Atypical 22q11.2 deletion in a patient with DGS/VCFS spectrum

Deletions in region 22q11.2 usually occur between two low copy repeat regions (LCRs), which are preferred chromosome sites for rearrangements. Most of the deletions encompass the same 3 or 1.5 Mb region, with breakpoints at LCR A and D or at LCR A and B, respectively. We report on a patient with clinical features of the 22q deletion syndrome who presents a novel, atypical deletion, smaller than 1.5 Mb, with distal breakpoint in LCR B and proximal breakpoint within no known LCR site.     

Phenotypic heterogeneity in a family with a small atypical microduplication of chromosome 22q11.2 involving TBX1

The chromosome 22q11.2 region is commonly involved in non-allelic homologous recombination (NAHR) events. Microduplications of 22q11.2, usually involving a 3 Mb or 1.5 Mb region constitute the 22q11 microduplication syndrome. Both microdeletions and microduplications of 22q11.21 are reported to share several phenotypic characteristics, including dysmorphic facial features, velopharyngeal insufficiency, congenital heart disease, urogenital abnormalities, and immunologic defects. We report a child who presented at 8 months of age for evaluation of microcephaly and mild motor delay. Head circumference at birth, at 8 months, and at 19 months of age was below the 3rd centile. Other findings included left-sided cryptorchidism and developmental dysplasia of the left hip. In addition, echocardiography revealed a restrictive patent ductus arteriosus. Chromosomal microarray analysis using Affymetrix Genome-Wide Human SNP Array 6.0 revealed a novel 437 kb interstitial duplication at 22q11.21, involving TBX1, whose breakpoints did not coincide with known low copy repeat (LCR) regions. The same duplication was confirmed by fluorescent in situ hybridization (FISH) in the patient's mother and an older sister. The mother has a history of anxiety disorder and depression. The sister had a history of delayed motor milestones. None of the three duplication carriers has any documented renal anomalies or other significant medical problems. This report demonstrates the clinical heterogeneity associated with microduplications of 22q11.2 and illustrates the difficulties related to providing prognostic information and accurate genetic counseling to families when this finding is detected. The described microduplication is the smallest in this genomic region reported to date and further implicates abnormal gene dosage of TBX1 in disorders resulting from 22q11.2 rearrangements.     

Atypical copy number abnormalities in 22q11.2 region: Report of three cases

The 22q11.2 Deletion Syndrome (22q11.2DS) is the most common microdeletion syndrome in humans, with a highly variable phenotype. This chromosomal region contains low copy repeat (LCR) sequences that mediate non-allelic homologous recombination which predispose to copy number abnormalities at this locus. This article describes three patients investigated for suspicion of 22q11.2DS presenting atypical copy number abnormalities overlapping or not with the common ～3 Mb deletion. They were investigated by G-banding karyotype, Multiplex-ligation dependent probe amplification (MLPA) and array Genomic Hibridization (aGH). Clinical and molecular data were compared with literature, in order to contribute to genotype–phenotype correlation. Atypical chromosomal abnormalities were detected: 3.6 Mb deletion at 22q11.21-q11.23 between LCRs B–F in patient 1 and approximately 1.5 Mb deletion at 22q11.21-q11.22 between LCRs D–E in patients 2 and 3. The breakpoints detected in patient 1 have not been previously described. These findings exemplify the complexity and genetic heterogeneity observed in 22q11.2 region and corroborates the idea that genetic modifiers contribute to the phenotypic variability observed in proximal and distal 22q11.2 deletion syndromes.     

Primary lymphedema and other lymphatic anomalies are associated with 22q11.2 deletion syndrome

Background

Lymphedema is an abnormal accumulation of interstitial fluid within the tissues. Primary lymphedema is caused by aberrant lymphangiogenesis and it has been historically classified based on age at presentation. Although most cases are sporadic, primary lymphedema may be familial or present in association with chromosomal abnormalities and syndromic disorders. To the best of our knowledge, primary lymphedema has never been described in patients with 22q11.2 deletion syndrome.

