Figure 2 - uploaded by Verayuth Praphanphoj
Content may be subject to copyright.
Partial karyotype of the patient's mother with ideograms. Left: der (19) and normal 19; right: der(22) and normal 22.
Source publication
Cryptic subtelomeric rearrangements are suspected to underlie a substantial portion of terminal chromosomal deletions. We have previously described two children, one with an unbalanced subtelomeric rearrangement resulting in deletion of 22q13-->qter and duplication of 1qter, and a second with an apparently simple 22q13-->qter deletion. We have exam...
Context in source publication
Context 1
... resolution G band analysis of the mater- nal chromosomes indicated the presence of a subtle 19qter and 22qter translocation (46,XX,t(19;22)(q13.42;q13.31)) (fig 2). This was confirmed by FISH studies using the 19qtel specific probe (D19S238E) and the 22q specific probe (ARSA) (not shown). ...
Citations
... Results of the remaining 28 patients with a parental translocation are summarized in Table 2. (For de novo translocations and their references, see Supplement 2). Of these 28 inherited translocations, thirteen were maternal, seven were paternal, and for the remaining eight, the sex of the carrier parent remained unclear [6,7,[12][13][14][17][18][19][20][21][22][23][24][25][26]. Chromosomes involved in the inherited translocations were 1 (n=2), 3 (n=9), 8 (n=1), 10 (n=2), 11 (n=2), 12 (n=3), 13 (n=1), 14 (n=2), 16 (n=1), 17 (n=2), 19 (n=2), and 20 (n=1). ...
... Her mother carried a translocation (19;22)(q13.42;q13.31), which is similar to our finding in the present study, although they did not carry out an array CGH analysis (Praphanphoj et al., 2000). Other chromosomal translocations associated with 22q13.3 ...
... Other chromosomal translocations associated with 22q13.3 deletion syndrome have been reported before, including t(6;22)(p25; q13) (Praphanphoj et al., 2000) and t(1;22)(q44;q13.32) (Doheny et al., 1997), indicating that subtelomeric rearrangement is an important mechanism contributing toward the 22q13.3 ...
Objectives:
Chromosome 22q13 is a hot region of genomic rearrangements that may result in deletion, duplication, and translocation, and that may lead to neurodevelopmental disorders in affected patients.
Materials and methods:
We carried out an array-based comparative genomic hybridization analysis to detect copy number variations (CNVs) of genomic DNA in patients with autism spectrum disorders (ASD) who were consecutively recruited into our molecular genetic study of ASD. Karyotyping, fluorescent in-situ hybridization analysis, and real time-quantitative PCR were used for validation tests.
Results:
We completed a genome-wide CNV analysis of 335 patients with ASD from Taiwan. Three unrelated male patients were found to carry three different CNVs at 22q13.3, respectively, including a de novo terminal deletion of ∼106 kb at 22q13.33, a de novo interstitial duplication of ∼1.8 Mb at 22q13.32-q13.33, and a microdeletion of ∼147 kb at 22q13.33. These three CNVs all involved the dosage change of the SHANK3 gene. The last patient also carried a genomic duplication of ∼3.86 Mb at 19q13.42-q13.4 in addition to a microdeletion of ∼147 kb at 22q13.33. His younger sister also carried these two CNVs, but she had developmental delay and other neurological deficits without ASD. These two CNVs were transmitted from their unaffected father, who carried a balanced translocation between chromosome 22q and 19q.
Conclusion:
Our data support that recurrent genomic rearrangements at 22q13.3 are part of the genetic landscape of ASD in our patients and changes in SHANK3 dosage are associated with neurodevelopmental disorders. However, the clinical symptoms of patients with 22q13.3 rearrangements can vary depending on other genetic and nongenetic factors, not limited to genes involved in CNVs in this region.
... : Petek et al. 2001;Aglan et al. 2002;Carer et al. 2010 ;van Bon et al. 2010. [8] : Praphanphoj et al. 2000;De Vries BB et al. 2000;Bonaglia et al. 2001;Phelan et al. 2001 ;Anderlid et al. 2002b;Wilson et al. 2003;Manning et al. 2004;Koolen et al. 2005;Lindquist et al. 2005;Bonaglia et al. 2006;Cusmano-Ozog et al. 2007;Durand et al. 2007;Philippe et al. 2008;Wilson et al. 2008;Delahaye et al. 2009 ;Sykes et al. 2009;Chen et al. 2010;Dhar et al. 2010; Phelan and Betancur 2011. [5] P6 CF in monosomy 10q26 [6] P7 CF in trisomy 10q26 [7] P8 CF in monosomy 22q13 [8] P9 Cranio-facial dismorphism Cranio-facial dismorphism Cranio-facial dismorphism Cranio-facial dismorphism intellectual disability associated with dysmorphism and malformations (incidence: 4.1%) (Baker et al. 2002). ...
