脏畸形、异常面容、低钙血症、胸腺发育不良等为特征的遗传性疾病,与人类22号染色体长臂1区1带(22q11)的1.5-3 Mb缺失有关,22q11区域中某些基因有可能是致病关键基因,22q11微缺失的检测有助于CATCH22综合征产前和产后的诊断,减少患病儿出生率,提高人口质量.     

22q11微缺失综合征的产前诊断

22q11微缺失综合征的临床表型变异范围广泛，其典型的临床表现是心脏畸形，面容异常，胸腺发育不全，腭裂和低钙血症。进行产前诊断的人群主要是：曾经有22q11微缺失综合征孕产史的夫妇，自身是22q11微缺失患者的夫妇和宫内监测到妊娠胎儿有心脏锥干畸形者。产前诊断的方法主要有：常规染色体核型分析，荧光原位杂交，多重PCR，实时定量PCR和微阵列一比较基因组杂交。     

39例生长受限胎儿染色体微阵列芯片分析

目的:探讨染色体微阵列分析技术(CMA)在胎儿生长受限(FGR)产前诊断中的应用价值。方法:对39例核型分析正常的FGR样本进行CMA检测,分析CMA异常的检出率。结果:39例FGR中CMA检出5例异常,检出率12.8%(5/39)。22例特发性FGR中检出4例异常,检出率18.2%(4/22),包括1例4q21.21微缺失,1例2q11.1q11.2微重复及2例7q11.23微缺失。17例FGR合并其他超声异常中检出1例异常,检出率5.9%(1/17),1例异常为4p16.3p16.2微重复。结论:对FGR行CMA检测有助于发现核型分析无法检出的染色体亚显微结构异常。CMA有利于提高对FGR遗传病因的诊断。     

胎儿畸形与22q11微缺失相关性的研究进展

22q11微缺失综合征是由于22号染色体长臂近着丝粒端微片段22q11.21~q11.23缺失引起的遗传综合征,是常见的遗传学疾病,在新生活产儿中发病率为1/4000[1],其主要表现为Di George综合征（DGS）：甲状旁腺发育不全、胸腺发育不全和锥干型心脏畸形（conotruncal defects,CTD）;     

17q12染色体微缺失综合征产前诊断分析

目的:通过分析17q12染色体微缺失综合征的临床资料,探讨该综合征的胎儿期临床表型谱和产前诊断方法,为17q12染色体微缺失综合征患者及携带者的遗传学咨询及产前诊断提供依据。方法:选取2018年1月至2019年6月因超声检查发现胎儿肾脏皮质回声增强就诊于河南省人民医院产前诊断中心的患者。经羊水取样,并行染色体微阵列分析(CMA)。结果:CMA检测共发现胎儿17 q12微缺失综合征者5例,缺失片段1.18～1.52Mb,缺失区域与肾囊肿和糖尿病综合征致病区域部分重叠(chr17:34815072-36215917)。结论:对于超声检测出肾脏异常的胎儿,无论其是否合并其它畸形,均应行染色体核型和CMA检查,以及时确诊17q12染色体微缺失综合征胎儿,为胎儿出生后临床表现提供理论支持,为孕妇及家庭提供更为精准的遗传咨询。     

1q21.1微缺失/微重复胎儿的临床表型和遗传学分析

目的:探讨1q21.1微缺失/微重复胎儿的表型异常及遗传学诊断。方法:回顾分析于泉州市妇幼保健行染色体核型分析及单核苷酸多态性微阵列(SNP-array)检测的产前诊断病例,8例产前诊断确认为1q21.1微缺失/微重复胎儿。分析胎儿的超声异常情况、父母溯源、妊娠结局和出生后随访情况。结果:3748例中共检出8例1q21.1微缺失/微重复胎儿,检出率为0.21%(8/3748),片段大小介于393.8Kb～3.8Mb。8例中4例微重复(其中1例涉及近端1q21.1微重复,3例涉及远端微重复),4例微缺失(其中1例涉及近端1q21.1微缺失,3例涉及远端微缺失)。8例胎儿中有5例产前超声异常,其中2例胎儿心脏畸形,1例胎儿泌尿系畸形,1例胎儿鼻骨缺失伴肠管回声增强,1例胎儿后颅窝池增宽伴颈部皱褶增厚。伴有心脏畸形和泌尿系畸形的病例均选择终止妊娠。病例4胎儿产前超声未发现异常,因既往有先心患儿生育史,经充分遗传咨询后选择终止妊娠,引产胎儿外观左手轴后多指。4例选择继续妊娠,其中3例出生后随访发育良好,1例出生后发现左耳听力异常。结论:1q21.1微缺失/微重复胎儿在产前可出现各个系统超声异常...     

