22q11.2 deletion syndrome
One of the most common genetic disorders causing learning disabilities and mild intellectual disability is 22q11.2 deletion syndrome (22q11.2 DS). It is now recognized that 22q11.2 DS encompasses the phenotypes previously described as DiGeorge syndrome (DGS), velocardiofacial syndrome (VCFS), conotruncal anomaly face syndrome (CTAF), some cases of autosomal dominant Opitz G/BBB syndrome, and Cayler cardiofacial syndrome (asymmetric crying facies) (GeneReviews). 22q11.22 DS is an autosomal dominant contiguous gene deletion syndrome. The overall live birth prevalence of 22q11.2 deletions appears to be approximately 1 in 3,000-6,000, with 75% of these patients having cardiac abnormalities, which represents the major cause of mortality in 22q11.2 DS. Furthermore, immunodeficiency is frequent (~75%), hypocalcemia due to hypoparathyroidism (~50% of patients) and other developmental deficiencies such as, facial dysmorphia, palatal dysfunction, and feeding difficulties are also seen in most infants with this syndrome (McDonald-McGinn et al. 2015). Presently, it is well established that 22q11.2 DS involves microdeletions of approximately 0.7–3 million base pairs in size. The chromosome 22q11.21 region contains a cluster of low copy repeats (LCRs) of high‑homology sequences, labelled A–H (LCRs A–H). These LCRs can mediate nonallelic homologous meiotic recombination leading to recurrent copy number variations with a resulting deletion or duplication of variable segments within this chromosomal region. LCR22A and LCR22D flank the most common 2.54-Mb deletion found in ~85% of patients. Two other deletions, the proximal nested 1.5-Mb (LCR22A–LCR22B) and 2-Mb (LCR22A–LCR22C), have a combined frequency 10-15% of all 22q11.2 deletions. The distal nested (LCR22B–LCR22D and LCR22C–LCR22D) and the other more distal deletions flanked by LCRs C–E; D–E; D–F; E–F; F–G are rare and in combination only explain a few percent (~2%) of cases. According to GeneReviews, 93% of all 22q11.2 DS cases occur de novo. There have been reports of asymptomatic individuals bearing central 22q11.2 deletions (Rump et al. 2014) and it is generally accepted that nested deletions in 22q11.2 are associated with reduced penetrance.
22q11.2 duplication syndrome
22q11.2 duplication syndrome (22q11.2 DupS) is a condition caused by an extra copy of a piece of chromosome 22 (~3 Mb) which contains about 30 to 40 genes. The features of this condition vary widely, even among members of the same family (intrafamilial variability). Affected individuals may have intellectual or learning disabilities, developmental delay (the two latter overlapping with 22q11.2 DS), slow growth leading to short stature, and weak muscle tone (hypotonia). Many people with the condition do not present any clinical manifestations. It is inherited in an autosomal dominant manner. 22q11.2 DupS is much rarer than 22q11.2 DS, and currently the prevalence remains undetermined. Estimation of prevalence is difficult due to the variable phenotype of the disease and the prevalence of asymptomatic patients (Draaken et al. 2010, Sedghi et al. 2015). Due to the limitations of detection techniques used in the past, duplications have been hard to identify (Lundin et al. 2010), and no established clinical image currently exists. The TBX1 gene is nonetheless generally seen as causative (Guo et al. 2017, Xu et al. 2011).
Cat eye syndrome
Cat eye syndrome (CES) presents wide clinical variability, but classic symptoms associated with the disease are ocular coloboma, anal atresia, down slanting palpebral fissures, preauricular tags and/or pits, frequent occurrence of heart and renal malformations. In general, the abnormalities associated with CES tend to involve the eyes, ears, anal region, heart, and/or kidneys, but other organs may be affected in individuals also presenting intellectual disability (thus overlapping with clinical features of 22q11.2 DS). Most CES cases are not inherited. The syndrome is very rare, and currently there are no accurate estimates of the incidence of CES in the population. The diagnosis of CES is based on the presence of extra copy of 22q11.2 which typically presents as a small extra chromosome, frequently having two centromeres. Disease management is directed toward the specific symptoms that are apparent in each individual. The treatment of CES may require the coordinated efforts of a team of medical professionals, such as pediatricians, surgeons, heart specialists (cardiologists), specialists of the digestive tract, eye specialists; health professionals who detect, evaluate, and help to manage hearing problems; physicians who diagnose and treat disorders of the skeleton, muscles, joints, and related tissues (orthopedists); and/or other health care professionals (OMIM).
8p23 deletion syndrome, DiGeorge syndrome/velocardiofacial syndrome complex 2, and HDR
There are several reports of patients presenting clinical manifestations of 22q11.2 DS in which distinct genetic aberrations are identified. Rather than the typical 22q11.2 deletion, these patients present deletions in regions 8p23 (Devriendt et al. 1999, Kumar et al. 2018, Páez et al. 2008, Wat et al. 2009) or 10p14 (Lichtner et al. 2000, Villanueva et al. 2002, Yatsenko et al. 2004), amongst others. In these rare cases, the syndrome by which the patients are affected is usually given a name eponymous to the region affected and the observed aberration type (yielding for example 8p23 duplication syndrome).
In the particular case of 10p deletion syndrome, there are different denominations which are used depending on the location affected within this region. Haploinsufficiency of the more proximal region of 10p13-10p14 (mainly affecting CUGBP2, also deletions involving GATA3, NEBL), which has been reported in a limited number of cases, is referred to as DiGeorge syndrome/velocardiofacial syndrome complex 2 (commonly referred to as DGS2). For deletions affecting the more distal region of 10p14-10pter that result in a hemizygosity of GATA3, the term hypoparathyroidism, sensorineural deafness and renal dysplasia (HDR) is used.
Nomenclature distinctions
DGS is among the syndromes which now fall under the umbrella term 22q11.2 DS. The main clinical manifestations of DGS are currently recognised as cardiac anomalies, hypoparathyroidism, and immunodeficiency, and the syndrome has over 180 features for which no single manifestation occurs in 100% of cases. As DGS and other related diseases such as VCFS, CTAF, some cases of autosomal dominant Opitz G/BBB syndrome, and Cayler cardiofacial syndrome (asymmetric crying facies) were previously used to describe variable clinical expressions of the same entity, and the association between deletions in 22q11.2 and this phenotypic spectrum strengthened, the term 22q11.2 DS became more commonly used in a clinical setting (Corsten-Janssen et al. 2013, Kozlova et al. 2014). For DGS, this grouping is somewhat limiting, as there are other regions which have been shown to be associated with the disease. In an effort to be as systematic and precise as possible, it is now recommended that patients with the classic chromosome 22q11.2 deletion be described according to their genetic nomenclature (Cillo et al. 2024, McDonald-McGinn et al. 2015). In this sense, such individuals would be referred to as 22q11.2 DS patients. Patients presenting a clinical phenotype without identifiable genetic origin, or one which differs from a 22q11.2 deletion are to be described using syndromic nomenclature. Such patients would therefore be characterised as having DGS. In practice, however, the terms DGS and 22q11.2 DS are used interchangeably.
All documentation related to SALSA MLPA Probemix P250 DiGeorge includes nomenclature usage as described in GeneReviews.
