Cases Of 22q11 Research Articles

Prenatal diagnosis of genetic aberrations in fetuses with pulmonary stenosis in southern China: a retrospective analysis

BackgroundThe genetic etiology of congenital pulmonary stenosis (PS) in fetuses remains inadequately studied. We used karyotype analysis and chromosomal microarray analysis (CMA) to investigate the genetic aberrations associated with PS in human fetuses.MethodsA retrospective analysis was performed on 84 fetuses with congenital PS in southern China. Fetal amniotic fluid and umbilical cord blood samples were obtained for chromosomal karyotype analysis and CMA.ResultsThe rate of pathogenic copy number variation (CNV) was 15.5% (13/84) after karyotyping and CMA. An abnormal karyotype was detected in five cases (6.0%, 5/84) via karyotyping, whereas pathogenic CNVs were detected in 13 cases (15.5%, 13/84) via CMA. In addition to the five abnormal karyotypes detected using karyotype analysis, eight additional chromosomal microduplications and microdeletions were detected using CMA, comprising three cases of 22q11.21 microdeletion; two cases of 16p11.2 microdeletion; one case of simultaneous 18q23 microdeletion and 22q13.33 microduplication; one case of 15q24.1q24.2 microdeletion; and one case of 1q21.1q21.2 microduplication. The rate of pathogenic CNV occurrence was 11.5% in fetuses with isolated PS and 17.2% in fetuses with PS combined with other ultrasound abnormalities. This difference between the two experimental groups was statistically significant. Among 84 fetuses with PS, 39 pregnancies were terminated, and five were lost to follow-up.ConclusionsCMA was not only conducive to detect PS-related pathogenic genomic abnormalities but also to accurately evaluate fetal prognosis in genetic counseling. The early detection of PS and genomic abnormalities will exerta positive impact on fetal intervention and the related prognosis of PS in perinatal infants.

Analysis of genome copy number variations in fetuses with isolated ventricular septal defect and a literature review

To assess the value of copy number variation sequencing (CNV-seq) for revealing the genetic etiology of fetuses with isolated ventricular septal defect (VSD). 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. 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. Fetuses with isolated VSD have a relatively high risk for chromosomal abnormalities, for which CNV-seq should be recommended.

Utility of Measuring Fetal Cavum Septum Pellucidum (CSP) Width During Routine Obstetrical Ultrasound for Improving Diagnosis of 22q11.2 Deletion Syndrome: A Case-Control Study.

ObjectiveTo evaluate the utility of measuring fetal cavum septum pellucidum (CSP) width during routine, mid-pregnancy ultrasound for improving diagnosis of 22q11.2 deletion syndrome amongst fetuses with and without conotruncal anomalies.Patients and MethodsThis was a retrospective case-control study (2005–2016). Fetuses and newborns with 22q11.2 deletion and/or conotruncal cardiac anomalies were identified using a regional, clinical database. A control group was assembled in a 2:1 ratio to create three groups for comparison: i) 22q11.2 deletion syndrome; ii) isolated conotruncal anomalies; and iii) controls. Eligibility was restricted to those with stored ultrasound images between 18–22 weeks’ gestation and a minimum biparietal diameter of 40 mm. Post-processing measurement of CSP width was performed in a standardized fashion by two blinded and independent study personnel. Descriptive and inferential statistics, regression modeling, and receiver operator curves (ROC) were used to compare outcomes between groups and evaluate sensitivity/specificity of CSP width as a marker of 22q11.2 deletion syndrome.ResultsTwenty-nine cases of 22q11.2 deletion and 64 cases of isolated conotruncal anomalies were matched to 186 healthy controls. Cases with 22q11.2 deletion syndrome had significantly larger CSP widths (5.36 mm; SD=1.2) compared to those with isolated conotruncal anomalies (3.75 mm; SD=1.11) and healthy controls (2.93 mm; SD=0.57; p<0.0001). There was no difference in CSP width amongst those with 22q11.2 deletion irrespective of the presence/absence of a conotruncal anomaly (p=0.362), or by type of conotruncal anomaly (p=0.211). Using a CSP width cutoff >4.3 mm, fetuses with 22q11.2 deletion can be accurately identified with good sensitivity (89.7%) and specificity (84%).ConclusionFetuses with 22q11.2 deletion syndrome have dilated CSPs when compared to those with isolated conotruncal anomalies or controls. Because CSP dilation can be evaluated during routine mid-pregnancy ultrasound using standard images of the fetal head, measurement could easily be incorporated to enhance prenatal diagnosis of this phenotypically diverse condition.