22q11.21微缺失与微重复综合征的产前临床表型分析及遗传咨询

目的探讨产前诊断22q11.21微缺失与微重复胎儿的不同临床表型、妊娠结局, 为临床遗传咨询提供依据。方法回顾性分析2015年1月至2022年1月在空军军医大学第一附属医院产前诊断中心因超声检查异常、高龄、血清学筛查高风险等行介入性产前诊断, 应用染色体微阵列分析(chromosome microarray analysis, CMA)技术确诊的22q11.21微缺失或微重复病例。对其临床表型及妊娠结局进行描述性分析。结果研究期间, 共9 141例行CMA检测的病例中, 有77例(0.8%)为22q11.21微缺失或微重复胎儿。77例中, 62例(80.5%)为22q11.21微缺失, 包括58例典型区域缺失和4例非典型区域缺失(均包含与先天性心脏病明确相关的TBX1基因);15例(19.5%)为22q11.21微重复, 包括14例典型区域重复和1例非典型区域重复。62例22q11.21微缺失胎儿中, 48例(77.4%)伴有先天性心脏病, 其中28例为圆锥动脉干畸形;15例22q11.21微重复胎儿中, 5例伴有先天性心脏病。预产期后3～6个月进行电话随访, 62例22q11.21微...     

Prenatal diagnosis and molecular cytogenetic characterization of chromosome 22q11.2 deletion syndrome associated with congenital heart defects

ObjectiveTo report prenatal diagnosis of 22q11.2 deletion syndrome in a pregnancy with congenital heart defects in the fetus.Case reportA 26-year-old, primigravid woman was referred for counseling at 24 weeks of gestation because of abnormal ultrasound findings of fetal congenital heart defects. The Level II ultrasound revealed a singleton fetus with heart defects including overriding aorta, small pulmonary artery, and ventricular septal defect. Cordocentesis was performed. The DNA extracted from the cord blood was analyzed by multiplex ligation-dependent amplification (MLPA). The MLPA showed deletion in the DiGeorge syndrome (DGS) critical region of chromosome 22 low copy number repeat (LCR) 22-A∼C. Conventional cytogenetic analysis revealed a normal male karyotype. Repeated amniocentesis and cordocentesis were performed. Whole-genome array comparative genomic hybridization (aCGH) on cord blood was performed. aCGH detected a 3.07-Mb deletion at 22q11.21. Conventional cytogenetic analysis of cultured amniocytes revealed a karyotype 46,XY. Metaphase fluorescence in situ hybridization (FISH) analysis on cultured amniocytes confirmed an interstitial 22q11.2 deletion.ConclusionPrenatal ultrasound findings of congenital heart defects indicate that the fetuses are at increased risk for chromosome abnormalities. Studies for 22q11.2 deletion syndrome should be considered adjunct to conventional karyotyping. Although FISH has become a standard procedure for diagnosis of 22q11.2 deletion syndrome, MLPA can potentially diagnose a broader spectrum of abnormalities, and aCGH analysis has the advantage of refining the 22q11.2 deletion breakpoints and detecting uncharacterized chromosome rearrangements or genomic imbalances.     

Persistent fifth aortic arch associated with 22q11.2 deletion syndrome.

BACKGROUND: Chromosome 22q11.2 deletion is frequently associated with conotruncal malformations and aortic arch anomalies. This study investigated the association of chromosome 22q11.2 deletion with clinical manifestations in four pediatric patients with persistent fifth aortic arch. METHODS: Four patients with persistent fifth aortic arch treated between July 1997 and June 2004 were included in this retrospective study. There were two girls and two boys, aged 2 days to 11.3 years, with persistent fifth aortic arch and cardiac conotruncal malformations. Chart recordings, plain chest films, two-dimensional and Doppler echocardiograms, cardiac catheterization with angiograms, surgical findings, and cytogenetic study were analyzed. RESULTS: Clinically, all four patients had the cardinal phenotypic features of 22q11.2 deletion syndrome, including cardiovascular malformations (conotruncal malformations and aortic arch anomalies), abnormal facies, thymic hypoplasia, canopy anomaly of the palate (high-arched palate, rather than cleft palate), and hypocalcemia (or hypoparathyroidism). All four patients were confirmed to have chromosome 22q11.2 deletion. CONCLUSION: Congenital conotruncal malformations, including tetralogy of Fallot with pulmonary atresia or stenosis, and aortic arch anomalies including a persistent fifth aortic arch or a right aortic arch, should lead to suspicion of chromosome 22q11.2 deletion when manifested together with any one of the other four cardinal phenotypic features.     