Behavior in preschool children with the 22q11.2 deletion syndrome

Children with the 22q11.2 deletion syndrome (22q11DS) are at an increased risk of psychiatric problems from pre‐adolescence; little is known, however, about behavioral problems at a preschool age and the relationship between speech and behavior in this group. Parents of 90 children (aged 1.42–5.99 years) with 22q11DS filled out the Child Behavior Checklist, documenting behaviors including speech problems. Their profiles were compared with those of a comparison group consisting of 33 children with nonsyndromic orofacial clefts without 22q11DS, since both children with 22q11DS and children with clefts are expected to have speech problems. In the 22q11DS group, data on intelligence was acquired by means of formal tests. Parents of children with 22q11DS reported significantly higher mean scores on withdrawn behavior, affective problems and pervasive developmental problems compared to children with nonsyndromic clefts. Approximately 30% of children with 22q11DS had a score above the 97th percentile on at least one of the behavior subscales, indicating psychopathology. In children with 22q11DS, the reported behavioral problems were not associated with speech problems. Behavioral problems were found in 30% of young children with 22q11DS and were unlikely to be caused by speech problems. Within the 22q11DS group, behavioral problems were not related to the degree of cognitive impairment. This shows that many children with 22q11DS, known to be at an increased risk of psychiatric problems from pre‐adolescence, already show behavioral problems before the age of 6 years. © 2012 Wiley Periodicals, Inc.     

Diagnosis of distal 22q11.2 deletion syndrome in a patient with a teratoid/rhabdoid tumour

We report an 18 year old patient with mild intellectual disability who was diagnosed with a late onset teratoid/rhabdoid tumour by histological and immunohistochemical studies. Array-CGH studies, performed on a peripheral blood sample, showed a 3.4Mb deletion of chromosome 22q11.2, distal to the common DiGeorge syndrome (DGS) or Velocardiofacial syndrome (VCFs) region. This deletion is consistent with a diagnosis of distal 22q11.2 deletion syndrome. The deletion encompasses the INI1/SMARCB1 tumour suppressor gene. Biallelic inactivation of this gene is characteristic of atypical teratoid/rhabdoid tumours. Although several constitutional chromosome conditions are known to have increased susceptibility to various forms of cancer, very little is known regarding the magnitude of risk for malignancy associated with distal 22q11.2 deletion syndrome. In view of this finding we suggest that patients diagnosed with distal 22q11.2 deletion syndrome undergo careful prolonged monitoring for this type of tumour. This case demonstrates the need to carefully assess regions found to be deleted in individuals, referred for dysmorphia and/or developments delay, by array-CGH for the presence of genes known to be implicated in malignancy.     

Prenatal and postnatal diagnosis of 22q11.2 deletion syndrome

Microdeletion of chromosome 22q11.2, the most common human deletion syndrome encompasses a wide spectrum of abnormalities. Many clinical or ultrasonographic findings may support deletion studies, either in utero or in the post-natal period. The objective of our study was to evaluate the circumstances of 22q11.2 deletion diagnosis in a single centre of genetics during a 12 years period. Testing for 22q11.2 deletion was performed in 883 cases. Congenital heart defect was the most common reason for referral. An antenatal 22q11.2 microdeletion was detected in 8 fetuses (4.7%) among 169 pregnancies, all presenting conotruncal anomalies. In one case prenatal diagnosis led to the identification of the deletion in the mildly affected father and had negative impact on the family. During the same period, postnatal 22q11.2 DS was diagnosed in 81 out of 714 patients aged from birth to 42 years (11.3%) (p = 0.02). A CHD was present in 37 (45.7%). This figure is significantly lower than the 75% commonly reported. These results suggest that deletion studies could be justifiable in fetuses with non-cardiac prenatal sonographic findings that have been reported in association with 22q11.2 DS. However, as most of these malformations are rather common and non specific, systematic 22q11.2 testing is not justifiable. In such cases, careful cardiac and thymus examination could provide additional clues for 22q11.2 testing. In addition parents should be given accurate information before antenatal or postnatal testing, including the wide variability of the clinical phenotype, the impossibility to establish a precise prognosis concerning psychomotor development and psychiatric risks.     

