Microdeletions within 22q11 associated with sporadic and familial DiGeorge syndrome

doi:10.1016/0888-7543(91)90501-5

Genomics

Volume 10, Issue 1, May 1991, Pages 201-206

https://doi.org/10.1016/0888-7543(91)90501-5 Get rights and content

Abstract

DiGeorge syndrome (DGS) is a developmental field defect of the third and fourth pharyngeal pouches. It is associated wit with deletion of 22q11 in 11% of cases. Molecular genetic analysis with probes from 22q11-pter reveals that a subset of markers is hemizygous in DGS patients with normal karyotypes. There is no apparent difference in the phenotype or the severity of the disorder between patients with the smallest detectable submicroscopic deletion and those with the largest cytogenetically visible abnormality. A microdeletion was found in a mildly affected child and in the severely affected child of a mildly affected father. Dysmorphology, especially cardiac outflow tract anomalies, resulting from 22q11 deletion may be more common than currently realized since chromosomes are unlikely to be checked if the complete spectrum of DGS is not present. Antenatal diagnosis, through detection of hemizygosity at 22q11, will be a possibility for mildly affected parents unwilling to risk the birth of a severely affected child.

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Cited by (211)

22q11.2 deletion syndrome: Setting the stage
2022, The Chromosome 22q11.2 Deletion Syndrome: A Multidisciplinary Approach to Diagnosis and Treatment
The chromosome 22q11.2 deletion syndrome (22q11.2DS) is the most common microdeletion thought to result from de novo nonallelic homologous meiotic recombination events in the majority of affected individuals, resulting in loss of ~ 50 genes in this ~ 2.5 Mb hemizygous deletion, occurring in approximately 1 in 1000 fetuses and 1 in 2000–6000 live births, and leading to significant morbidity and some mortality. The first description in the English language of the constellation of findings now known to be due to this chromosomal difference was made in the mid-1960s in children with DiGeorge syndrome (DGS), who presented with the clinical triad of immunodeficiency, hypoparathyroidism, and congenital heart disease. 22q11.2DS is now known to have a heterogeneous presentation that includes multiple additional congenital anomalies and later-onset conditions such as palatal, gastrointestinal, renal, and skeletal anomalies, autoimmune disease, variable cognitive delays, behavioral differences, and psychiatric illness—all far extending the original description of DGS. Management requires a multidisciplinary approach involving pediatrics, general medicine, surgery, psychiatry, psychology, radiology, pathology, interventional therapies (physical, occupational, speech, language, educational, and behavioral), and genetic counseling. Although common, lack of recognition of the condition and/or lack of familiarity with genetic testing methods, together with the wide variability of clinical presentations, often delays diagnosis. Early identification, preferably prenatally or neonatally, could improve outcomes, thus underscoring the importance of enhanced ascertainment, perhaps by way of newborn screening. Equally important, 22q11.2DS has become a model for understanding rare and frequent congenital anomalies and medical conditions including psychiatric and developmental differences, which could well provide the chance to better understand these distinct conditions while affording opportunities for translational strategies across the lifespan for both patients with 22q11.2DS and individuals with these associated features in the general population.
Prenatal diagnosis of familial 22q11.2 deletion syndrome in a pregnancy with concomitant cardiac and urinary tract abnormalities in the fetus and the mother
2021, Taiwanese Journal of Obstetrics and Gynecology
Citation Excerpt :
In that case, prenatal ultrasound showed tetralogy of Fallot (TOF) and thymic hypoplasia in the fetus. Fluorescence in situ hybridization (FISH) analysis on metaphase amniocytes showed the result of mos 46,XY.ish del(22)(q11.2q11.2)(D22S553-) [5]/46,XY.ish 22q11.2 (D22S553 × 2) [1] and a ratio of 61 (del.22q11.2)/39 (normal) in 100 interphase amniocytes. After birth, the neonate postnatally manifested hypocalcemia, hypoplasia of the thymus, overriding of the aorta, a large VSD, a small ASD, PDA and hypoplastic pulmonary arteries.
We present prenatal diagnosis of familial 22q11.2 deletion syndrome in a pregnancy with concomitant cardiac and urinary tract abnormalities in the fetus and the mother.