Labyrinthine malformation in the 22q11.2 deletion syndrome

Velocardiofacial syndrome and DiGeorge syndrome, integrating to form the 22q11.2 deletion syndrome, manifest frequently with hearing loss. Instead, a labyrinthine anomaly is only occasionally described in velocardiofacial syndrome/DiGeorge syndrome. We report a vestibular labyrinthine malformation demonstrated with computed tomographic scan in a patient with a palatal cleft and a 22q11.2 deletion presenting as velocardiofacial syndrome.     

Risk of missed diagnosis of 22q11.2 deletion in a fetal cardiac conotruncal malformation when another chromosomal abnormality is detected

We present a rare case of prenatal diagnosis of two de novo chromosome structural rearrangements including a translocation (1;3) associated with a 22q11.2 deletion. The amniocentesis was performed because the systematic ultrasound examination revealed: right aortic cross with double aortic arch, with normal size of aorta and pulmonary artery. Our report emphasises that 22q11.2 deletion must be looked for when a fetal cardiac conotruncal malformation is diagnosed, even in the presence of another chromosomal abnormality. In prenatal diagnosis, this can have implication for patient management and genetic counselling.     

DiGeorge syndrome: new insights

Most patients with the clinical features of DiGeorge, velocardiofacial, and conotruncal anomaly face syndromes share a common genetic cause, namely, a deletion of chromosome 22q11, and define the most common deletion syndrome known at this time. The clinical features of the 22q11 deletion syndrome are highly variable between individuals; some have subtle findings, whereas others are severely affected. The most common clinical features include specific types of congenital heart disease, hypocalcemia, immunodeficiency, facial dysmorphia, palate anomalies, velopharyngeal dysfunction, renal anomalies, and speech and feeding disorders as well as neurocognitive, behavioral, and psychiatric disorders. A significant number of patients with tetralogy of Fallot, truncus arteriosus, an interrupted aortic arch, isolated aortic arch anomalies, and perimembranous ventricular septal defects have a 22q11 deletion. Routine testing for a 22q11 deletion in this subset of patients should be considered to provide anticipatory medical intervention and appropriate family counseling.     

Further delineation of the 22q13 deletion syndrome

A chromosomal deletion syndrome associated with a 22q13 microdeletion has previously been reported in approximately 75 children. We report six cases from Denmark with a deletion of 22q13. One was cytogenetically visible by conventional karyotyping, one was diagnosed by high resolution karyotyping after the demonstration of low arylsulfatase A activity. Two were diagnosed by high resolution CGH analysis, one was diagnosed by multisubtelomeric FISH analysis and one was diagnosed serendipitously as lack of the control signal in a FISH analysis for 22q11 deletion. One of the cases was a mosaic with 16% of cells showing two signals. The phenotype of the children included: generalized developmental delay, compromised language development, hypotonia, normal or accelerated growth and minor facial dysmorphism. Other features were partial agenesis of the corpus callosum, bilateral ureteropelvic stricture, gastroesophageal reflux and hearing loss. One case had a different phenotype, and showed a deletion as well as a duplication. The extent of the deletion was studied by quantitative PCR analysis of a number of DNA markers in the 22q13 region. The deletions varied in size, extending from 4.0 to 9.0 Mb. The clinical phenotype seemed rather similar although some specific features might be attributable to differences in deletions.     