67 Multicenter prospective study of SNP-based cfDNA for 22q11.2 deletion in 18,289 pregnancies with genetic confirmation

Cell free DNA (cfDNA) screening for pathogenic copy number variants (CNV) such as 22q11.2 deletion syndrome (22q11.2DS) is clinically available. Data on test performance are limited. we report on the performance of SNP-based cfDNA in a large prenatal cohort. We hypothesized that SNP-based cfDNA can detect 22q11.2DS deletions that are >500kb. Patients who had SNP-based cfDNA for aneuploidy and 22q11.2DS were recruited at 21 centers in 6 countries. Genetic confirmation was obtained for all pregnancies from prenatal or newborn DNA samples. All microdeletions larger than 500kb associated with 22q11.2DS were included in the test performance analysis, including the 2.5-3Mb LCR22A-D classic deletion as well as smaller nested deletions. An updated cfDNA algorithm that was blinded to pregnancy outcome was also evaluated. Of 20,887 women enrolled, 18,289 (87.6%) had both cfDNA and DNA confirmation results for 22q11.2DS. Mean maternal age and gestational age at enrollment were 33.7 years and 13.3 weeks, respectively. Twelve 22q11.2DS cases were identified by prenatal (n=3) or postnatal (n=9) testing, yielding a cohort prevalence of 1:1524. Deletion sizes are detailed in the table below. The screen positive rate of cfDNA for 22q11.2DS was 0.2% (37/18,289). Sensitivity was 75.0% (95% CI: 50.5, 99.5); specificity was 99.84% (95% CI: 99.79, 99.90); and PPV was 24.3% (95% CI: 10.5, 38.2). Sensitivity, specificity and PPV were all higher using the updated algorithm (83.3%; 99.95%, and 52.6%, respectively) and the screen positive rate was significantly lower (0.1%; p=0.0004). There were no cases of 22q11.2DS in the 1.46% of cases without results (“no call” cases). In a prospective cohort of 18,289 pregnancies with genetic confirmation, SNP-based cfDNA screening for 22q11.2DS had high sensitivity and specificity and detected both classic and nested deletions with a PPV greater than 50% using an updated algorithm.

Microarray analysis has no additional value in fetal aberrant right subclavian artery: description of 268 pregnancies and systematic literature review.

Fetal aberrant right subclavian artery (ARSA) is a relatively common sonographic finding. Several studies have reported a significant association between ARSA and Down syndrome, as well as 22q11.2 microdeletion. The objective of this study was to assess the risk of abnormal chromosomal microarray analysis (CMA) findings in a large cohort of pregnancies with fetal ARSA as an isolated, as well as a non-isolated, sonographic anomaly. A secondary objective was to review the literature, examining the frequency of chromosomal microarray aberrations in fetuses with isolated ARSA. Data from all pregnancies referred for invasive testing and CMA due to sonographic diagnosis of fetal ARSA, between 2013 and 2017, were obtained retrospectively from the computerized database of the Israeli Ministry of Health. The rate of clinically significant CMA findings in these fetuses was compared to that in a local control population of 2752 low-risk pregnancies with normal ultrasound and serum screening results. In addition, a literature search was conducted in PubMed, from inception to February 2018, of original studies in the English language describing the frequency and nature of microscopic and submicroscopic aberrations in fetuses with isolated ARSA. Of 246 pregnancies with isolated ARSA that underwent CMA analysis, a clinically significant finding was detected in one (0.4%) pregnancy (trisomy 21). This rate did not differ significantly from that in the control population (P = 0.1574). Of 22 fetuses with non-isolated ARSA, one (4.5%) additional case of trisomy 21 was noted. The frequency of trisomy 21 in this cohort also did not differ from that in the control population (relative risk, 5.5 (95% CI, 0.8-37.6)). The literature search yielded 13 additional relevant papers, encompassing 333 cases of isolated ARSA. Of 579 cases overall (including those of the present study), 13 (2.2%) cases of trisomy 21 were detected, with no cases of 22q11.2 microdeletion. While an association may exist between non-isolated ARSA and Down syndrome, isolated ARSA might better serve as a soft marker for Down syndrome, rather than a routine indication for invasive prenatal testing. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.