A 28-year-old woman primigravid underwent amniocentesis at 23 weeks of gestation because of fetal ultrasound findings of aortic stenosis, interrupted aortic arch (IAA), left multicystic kidney, right hydronephrosis and ureterocele. Amniocentesis revealed a karyotype of 46,XX. Simultaneous array comparative genomic hybridization (aCGH) analysis on the DNA extracted from uncultured amniocytes revealed the result of arr 22q11.21 (18,894,835-21,505,417) × 1.0 [GRCh37 (hg19)] with a 2.611-Mb 22q11.21 deletion encompassing 41 Online Mendelian Inheritance in Man (OMIM) genes including UFD1L, TBX1, GNB1L, COMT and MED15. aCGH analysis on the DNAs extracted from parental bloods confirmed that the mother carried the same 22q11.21 microdeletion. Level II ultrasound additionally found ventricular septal defect (VSD) and persistent left superior vena cava (PLSVC). Examination of the woman showed short stature, malar hypoplasia, hypertelorism, bulbous nasal tip, prominent nasal root, hypoplasia of nasal wings, right renal agenesis, left ureterovesical reflux and VSD with repair, but normal intelligence and normal neuropsychiatric development. The woman decided to continue the pregnancy, and a 2903-g female baby was delivered at 38 weeks of gestation with left multicystic kidney, right hydronephrosis, dysgenesis of corpus callosum, IAA, VSD, PLSVC, patent ductus arteriosus, patent foramen ovale, atrial septal defect, dilated main pulmonary artery and tricuspid regurgitation. The neonate died at the age of one month.
Prenatal diagnosis of concomitant congenital heart defects and urinary tract abnormalities in the fetus and the parent should raise a suspicion of familial 22q11.2 deletion syndrome.
Child psychiatry interventions in patients with 22q11 deletion syndrome: From treatment to prevention
2019, Encephale
Le syndrome microdélétionnel 22q11.2 (22q11.2DS) est l’un des syndromes génétiques le plus fréquemment associé aux troubles psychiatriques, dans l’enfance et à l’âge adulte. Son association à un risque accru de développer une schizophrénie est connue depuis plusieurs années. Le repérage de prodromes dans l’enfance ou au début de l’adolescence, afin de prévenir ces évolutions péjoratives, suppose de bien connaître la clinique pédopsychiatrique associée à ce syndrome. Dans cet article, nous proposons une revue de la littérature concernant le 22q11DS, en ciblant plus particulièrement les manifestations pédopsychiatriques et les facteurs de risque associés à une transition vers la psychose. Nous présentons l’intérêt d’une consultation pédopsychiatrique spécialisée systématique s’inscrivant dans un réseau associant généticiens, pédopsychiatres, psychiatres d’adultes et associations de parents, pour l’amélioration du parcours de soins de ces patients, la prévention et la recherche.
22q11.2DS is one of the more frequent genetic syndromes associated to psychiatric symptoms. It has been associated to an increased risk to develop schizophrenia in adolescence or early adulthood. However, psychiatric symptoms appear early on, and should be recognized as soon as possible by child psychiatrists in order to improve the present well-being of children and their family, and to prevent further risks of developing severe and chronic psychiatric diseases later on. In this paper, we present a review of the recent literature concerning the 22q11.2DS syndrome focused on the risk factors that may be associated to an increased risk of psychotic transition. We advocate for the development of systematic specialized child psychiatry consultations for these patients, included in networks with geneticists, adult psychiatrists, and family associations, in order to improve their psychiatric prognosis and to support the development of translational research.
Genetic regulation of parathyroid gland development
2019, Principles of Bone Biology
Congenital anomalies of parathyroid gland development, which lead to hypoparathyroidism, are common and occur in more than 1 in 4000 births. The four human parathyroid glands develop from transient bilateral outpocketings of the pharyngeal endoderm, which are referred to as the pharyngeal pouches. There are four pairs of pharyngeal pouches; the superior parathyroid glands develop from the fourth pharyngeal pouches, which are the most caudal, while the inferior parathyroid glands together with the thymus develop from the third pharyngeal pouches. The pharyngeal pouches together with the branchial arches and grooves form the branchial apparatus that gives rise to a number of structures that include the