Prenatal diagnosis of an unexpected interstitial 22q11.2 deletion causing truncus arteriosus and thymic hypoplasia in a ring 22 chromosome derived from a maternally inherited paracentric inversion

OBJECTIVE: To present the prenatal diagnosis of an interstitial 22q11.2 deletion involving a ring 22 chromosome associated with truncus arteriosus and a hypoplastic thymus. CASE: Following the sonographic diagnosis of a cystic hygroma at 12 weeks of gestation, chromosome analysis revealed a ring 22 chromosome. RESULTS: Ring chromosomes typically result in the deletion of genetic material from the distal long and short arms of the affected chromosome. The presence of an interstitial deletion in a ring chromosome is therefore unusual. FISH analysis revealed an unexpected deletion involving the TUPLE1 gene in the DiGeorge/Velocardiofacial syndrome region in 22q11.2. Maternal chromosome analysis revealed the cause of the apparent interstitial deletion, a paracentric inversion in the long arm of chromosome 22, resulting in the distal long arm of 22q being located adjacent to the centromere and the proximal end being located near the telomere. The fetus was subsequently diagnosed with truncus arteriosus and a hypoplastic thymus, consistent with DiGeorge syndrome. CONCLUSION: The ring chromosome 22 found in the fetus appears to have been derived from a rearrangement of the mother's inverted 22, resulting in ring formation and loss of the end of the distal long arm of the inverted 22, including the TUPLE1 locus, causing DiGeorge syndrome in the fetus. The apparent interstitial deletion was actually a terminal deletion in a maternally inherited rearranged chromosome 22.     

Expanding the phenotype of 22q11 deletion syndrome: the MURCS association

The MURCS association [Müllerian Duct aplasia or hypoplasia (M), unilateral renal agenesis (UR) and cervicothoracic somite dysplasia (CS)] manifests itself as Müllerian Duct aplasia or hypoplasia, unilateral renal agenesis and cervicothoracic somite dysplasia. We report on a 22-year-old woman with bicornuate uterus, right renal agenesis, C2-C3 vertebral fusion (MURCS association) and 22q11.2 deletion. Angio-MRI revealed the aberrant origin of arch arteries. Hashimoto thyroiditis, micropolycystic ovaries with a dermoid cyst in the right ovary and mild osteoporosis were also diagnosed. Accurate revision of radiographs enabled us also to identify thoracolumbar and lumbosacral vertebral-differentiation defects. Audiometry and echocardiogram were normal. Bone densitometry showed osteoporosis. As per our evaluation, the patient had short stature, obesity (BMI 30.7) and facial features suggestive of the 22q11 deletion syndrome. Multiplex ligation-dependent probe amplification analysis showed a de-novo 22q11.2 deletion confirmed by array-comparative genomic hybridization analysis. We discuss whether this is a casual association or whether it is an additional syndrome owing to the well known phenotype extensive variability of the 22q11 deletion syndrome.     

Prenatal detection of a tetralogy of Fallot with origin of the left pulmonary artery from the ascending aorta in a familial 22q11 microdeletion

Here we report a case of prenatal diagnosis of anomalous origin of the left pulmonary artery from the ascending aorta associated with a tetralogy of Fallot in a familial form of 22q11 deletion. The mother, who had a normal heart and a velo-cardio-facial syndrome, had a first child with a pulmonary atresia plus ventricular septal defect associated with a 22q11 deletion. Prenatal diagnosis during the second pregnancy identified the above-described cono-truncal anomaly and FISH study showed a recurrent 22q11 deletion. This case illustrates the intrafamilial variability of cardiac involvement in 22q11 deletion as well as the possibility of diagnosing complex cono-truncal malformations during fetal life.     

Prenatal diagnosis of trisomy 21 without the Down syndrome phenotype

OBJECTIVE: To report a patient with the prenatal diagnosis of trisomy 21 without the clinical Down syndrome (DS) phenotype secondary to the absence of the Down syndrome chromosomal region (DSCR) in a derivative chromosome 21. CASE REPORT AND METHODS: A newborn patient with prenatal diagnosis of duodenal atresia. Cytogenetic studies revealed a regular trisomy 21. At birth, she did not present the clinical features of DS. FISH analysis was performed in the patient with the LSI spectrum probe for the DSCR and in the mother with FISH multicolor analysis using painting probes for chromosomes 20 and 21. RESULTS: FISH analysis in the patient showed two hybridization signals suggesting that the third chromosome 21 did not have the DSCR region explaining the absence of the DS phenotype. FISH multicolor analysis in the mother showed three hybridization signals for chromosomes 20 and 21, concluding a maternal karyotype, 46,XX,t(20;21)(p11.2;q22.1). CONCLUSIONS: The patient was found to have a derivative chromosome 21 secondary to a nondisjunction error in meiosis II without the DS critical region and the phenotype was mostly secondary to the combination of the two partial trisomies.