... Cranio-facial dismorphism was characterized by epicanthal folds, large ears, pointed chin and a dolichocephaly, ptosis and limb abnormalities. This syndrome was usually associated with brain and heart congenital malformations may also be present in this deletion (Praphanphoj et al. 2000;De Vries BB et al. 2000;Bonaglia et al. 2001;Phelan et al. 2001 ;Anderlid et al. 2002b;Wilson et al. 2003;Manning et al. 2004;Koolen et al. 2005;Lindquist et al. 2005;Bonaglia et al. 2006;Cusmano-Ozog et al. 2007;Durand et al. 2007;Philippe et al. 2008;Wilson et al. 2008;Delahaye et al. 2009 ;Sykes et al. 2009;Chen et al. 2010;Dhar et al. 2010;Betancur 2011Knight et al. 2000) ( Table 2). The patient (P9) in our series showed major signs described above, including hypotonia, autism and the lack of language. ...
ABSTRACT With the development of molecular cytogenetic techniques, it is possible to identify cryptic rearrangements involving the end of chromosomes. Subtelomeric chromosomal rearrangements represent a significant cause of idiopathic intellectual disability accounting for 6-10% of moderate to severe cases and 0.5% in individuals with mild intellectual disability. We investigated 50 patients with severe intellectual disability combined with a dysmorphic features and normal 400-550 band karyotype for unbalanced subtelomeric rearrangements by using fluorescence in situ hybridization with probes mapping to forty one telomeric-specific regions. Nine positive cases (18%) were found. Six were de novo deletions (1p, 2q, 6p, 9q, 10q, 22q) and one wasis de novo duplication (10q) .Two unbalanced translocation (a der(3)t(3p; 2q) and a der(3)t(3p; Xq)) were inherited from the balanced mothers. Our study supportsed the hypothesis that subtelomeric rearrangements are a significant cause of idiopathic intellectual disability. The clinical features of patients with subtelomeric abnormalities and the candidate genes proposed inside each region will help to better delineate the phenotype- genotype correlation.
... ? qter has been reported in 23 cases of trisomy, 8 of which are pure 19q trisomies (Schmid, 1979;Boyd et al., 1992;Bhat et al., 2000;Dorn et al., 2001;Rombout et al., 2004;Ravnan et al., 2006;DeScipio et al., 2008), whereas 15 are combined with other rearrangements involving chromosomes 6, 7, 9, 10, 12, 17, 14, 19, and 22 (Zonana et al., 1982;James et al., 1996;Praphanphoj et al., 2000;Su et al., 2005;Ravnan et al., 2006;Sauter et al., 2007;DeScipio et al., 2008). ...
The role of cryptic translocations in human syndromes is a matter of fact, though this phenomenon is apparently rare. Apart from episodic case reports due to the increasing application of new molecular cytogenetic techniques, no data on its frequency in the general population are currently available. Rearrangements due to the unbalanced segregation of cryptic translocations are found in many anomalies responsible for different clinical pictures. In nearly 50% of cases, subtelomeric abnormalities are inherited from a parent carrying a balanced cryptic chromosome rearrangement. To date, very few cases of partial trisomies of 19q have been reported, with different breakpoints. Involvement of the distal region 19q is even more rare, and the delineation of its main clinical characteristics is still vague and awaiting better definition. We report two new cases of partial 19q13.42-qter trisomy associated with a partial 20p13-pter monosomy in a family found to have the cryptic translocation t(19;20)(q13.42;p13). We investigated a 5-year-old boy and his 49-year-old paternal uncle, and both had a similar, previously unrecognized mental retardation pattern, associated with the same subtelomeric rearrangement.
... Behavioural characteristics include autistic-like features such as poor eye contact, stereotypic movements, decreased socialization, chewing/mouthing of non-food items, and aggressive behaviour [2,3]. Recent studies have suggested that an alteration of SHANK3/PROSAP2 is responsible for the clinical findings in this deletion syndrome [4]. We report the case of a female with de novo microduplication of 1 Mb in 22q13.33 bands and microdeletion involving the last 600 kb of chromosome 22 (checked by array-CGH and confirmed by FISH), with an unbalance in the SHANK3/PROSAP2 gene. ...
We describe a 18-year-old female with 22q13.3 deletion syndrome characterized by an alteration of SHANK3/PROSAP2 and severe mental retardation, intense psychomotor agitation and aggressive behaviour. When the patient was given risperidone, different therapeutic results were observed: at a 6 mg dose, risperidone had no therapeutic effect and the patient's behavioural problems increased; at a low dose (1mg), risperidone treatment resulted in rapid improvement of mood and behaviour. Recent findings suggest that risperidone exerts dose-dependent effects on Glu receptors in developing rats. An altered preset of the glutamate receptors, due to the presence of a haploinsufficiency of SHANK3/PROSAP2, could explain the different results of risperidone therapy observed in our patient with 22q13.3 deletion syndrome.