face, jaws, oral cavity, neck, pharynx, larynx, ear, aortic arch, tonsils, thyroid, parathyroids, thymus, ultimobranchial body that results in calcitonin-producing cells, carotid glomus, and the epibranchial placodes that contribute to the facial, glossopharyngeal, and vagus nerves. Thus, developmental abnormalities of the branchial apparatus and pharyngeal pouches may lead to hypoparathyroidism that may be part of a complex congenital defect, as for example in the DiGeorge syndrome or a solitary endocrinopathy which is called isolated or idiopathic hypoparathyroidism. In addition, hypoparathyroidism may occur in association with other developmental anomalies involving dysmorphic features, sensorineural deafness, lymphoedema, nephropathy, and growth retardation. The molecular genetic basis for such forms of hypoparathyroidism has been investigated and this has helped to elucidate further the mechanisms involved in the genetic regulation of parathyroid gland development. This chapter will focus on those forms of hypoparathyroidism that often present in early life, as these are likely to be associated with parathyroid gland agenesis or hypoplasia, or a congenital deficiency of parathyroid hormone (PTH), or an early destruction of the parathyroids. The hypoparathyroidism in these forms is characterized by hypocalcemia and hyperphosphatemia due to a deficiency in PTH secretion.
Hypoparathyroidism
2018, Genetics of Bone Biology and Skeletal Disease: Second Edition
Hypoparathyroidism is characterized by hypocalcemia and hyperphosphatemia due to a lack of parathyroid hormone (PTH) secretion or action. Hypoparathyroidism may occur as part of a pluriglandular autoimmune disorder or as a complex congenital defect, as for example in the autosomal dominant DiGeorge or hypoparathyroidism, deafness, and renal dysplasia (HDR) syndromes. In addition, hypoparathyroidism may occur as a solitary endocrinopathy and this has been called isolated or idiopathic hypoparathyroidism. Familial occurrences of isolated hypoparathyroidism with autosomal dominant, autosomal recessive, and X-linked inheritances have been established. Studies of patients with these forms of hypoparathyroidism and mouse models with parathyroid defects have elucidated important roles for: transcription factors (e.g., TBX1, GATA3, GCMB, AIRE1, and SOX3), the tubulin-specific chaperone (TBCE), and the mitochondrial genome in determining parathyroid development; the calcium-sensing receptor (CaSR) and G-protein subunit α11 in regulating extracellular calcium and PTH secretion; and PTH gene expression for synthesis and secretion of PTH. Moreover, recombinant PTH and drugs targeting the CaSR have been shown to be of benefit for the management of hypoparathyroidism.
Genetic Mechanisms Emerging from Mouse Models of CNV-Associated Neuropsychiatric Disorders
2016, The Neurobiology of Schizophrenia
Many chromosomal deletions and duplications, up to a few million base pairs, are robustly and reproducibly associated with neuropsychiatric disorders. These genomic variants, termed copy number variants (CNVs), confer unprecedented degrees of risk for schizophrenia, autism spectrum disorder, intellectual disability, and attention deficit hyperactivity disorder. These associations spurred the generation of genetic mouse models with construct validity, which in turn provided insights into the mechanisms through which CNV-encoded genes contribute to dimensional features of neuropsychiatric disorders. Evidence suggests that the ultimate phenotypic expression of a gene dose alteration within a CNV is determined by the collective action of multiple, noncontiguously located genes along predetermined developmental trajectories under the modulatory influences of genetic background and environmental factors. Mouse models of CNVs provide opportunities to better understand the genetic origin of neuropsychiatric disorders.

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¹: Current address: Green College, Oxford, UK.

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Microdeletions within 22q11 associated with sporadic and familial DiGeorge syndrome

Abstract

Int. J. Cardiol

Genomics

J. Pediatr

Anal. Biochem

J. Pediatr

Genomics

Clin. Immunol. Immunopathol

Int. J. Cardiol

J. Pediatr

DiGeorge syndrome and 22q11 rearrangements

Hum. Genet

Dependence of thymus development on derivatives of the neural crest

Science

A deletion in chromosome 22 can cause DiGeorge syndrome

Hum. Genet

Molecular cytogenetics: Toward dissection of the contiguous gene syndromes

Am. J. Hum. Genet