Prevalence of 22q11 region deletions in patients with velopharyngeal insufficiency

Velo-cardio-facial syndrome, DiGeorge syndrome, conotruncal anomaly face syndrome, tetralogy of Fallot, and pulmonary atresia with ventricular septal defect are all associated with hemizygosity of 22q11. While the prevalence of the deletions in these phenotypes has been studied, the frequency of deletions in patients presenting with velopharyngeal insufficiency (VPI) is unknown. We performed fluorescence in situ hybridization for locus D22S75 within the 22q11 region on 23 patients with VPI (age range 5–42 years) followed in the Craniofacial Clinic at the University of Florida. The VPI occurred either as a condition of unknown cause (n=16) or as a condition remaining following primary cleft palate surgery (n=7). Six of sixteen patients with VPI of unknown cause and one of seven with VPI following surgery had a deletion in the region. This study documents a high frequency of 22q11 deletions in those presenting with VPI unrelated to overt cleft palate surgery and suggests that deletion testing should be considered in patients with VPI. Am. J. Med. Genet. 77:8–11, 1998. © 1998 Wiley-Liss, Inc.     

Velo-cardio-facial syndrome: Frequency and extent of 22q1l deletions

Velo-cardio-facial. (VCFS) or Shprintzen syndrome is associated with deletions in a region of chromosome 22q11.2 also deleted in DiGeorge anomaly and some forms of congenital heart disease. Due to the variability of phonotype, the evaluation of the incidence of deletions has been hampered by uncertainty of diagnosis. In this study, 54 patients were diagnosed with VCFS by a single group of clinicians using homogeneous clinical criteria independent of the deletion status. Cell lines of these patients were established and the deletion status evaluated for three loci within the commonly deleted region at 22q11.2 using fluorescence in situ hybridization (FISH). In 81% of the patients all three loci were hemizygous. In one patient we observed a smaller interstitial deletion than that defined by the three loci. The phenotype of this patient was not different from that observed in patients with larger deletions. © 1995 Wiley-Liss, Inc.     

Clinical features of chromosome 22q11.2 microdeletion syndrome in 208 Chilean patients

Patients with chromosome 22q11 deletion syndrome exhibit significant phenotypic variability. Epidemiologic data suggest a higher incidence in Hispanics, but limited clinical information is available from Latin-American patients. We describe the clinical features of Chilean patients with 22q11 deletion syndrome and compare their findings with those reported in large European, Japanese and US series. Data were obtained from 208 patients from five medical centers. Mean age at diagnosis was 5.2 years, with a median of 2.3 years. Congenital heart defects were present in 59.6%, lower than other large series that averaged 75.8%. Palate abnormalities were present in 79%, higher than previous reports averaging 56%. Patients with congenital heart disease were diagnosed earlier (median 0.3 years of age) than those without heart defects (median 5.6 years) and had greater mortality attributable to the syndrome (9.8% vs 2.4%, respectively). The differences in frequencies of major anomalies may be due to growing awareness of more subtle manifestations of the syndrome, differences in clinical ascertainment or the presence of modifier factors. These observations provide additional data useful for patient counseling and for the proposal of health care guidelines.     

Hypoparathyroidism as the major manifestation in two patients with 22q11 deletions

We report on two adolescents with 22q11 deletion. Their main clinical manifestation was chronic symptomatic hypocalcemia secondary to hypoparathyroidism, together with seizures and cerebral calcifications. Neither congenital cardiac abnormality nor T cell deficiency were detected. The pheno-typic manifestations of the observed patients were consistent with velo-cardio-facial syndrome (VCFS). A microdeletion of chromosome region 22q11 has been demonstrated in approximately 90% of DiGeorge syndrome (DGS) patients and in 75% of VCFS patients; the association of the deletion with a wide spectrum of clinical findings suggests the existence of a contiguous gene syndrome. The presence of certain traits of DGS/VCFS should lead to investigations of the parathyroid function and molecular analysis of the 22q11 region hybridization studies. © 1994 Wiley-Liss, Inc.     