Translocation (1;22)(p36;q11.2) with concurrent del(22)(q11.2) resulted in homozygous deletion of <Emphasis Type="Italic">SNF5/INI1</Emphasis> in a newly established cell line derived from extrarenal rhabdoid tumor

Malignant rhabdoid tumor (MRT) is a highly malignant pediatric cancer, which arises in various sites such as the kidney, brain, and soft tissues. Cytogenetic studies have revealed alterations of 22q11 in MRT. Recently, deletions and mutations of the SNF5/INI1 locus in 22q11.2 have been reported in MRT, suggesting that SNF5/INI1 is a tumor suppressor gene for MRT. Here we report our molecular cytogenetic study for a newly established cell line from extrarenal MRT with t(1;22)(p36;q11.2). Consequently, the reciprocal translocation was associated with the interstitial deletion of a small segment including SNF5/INI1, and another, chromosome 22, showed terminal deletion, the breakpoint of which was located 70–80 kb centromeric to SNF5/INI1, resulting in homozygous deletion of SNF5/INI1 in this cell line.     

Immune status of the murine 22q11.2 deletion syndrome model

Mice modeling the hemizygous deletion of chromosome 22q11.2 (22qMc) have been utilized to address various clinical phenotypes associated with the disease, including cardiac malformations, altered neural circuitry, and behavioral deficits. Yet, the status of the T cell compartment, an important clinical concern among 22q11.2 deletion syndrome (22qDS) patients, has not been addressed. While infancy and early childhood in 22qDS are associated with deficient T cell numbers and thymic hypoplasia, which can be severe in a small subset of patients, studies suggest normalization of the T cell counts by adulthood. We found that adult 22qMc do not exhibit thymic hypoplasia or altered thymic T cell development. Our findings that immune cell counts and inflammatory T cell activation are unaffected in 22qMc lend support to the hypothesis that human 22qDS immunodeficiencies are secondary to thymic hypoplasia, rather than intrinsic effects due to the deletion. Furthermore, the 22q11.2 deletion does not impact the differentiation capacity of T cells, nor their activity and response during inflammatory activation. Thus, 22qMc reflects the T cell compartment in adult 22qDS patients, and our findings suggest that 22qMc may serve as a novel model to address experimental and translational aspects of immunity in 22qDS.     

The effect of visual arrangement on visuospatial short-term memory: Insights from children with 22q11.2 deletion syndrome

Recent models of visuospatial (VSSP) short-term memory postulate the existence of two dissociable mechanisms depending on whether VSSP information is presented simultaneously or sequentially. However, they do not specify to what extent VSSP short-term memory is under the influence of general VSSP processing. This issue was examined in people with 22q11.2 deletion syndrome, a genetic condition involving a VSSP deficit. The configuration of VSSP information was manipulated (structured vs. unstructured) to explore the impact of arrangement on VSSP short-term memory. Two presentation modes were used to see whether the VSSP arrangement has the same impact on simultaneous and sequential short-term memory. Compared to children matched on chronological age, children with 22q11.2 deletion syndrome showed impaired performance only for structured arrangement, regardless of the presentation mode, suggesting an influence of VSSP processing on VSSP short-term memory abilities. A revised cognitive architecture for a model of VSSP short-term memory is proposed.     

Anomalies of the genitourinary tract in children with 22q11.2 deletion syndrome

The 22q11.2 deletion syndrome (22q11.2DS) involves multiple organ systems with variable phenotypic expression. Genitourinary tract abnormalities have been noted to be present in up to 30–40% of patients. At our institution, an internationally recognized, comprehensive, and multidisciplinary 22q11.2DS care center has been providing care to these children. We sought to report on the incidence of genitourinary tract anomalies in this large cohort and, therefore, retrospectively reviewed all patients who underwent a complete evaluation from 1992 to March 2017. We identified all children with any genital or urinary tract anomaly. For all children with a diagnosis of hydronephrosis, the underlying etiology was determined, when possible. Overall, 1,073 of 1,267 children with 22q11.2DS underwent renal evaluations at our institution. Hundered Sixty‐Two (15.1%) children had structural abnormalities of their kidneys/urinary tracts. The majority of children with hydronephrosis (63%) had isolated upper tract dilation without any additional diagnoses. Boys were significantly more likely to be diagnosed with a genital abnormality than girls (7.7 vs. 0.5%, p < 0.001). Of the 649 boys in the entire cohort, 24 (3.7%) had cryptorchidism and 24 (3.7%) had hypospadias, which was noted to be mild in all except one boy. Overall, findings of hydronephrosis, unilateral renal agenesis, and multicystic dysplastic kidney occur at higher rates than expected in the general population. Given these findings, in addition to routine physical examination, we believe that all patients with 22q11.2DS warrant screening RBUS at time of diagnosis.     