Prevalence of chromosomal abnormalities and 22q11.2 deletion in conotruncal and non-conotruncal antenatally diagnosed congenital heart diseases in a Chinese population.

The aim of the present study was to calculate the prevalence of chromosomal abnormalities among antenatally diagnosed congenital heart diseases (CHDs), and the prevalence of 22q11.2 deletion in those with conotruncal CHDs versus isolated non-conotruncal CHDs. All patients with antenatal ultrasound finding of fetal CHDs in two obstetric units in a 5-year period were retrospectively reviewed. Detected CHDs were classified as conotruncal if the malformation involved either the aortic outflow tract or the pulmonary outflow tract; otherwise they were classified as non-conotruncal. Karyotyping, fluorescence in situ hybridisation for 22q11.2 deletion (22q11FISH), and array comparative genomic hybridisation (aCGH) results were retrieved from patient medical records. The primary outcome was prevalence of chromosomal abnormalities in CHDs. The secondary outcomes were prevalence of 22q11.2 deletion and its prevalence in conotruncal versus non-conotruncal CHDs. A total of 254 Chinese patients were diagnosed to have fetal CHDs. In all, 50 (19.7%) were found to have chromosomal abnormalities with seven (2.8%) patients having 22q11.2 deletion, of whom all seven had conotruncal CHDs and none had non-conotruncal CHDs (P<0.05). Conventional karyotyping detected 35 (70%) cases of the chromosomal abnormalities. The 22q11FISH detected three cases of 22q11.2 deletion; aCGH was performed to detect four cases of 22q11.2 deletion and eight other cases of copy number variations. Our results suggest that invasive testing for karyotyping is recommended for fetal CHDs. Although the prevalence of 22q11.2 deletion was low, testing for 22q11.2 deletion should be offered for conotruncal CHDs.

Two Cases of 22Q11.2 Deletion Syndrome and Type 1 Diabetes

Objective: 22q11.2 Deletion syndrome (22q11.2DS) is the most common chromosome deletion syndrome and increases the risk of autoimmune conditions, including thyroid disease, cytopenias, and juvenile rheumatoid arthritis. We report two unusual cases of pediatric patients with 22q11.2DS who subsequently developed type 1 diabetes (T1D). Methods: Clinical and laboratory data were isolated and are presented. Results: A 7-year-old male with genetically confirmed 22q11.2DS and related characteristics presented with polyuria, nocturia, and polydipsia and was found to have an elevated hemoglobin A1c of 9.8% (84 mmol/mol) with subsequent positive pancreatic autoantibodies (islet antigen 2 [IA-2] antibody and glutamic acid decarboxylase antibody). Screening labs for other autoimmune conditions identified thyroid antibodies, but thyroid function has been normal thus far. A 4-year-old female with genetically confirmed 22q11.2DS and associated features presented in severe diabetic ketoacidosis and was found to have one ...