Expanding the fetal phenotype: Prenatal sonographic findings and perinatal outcomes in a cohort of patients with a confirmed 22q11.2 deletion syndrome

22q deletion syndrome (22q11.2DS) is most often correlated prenatally with congenital heart disease and or cleft palate. The extracardiac fetal phenotype associated with 22q11.2DS is not well described. We sought to review both the fetal cardiac and extracardiac findings associated with a cohort of cases ascertained prenatally, confirmed or suspected to have 22q11.2DS, born and cared for in one center. A retrospective chart review was performed on a total of 42 cases with confirmed 22q11.2DS to obtain prenatal findings, perinatal outcomes and diagnostic confirmation. The diagnosis was confirmed prenatally in 67% (28/42) and postnatally in 33% (14/42). The majority (81%) were associated with the standard LCR22A‐LCR22D deletion. 95% (40/42) of fetuses were prenatally diagnosed with congenital heart disease. Extracardiac findings were noted in 90% (38/42) of cases. Additional findings involved the central nervous system (38%), gastrointestinal (14%), genitourinary (16.6%), pulmonary (7%), skeletal (19%), facial dysmorphism (21%), small/hypoplastic thymus (26%), and polyhydramnios (30%). One patient was diagnosed prenatally with a bilateral cleft lip and cleft palate. No fetus was diagnosed with intrauterine growth restriction. The average gestational age at delivery was 38 weeks and average birth weight was 3,105 grams. Sixty‐two percentage were delivered vaginally and there were no fetal demises. A diagnosis of 22q11.2 deletion syndrome should be considered in all cases of prenatally diagnosed congenital heart disease, particularly when it is not isolated. Microarray is warranted in all cases of structural abnormalities diagnosed prenatally. Prenatal diagnosis of 22q11.2 syndrome can be used to counsel expectant parents regarding pregnancy outcome and guide neonatal management.     

Chromosome 22q11 deletions are not found in autistic patients identified using strict diagnostic criteria

A group of 103 subjects with a strict diagnosis of autism were tested for deletion of band q11.2 on the long arm of chromosome 22. No deletions were found, indicating that when a patient has been diagnosed with autism using strict and consistent criteria, in the absence of other indications, it is unlikely that this individual will have a 22q11 deletion. Testing for 22q11 deletions is therefore unlikely to be necessary in these patients. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:15–17, 2000. © 2000 Wiley‐Liss, Inc.     

Chromosome 22q11.2 deletion syndrome in African-American patients: a diagnostic challenge

Chromosome 22q11.2 deletion syndrome (22q11DS) is associated with numerous and variable clinical manifestations including conotruncal heart abnormalities, palatal anomalies, hypoparathyroidism, immune deficiency, and cognitive deficits. The clinical suspicion of this syndrome is often heightened by the presence of characteristic facial features. A previous report highlighted the under‐diagnosis of this condition in African Americans, thought to be related to a paucity of typical facial features. We ascertained the largest cohort (n = 50) of African‐American individuals with 22q11DS reported thus far, across five genetics centers in the United States and report on their facial and other phenotypic features. About of our cohort has at least one dysmorphic facial feature. Auricular abnormalities, especially small ears, are the most common dysmorphic facial feature followed by nasal and ocular abnormalities. Skeletal findings are seen in about 2/3 of our cohort, higher than the typical frequency reported in 22q11DS. Cardiac anomalies, developmental delay, and palatal abnormalities are seen at a lower frequency in our cohort. Thus, it is evident that the features traditionally associated with 22q11DS are difficult to recognize in African‐American individuals with this syndrome, due to both altered frequencies of major anomalies and a non‐classic facial appearance. Therefore, a high index of suspicion is needed to recognize 22q11DS in African‐American individuals. © 2011 Wiley‐Liss, Inc.     