Under-recognition of 22q11.2 deletion in adult Chinese patients with conotruncal anomalies: Implications in transitional care

22q11.2 deletion syndrome (22q11.2DS) is a multi-systemic disorder with high phenotypic variability. Under-diagnosis in adults is common and recognition of facial dysmorphic features can be affected by age and ethnicity. This study aims to determine the prevalence of undiagnosed 22q11.2DS in adult Chinese patients with conotruncal anomalies and to delineate their facial dysmorphisms and extra-cardiac manifestations. We recruited consecutively 156 patients with conotruncal anomalies in an adult congenital heart disease (CHD) clinic in Hong Kong and screened for 22q11.2DS using fluorescence-PCR and fluorescence in-situ hybridization. Assessment for dysmorphic features was performed by a cardiologist at initial screening and then by a clinical geneticist upon result disclosure. Clinical photographs were taken and childhood photographs collected. Eighteen patients (11.5%) were diagnosed with 22q11.2DS, translating into 1 previously unrecognized diagnosis of 22q11.2DS in every 10 adult patients with conotruncal anomalies. While dysmorphic features were detected by our clinical geneticist in all patients, only two-thirds were considered dysmorphic by our cardiologist upon first assessment. Evolution of facial dysmorphic features was noted with age. Extra-cardiac manifestations included velopharyngeal incompetence or cleft palate (44%), hypocalcemia (39%), neurodevelopmental anomalies (33%), thrombocytopenia (28%), psychiatric disorders (17%), epilepsy (17%) and hearing loss (17%). We conclude that under-diagnosis of 22q11.2DS in Chinese adults with conotruncal defects is common and facial dysmorphic features may not be reliably recognized in the setting of adult CHD clinic, referral for genetic evaluation and molecular testing for 22q11.2DS should be offered to patients with conotruncal defects.     

Molecular characterization of 22q11 deletion in a three‐generation family with maternal transmission

Haploinsufficiency of chromosome 22q11.2 is a well‐established cause of both the DiGeorge anomaly and the velocardiofacial syndrome. This condition shows a continuous spectrum of phenotypic manifestations with a considerable inter‐ and intrafamilial variability. We report on a three‐generation family with four members sharing the same 3 Mb long deletion but showing different phenotypic expression. In the first generation, the deleted patient has hypernasal speech and suffers from recurrent psychotic episodes. Two of her offspring inherited the deletion. One of these, a male, has hypernasal speech, low‐set ears, hypocalcemia, severe development delay, and tetralogy of Fallot. The other, a female, has hypernasal speech, minor facial anomalies, and very mild mental retardation. Her daughter has tetralogy of Fallot, velopharyngeal insufficiency, and mild facial anomalies. This family is an example of the widely variable phenotypic expressivity of the 22q11.2 deletion. There is no correlation between the size of the deletion and the phenotypic manifestations. Genetic background and/or environmental factors could explain the different phenotypes observed in the affected members of the family. © 2002 Wiley‐Liss, Inc.     

Familial 22q11.2 duplication: a three-generation family with a 3-Mb duplication and a familial 1.5-Mb duplication

We report two familial cases of 22q11.2 duplication detected using multiplex ligation-dependent probe amplification (MLPA). In the first case, eight individuals from a three-generation family were found to carry a 3-Mb 22q11.2 duplication. The individuals carrying the duplication show phenotypic variation. This phenotypic variation includes heart defect (1 in 8 individuals, 1/8), submucous cleft palate (2/8), intellectual disability (2/8), speech delay (2/8), behaviour problems (3/8) and brachydactyly (3/8). In the second case, a 1.5-Mb 22q11.2 duplication was detected in a neonate and her normal mother. The neonate presented with severe laryngomalacia causing intermittent stridor. Cranial ultrasound showed small subependymal cysts bilaterally. There was no heart defect or cleft palate, her chest X ray and renal ultrasound were normal. Review at 2 months of age revealed normal growth and development. Our findings broaden the understanding of 22q11.2 duplication syndrome and demonstrate that MLPA is sensitive for detection and sizing of 22q11.2 microduplications.