Identification of 22q11.2 microdeletion among patients with congenital heart diseases using droplet digital PCR

OBJECTIVE To develop a new method for detecting 22q11.2 deletion syndrome (22q11.2 DS) in clinical settings. METHODS Specific primers and fluorescence probes were designed to target the TBX1 gene within the 22q11.2 deletion region and a reference gene RPP30. Multiplexed droplet digital PCR (ddPCR) was run to detect the 22q11.2 microdeletion by calculating the ratio of positive droplet number of TBX1/RPP30. RESULTS Three cases of 22q11.2 microdeletion previously confirmed by array comparative genome hybridization were successfully identified. Subsequently, the ddPCR detected two further cases of 22q11.2 microdeletion among 14 children with congenital heart diseases. CONCLUSION The ddPCR technique has provided a rapid and cost-effective method for detecting 22q11.2 microdeletion in clinical settings.

Bacterial artificial chromosome on beads (BoBs) technology in prenatal diagnosis

Objective To assess the feasibility of bacterial artificial chromosome on beads, (BoBs) in prenatal diagnosis. Methods A total of 287 pregnant women who underwent amniocentesis and 16 underwent cordocentesis, from March 2015 to February 2016 in Center of Prenatal Diagnosis of Fujian Provincial Maternity and Child Health Care Hospital, were recruited. Karyotyping and BoBs technology were both performed for each sample to detect chromosomal abnormalities. Gene microarray was further performed when microduplication or microdeletion was identified by BoBs. The consistency of BoBs technology and karyotype analysis combined with gene microarray was compared. Results Fourteen cases of trisomy 21, five cases of trisomy 18, four cases of trisomy 13, one case of 48, XXYY and one case of 47, XXX were detected by BoBs technology with specific enhanced signal and results were consistent with karyotype. Three cases of 22q11.2 microdeletion and one case of microduplication in 22q11.2 area were detected by BoBs technology and these were confirmed by gene array. However, none of the above four cases were identified by karyotype. The positive detection rates of BoBs technology and karyotype alone were 9.57% (29/303) and 8.25% (25/303), respectively. Among the 15 elderly pregnant women with abnormal ultrasound findings, 11 were detected with fetal chromosome abnormality. Conclusions BoBs, a bead-based multiplex assay being qualified to detect chromosomes 13, 18, 21, X/Y aneuploidies and nine microdeletion regions, with its speediness, reliability and easy operability, is promising in prenatal diagnosis. Key words: Prenatal diagnosis; Karyotyping; Chromosome aberrations; Chromosome deletion; Chromosomes, artificial, bacterial

SNP Microarray in FISH Negative Clinically Suspected 22q11.2 Microdeletion Syndrome.

The present study evaluated the role of SNP microarray in 101 cases of clinically suspected FISH negative (noninformative/normal) 22q11.2 microdeletion syndrome. SNP microarray was carried out using 300 K HumanCytoSNP-12 BeadChip array or CytoScan 750 K array. SNP microarray identified 8 cases of 22q11.2 microdeletions and/or microduplications in addition to cases of chromosomal abnormalities and other pathogenic/likely pathogenic CNVs. Clinically suspected specific deletions (22q11.2) were detectable in approximately 8% of cases by SNP microarray, mostly from FISH noninformative cases. This study also identified several LOH/AOH loci with known and well-defined UPD (uniparental disomy) disorders. In conclusion, this study suggests more strict clinical criteria for FISH analysis. However, if clinical criteria are few or doubtful, in particular newborn/neonate in intensive care, SNP microarray should be the first screening test to be ordered. FISH is ideal test for detecting mosaicism, screening family members, and prenatal diagnosis in proven families.

GH deficiency and phenotypic features in four cases of 22q11.2 deletion syndrome

GH deficiency and phenotypic features in four cases of 22q11.2 deletion syndrome

Height and Bone Phenotype of 22q11.2 Deletion Syndrome: Lessons from the Gene Analysis of Three Cases

This report describes three cases of 22q11.2 deletion syndrome (22q11.2DS) diagnosed by array comparative genomic hybridization with final adult...

Incidence of severe combined immunodeficiency through newborn screening in a Chinese population.