Skeletal anomalies and deformities in patients with deletions of 22q11

Skeletal anomalies in patients with a 22q11.2 deletion are reported infrequently. We report the skeletal findings in 108 patients with a 22q11.2 deletion, of whom 37 (36%) had a skeletal anomaly. Twenty-two patients (20%) had anomalies of the limbs, 7 of the upper limb, including preaxial or postaxial polydactyly. An anomaly of the lower limb was found in 16 patients, including postaxial polydactyly, clubfoot, severely overfolded toes, and 2-3 toe cutaneous syndactyly. Chest films of 63 patients were examined; 30% of them had abnormal findings, most commonly supernumerary ribs (17%) or a “butterfly” vertebral body (11%). Hypoplastic vertebrae, hemivertebrae, and vertebral coronal clefts were also noted. Thus, skeletal anomalies are not uncommon in patients with a 22q11.2 deletion and may occur more frequently than recognized previously. Am. J. Med. Genet. 72:210–215, 1997. © 1997 Wiley-Liss, Inc.     

Wilms tumor in a patient with 22q11.2 microdeletion

22q11.2 deletion syndrome is the most common microdeletion syndrome. Wilms tumor is one of the most common solid tumors in childhood yet 22q11.2 deletion and Wilms tumor only once have been reported in the same patient. Here we describe a young patient with subtle clinical findings suggestive of 22q11.2 at the time of diagnosis who subsequently developed Wilms tumor. We assert the importance of a low threshold for screening for 22q11.2 deletion and the associated phenotypes and maintaining vigilance in screening for common primary malignancies in patients with known 22q11.2 deletion.     

Nasal dimple as part of the 22q11.2 deletion syndrome

The phenotype of the 22q11.2 microdeletion syndrome is quite variable. We describe 2 patients with a 22q11.2 deletion and a dimpled nasal tip, which, we suggest can be the extreme of the broad or bulbous nose commonly found in the 22q11.2 deletion syndrome, and should not be confused with the more severe nasal abnormalities seen in frontonasal dysplasia. Am. J. Med. Genet. 69:290–292, 1997. © 1997 Wiley-Liss, Inc.     

22q11.2 deletions in a series of patients with non-selective congenital heart defects: incidence, type of defects and parental origin

Previous studies have indicated a wide spectrum of incidences of 22q11.2 deletions in isolated and syndromic (sporadic or familial) cases of conotruncal heart defects, whereby the detection rate of the deletion varied from 65% in one study to 0 in another. We analysed 110 patients with non-selective syndromic or isolated non-familial congenital heart malformations by fluorescence in situ hybridization (FISH) using the D22S75 DiGeorge chromosome (DGS) region probe. A 22q11.2 microdeletion has been detected in 9/51 (17.6%) syndromic patients. Five were of maternal origin and four of paternal origin. None of the 59 patients with isolated congenital cardiac defect had a 22q11.2 deletion. We compared the cardiac anomalies of our patients with a 22q11.2 deletion with those of previously published series and we describe types of congenital heart defects which appear to be often associated with a 22q11.2 deletion. The ability to detect such types of heart defects and to provide an early diagnosis of 22q11.2 deletion is particularly relevant in very young infants, who often show only very mild expression of the otherwise well-characterized phenotypes of the DiGeorge/velo–cardio–facial syndrome (DG/VCFS).     

Chromosome 22q11.2 microdeletions in velocardiofacial syndrome patients with widely variable manifestations

Velocardiofacial syndrome (VCFS) and the DiGeorge sequence (DGS) are caused by 22q11.2 deletions. Fluorescence in situ hybridization (FISH) using the DiGeorge chromosome region (DGCR) probe (Oncor) was used to detect 31 deletions in 100 patients with possible VCFS. Retrospective FISH analysis of archived slides from 14 patients originally studied only by high-resolution G banding detected 6 patients with a DGCR deletion, and only 2 of these 6 had a microscopically visible chromosome deletion. The 4 familial deletions found exhibited a wide range of clinical presentations within each family. Comparison of clinical characteristics of patients with and without the DGCR deletion determined findings predictive of the deletion: abundant or unruly scalp hair; narrow palpebral fissures; a laterally “built-up” nose; velopharyngeal inadequacy; thymic hypoplasia; and congenital heart defects, specifically tetralogy of Fallot, ventriculoseptal defect, and interrupted aortic arch. © 1996 Wiley-Liss, Inc.     