In order to know the true incidence of severe combined immunodeficiency (SCID) in a Chinese population, we conducted and implemented SCID newborn screening in Taiwan. Between May 1, 2010 and December 31, 2011, the National Taiwan University Hospital Newborn Screening Center screened all newborns for T-cell lymphopenia by measuring the copy number of T-cell receptor excision circles (TRECs) and RNase P. Newborns with low TREC values were subjected to complete blood cell counts and flow cytometry. A total of 106,391 newborns were screened using the TREC assay over a period of 19 months. Five newborns were immediately referred for confirmatory tests, including two SCID patients and two patients with persistent T-cell lymphopenia; a third SCID patient was found 2 months after the study period. All three SCID cases received stem cell transplantation at the age of 2-5 months. We also identified five cases of 22q11.2 microdeletion syndrome. During this period, two SCID patients from among the unscreened newborns were reported, and they died at ages 3 months and 4 months, respectively. Newborn screening to measure the number of TREC copies successfully identifies newborns with T-cell lymphopenia, 22q11.2 microdeletion syndrome, and other high-risk conditions. Taken together, the incidence of T-cell lymphopenia in apparently healthy newborns is more than 1 in 11,821, and further attention to their immune functions is warranted.

Épidémiologie des fentes labio-palatines : expérience du Registre de malformations congénitales d’Alsace entre 1995 et 2006

To review clinical and epidemiologic data of orofacial clefts and to evaluate the efficacy and the impact of prenatal diagnosis. A population-based retrospective study was carried out on data from the Congenital Malformations of Alsace Registry (France) between 1995 and 2006. A total of 321 orofacial clefts were recorded (overall prevalence, 2.1 per 1000), divided into cleft lip (CL) or cleft lip palate (CLP) (204 cases) and cleft palate (117 cases). The cleft lip and cleft lip palate CL±P sex-ratio was 1.87, whereas the CP sex-ratio was 1. CLs were more often unilateral than CLPs (79% versus 59%). CLs were unilateral in 79% of the cases (60/76), bilateral in 20% of the cases (15/76), and median in 1% (1/76); 55% of the unilateral CLs were right and 45% were left. CLPs were unilateral in 59% of the cases (76/128), bilateral in 39% of the cases (50/128), and median in 2% (2/128); 45% of the unilateral CLPs were right and 55% were left. The 117 CPs were divided into 50 clefts of the total palate (43%) and 67 clefts of the posterior palate (57%); 25 cases (21%) of Pierre Robin sequence were collected. Sixty-six percent of CL±P (134/204) were associated with other congenital anomalies, including chromosome abnormality in 31 cases and identified monogenic syndrome or association in 12 cases. The most frequent chromosome abnormalities were 16 cases of trisomy 13 and 7 cases of trisomy 18. No cases of 22q11.2 microdeletion or duplication were detected among CL±P. Monogenic syndromes were identified in 6% (12/204) of CL±P cases: Van der Woude syndrome (2 cases); CHARGE syndrome (2 cases); ectrodactyly, ectodermal dysplasia, and cleft/lip palate (EEC) syndrome (2 cases); branchiooculofacial (BOF) syndrome (1 case); Treacher-Collins syndrome (1 case); Nager syndrome (1 case); Goldenhar syndrome (1 case); holoprosencephaly spectrum (1 case); and Meckel syndrome (1 case). Forty-two percent of CPs (49/117) were associated with other congenital anomalies; chromosome abnormality was identified in 12 cases and monogenic syndrome was diagnosed in 14 cases. The most frequent chromosome abnormality was 22q11 microdeletion (5 cases). Monogenic syndromes were recognized in 12% of the CP cases (14/117): fragile X syndrome (2 cases), Meckel syndrome (2 cases), Orofaciodigital syndrome type I (OFD1) (1 case), Stickler syndrome (1 case), Larsen syndrome (1 case), Kniest syndrome (1 case), Cornelia de Lange syndrome (1 case), thanatophoric dysplasia (1 case), other unknown bone chondrodysplasia (1 case), Fryns syndrome (1 case), fetal akinesia sequence (1 case), and Silver-Russel syndrome (1 case). Fifty-two percent of CL cases (106/204) were prenatally diagnosed. An increasing tendency was observed between the 1995-2000 and 2001-2006 periods with a detection rate increasing from 47% to 56%. During the whole period, only 1 case of CP was prenatally diagnosed. Eighty-two percent of all cases (263/321) were livebirths; 8 stillbirths were reported (2%); 50 syndromic or associated cases (16%) led to medical abortion (no termination of pregnancy was performed for isolated cleft). Orofacial clefts are a frequent malformation with a total prevalence of 2.1 per 1000 total births. Sonbographic prenatal diagnosis of orofacial clefts remains difficult with a mean detection rate about 50% for CL±P and is extremely rare for CP. Associated malformations and genetic syndromes are frequent and require a systematic survey. This study also highlights the different pathogenic background of CL±P compared to CP, regarding the sex-ratio and the proportion and type of associated malformations.

Atypical presentations of 22q11.2 deletion syndrome: explaining the genetic defects and genome architecture

22q11.2 deletion syndrome, the most common microdeletion syndrome, exhibits a broad range of phenotypes, implying a cumbersome diagnosis due to atypical or paucisymptomatic presentations. We present two atypical cases of 22q11.2 deletion syndrome and suggest a preferential occurrence of the breakpoints in regions poor in repetitive elements of SINE/Alu family.

Two cases of 22q11.2 deletion syndrome with anorectal anomalies and growth retardation

Clinical features associated with the deletion of 22q11.2 are highly variable. Most are diagnosed by cardinal congenital heart disease or hypoparathyroidism. In cases without major features, an early accurate diagnosis of 22q11.2 deletion syndrome is difficult. Congenital anorectal malformations (ARM), which can be detected soon after birth, have been rarely reported in 22q11.2 deletion syndrome. We report two cases of 22q11.2 deletion syndrome with ARM who showed growth retardation. ARM was detected in both patients without congenital heart disease or hypoparathyroidism at early infancy and they were followed by pediatric surgeons. Later, failure to thrive or short stature became evident, and they consulted with pediatric endocrinologists who subsequently confirmed the diagnosis of 22q11.2 deletion by fluorescent in situ hybridization analysis. The combination of ARM and growth retardation may lead to an early diagnosis of 22q11.2 deletion syndrome.

２２ｑ１１．２欠失症候群（ＣＡＴＣＨ２２）の３例

We report three cases of 22q11.2 deletion syndrome (CATCH22; cardiac defects, abnormal faces, thymic hypoplasia, cleft palate and hypocalcemia with chromosome 22q11.2 deletion) with various complications including hearing loss and nasopharyngeal problems. All three cases we report here had congenital cardiac defects. Two of the three cases had cleft palate, one overt and the other submucoals. Although one of the three cases had a normal hearing level, the other two were almost deaf, one with and the other without inner ear anomalies. The former case was prescribed a hearing aid, and for the latter case, cochlear implantation operation was conducted at the age of three years and seven months. Both of these patients have successfully developed communication skills.CATCH22 shows a variety of phenotypes, including hearing loss and nasopharyngeal malformations, either of which may disturb speech ability and thus, furthermore, mental development of the child. However, this condition may be improved by early and adequate intervention. Thus, otolaryngologists should be familiarized with the typical facial abnormality and most frequent manifestations of this syndrome, and be ready to treat patients with 22q11 deletion, providing them with intensive and individualized prescription at their early stages.

口蓋裂を伴った２２ｑ１１．２欠失症候群の２例

DiGeorge syndrome (DGA), velocardiofacial syndrome (VCFS), and conotruncal anomaly face syndrome (CTAF) are frequently associated with 22q11.2 deletion syndrome. We report two cases of 22q11.2 deletion syndrome. Two patients had cleft palate, and facial dysmorphism. Fluorescence in situ hybridization (FISH) was used to show deletion of chromosome 22q11.2. Palatoplasty was performed at about two years of age with the patients under general anesthesia. The postoperative course was uneventful in both patients.