Detailed analysis of 22q11.2 with a high density MLPA probe set

The presence of chromosome-specific low-copy repeats (LCRs) predisposes chromosome 22 to deletions and duplications. The current diagnostic procedure for detecting aberrations at 22q11.2 is chromosomal analysis coupled with fluorescence in situ hybridization (FISH) or PCR-based multiplex ligation dependent probe amplification (MLPA). However, there are copy number variations (CNVs) in 22q11.2 that are only detected by high-resolution platforms such as array comparative genomic hybridization (aCGH). We report on development of a high-definition MLPA (MLPA-HD) 22q11 kit that detects copy number changes at 37 loci on the long arm of chromosome 22. These include the 3-Mb region commonly deleted in DiGeorge/velocardiofacial syndrome (DGS/VCFS), the cat eye syndrome (CES) region, and more distal regions in 22q11 that have recently been shown to be deleted. We have used this MLPA-HD probe set to analyze 363 previously well-characterized samples with a variety of different rearrangements at 22q11 and demonstrate that it can detect copy number alterations with high sensitivity and specificity. In addition to detection of the common recurrent deletions associated with DGS/VCFS, variant and novel chromosome 22 aberrations have been detected. These include duplications within as well as deletions distal to this region. Further, the MLPA-HD detects deletion endpoint differences between patients with the common 3-Mb deletion. The MLPA-HD kit is proposed as a cost effective alternative to the currently available detection methods for individuals with features of the 22q11 aberrations. In patients with the relevant phenotypic characteristics, this MLPA-HD probe set could replace FISH for the clinical diagnosis of 22q11.2 deletions and duplications.     

Incidence and significance of 22q11.2 hemizygosity in patients with interrupted aortic arch

Interruption of the aortic arch (IAA) is a severe malformation of the heart with known association to DiGeorge syndrome (DGS) and 22q11.2 hemizygosity. The aim of this study was to establish incidence and significance of 22q11.2 hemizygosity in an unbiased sample of patients with IAA. All 15 children with IAA who were referred to our hospital in a 3-year period were tested by chromosome and fluorescence in situ hybridization (FISH) analysis with the probes D22S75, Tuple1, and cHKAD26 and by a set of 10 simple tandem repeat polymorphic (STRP) markers. In nine of 11 children with IAA type B, 22q11.2 hemizygosity was demonstrated by FISH and STRP analysis, but in none of the four children with type A. In all but one child, deletion size was ∼3 Mb. The girl with the smaller deletion of ∼1.5 Mb differed because of an Ullrich-Turner syndrome-like phenotype and severe T-cell defect. Additionally, in one patient with phenotypic signs of DGS, a small deletion distal to the known DGS region containing the marker D22S308 was suspected by STRP analysis. One deletion was shown to be inherited from a healthy father and one IAA type A recurred in a sib. T-cell anomalies were evident in eight of the nine children with classical deletion, five of whom suffered also from hypoparathyroidism. With respect to cause and clinical course, IAA type A and B were shown to represent different entities. This study showed that variable symptoms of 22q11.2 hemizygosity may cluster. Am. J. Med. Genet. 78:322–331, 1998. © 1998 Wiley-Liss, Inc.     

Spectrum of clinical variability in familial deletion 22q11.2: from full manifestation to extremely mild clinical anomalies

The 22q11.2 deletion (del22q11.2) syndrome is a genetic condition with wide interfamilial and intrafamilial variability in clinical expression. The aim of the present study was to review the prevalence of parental transmission in our series of patients with del22q11.2, and to analyse clinical findings of the affected parents. Parental transmission of del22q11.2 in our series was 17.2% (15/87), with a preferential maternal transmission (10/15). One or more major features of del22q11.2 were found in all deleted parents, but one of the mothers showed extremely mild clinical anomalies. The present data demonstrate that it should be current policy to test both parents of patients with del22q11.2, irrespective of the parental phenotype, in view of the fact that extremely mild clinical features can be detected in parents of deleted patients. This would provide accurate genetic counselling to del22q11.2 families, as relatively asymptomatic parents must be advised of the 50% risk of transmitting the deletion in a subsequent pregnancy. Various genetic and non-genetic factors, including modifier genes at separate loci, mosaicism, unstable mutations, allelic variations at the haploid locus, chance and environmental interaction, can be hypothesized to be involved in variable clinical expression, even in the same family.