... Subsequently, a number of case reports and small series of affected patients further delineated a recognizable del 22q13.3 syndrome [Doheny et al., 1997;Slavotinek et al., 1997;Fujita et al., 2000;Praphanphoj et al., 2000;Prasad et al., 2000;Anderlid et al., 2002;Barakat et al., 2004;Lindquist et al., 2005;Tabolacci et al., 2005;Babineau et al., 2006]. In addition, several larger series of affected individuals have delineated a widely variable disorder in which normal to accelerated growth, hypotonia and marked speech and language impairment are the most reproducible features. ...
The 22q13.3 deletion syndrome is a recognizable malformation syndrome associated with developmental delay, hypotonia, delayed or absent speech, autistic-like behavior, normal to accelerated growth and dysmorphic facies. The prevalence of this disorder is unknown, but it is likely under-diagnosed. Age at diagnosis has varied widely, from cases diagnosed prenatally to 46 years. Males and females are equally affected. The distal 22q deletion can be detected occasionally by routine or high resolution chromosome analysis; however, the majority of cases are detected by FISH analysis, associated with deletion of the ARSA (control) probe when performing a FISH analysis for the velocardiofacial syndrome (del 22q11.2). The 22q13.3 deletion syndrome can accompany a simple chromosome deletion, an unbalanced translocation, or a ring chromosome. Primary care physicians, in addition to numerous specialists, play an important role in caring for patients with this disorder. Although the dysmorphic features observed in this condition are nonspecific, it is an important consideration in the differential diagnosis of children with developmental delay, hypotonia, marked speech and language disability, autistic-like features, multiple minor anomalies, and normal growth and head circumference.
... It is coded by 22 exons. Bonaglia et al 33 described a patient with severe expressive language delay, mild MR, minor facial dysmorphisms, hypotonia, joint laxity, and dolichocephaly in which the breakpoints of a de novo balanced translocation (46,XY,t[12,22][q24.1;q13.3]) interrupted the ProSAP2 gene within exon 21. ...
Cryptic subtelomeric chromosome rearrangements account for 6% to 10% of idiopathic mental retardation. As cytogenetic and molecular techniques have become more sophisticated, the number of genetic syndromes attributed to these microdeletions has increased. To date, 64 patients have been described in the literature with a more recently recognized microdeletion syndrome, del 22q13.3. The purpose of this study is to present 11 new cases of this recently described syndrome to delineate further the phenotype and to alert the clinician to another genetic condition that should be considered in the differential diagnosis of early hypotonia, delayed speech acquisition, and autistic behavior.
Eleven patients were evaluated in 3 academic institutions. Clinical features and results of cytogenetic testing were recorded and tabulated. Reasons for referral for genetic evaluation included developmental delay, severe expressive speech and language delay, and dysmorphic features.
Age of presentation ranged from 5 months to 46 years. There were 10 female patients and 1 male patient. All of the patients exhibited delayed motor development, some degree of hypotonia, and severe expressive speech and language delay. Dysmorphic facial features included epicanthal folds, large cupped ears, underdeveloped philtrum, loss of cupid's bow, and full supraorbital ridges. Six patients exhibited autistic-like behaviors. Microscopically visible chromosome deletions were observed in 6 patients. In the remainder, the deletion was detected with the use of fluorescence in situ hybridization.
Hypotonia and developmental delay are nonspecific findings observed in many malformation and genetic syndromes. However, in association with severe speech and language delay and autistic-like behavior, this phenotype may be a significant indication to consider the 22q13 deletion syndrome as a potential cause.
... There is anecdotal evidence that there is an increased occurrence of arachnoid cysts in children with 22q13 deletion. Although only 1 case has been reported in the literature, 31 parents have reported 2 more cases. Arachnoid cysts are quite rare and account for only 1% of intracranial space occupying lesions; hence, these unpublished cases may represent an increased incidence among children with 22q13 deletion. ...
... Findings noted in 19 patients with brain imaging have revealed the following: normal (8/19), mild dilation of the cerebral ventricles (5/19), delayed mylenation (3/19), and decreased periventricular white matter (2/19). Also described are arachnoid cyst, 31 frontal lobe hypoplasia, and frontotemporal hypoplasia. 26 ...
Recent advances in genetic testing can help to provide a specific diagnosis to children born with syndromes that result in congenital anomalies and developmental delay. One such emerging condition is the 22q13 deletion syndrome. With the introduction of subtelomeric fluorescence-in-situ hybridization (FISH) analysis, the 22q13 deletion has become recognized as a relatively widespread and underdiagnosed cause of mental retardation. Primary-care physicians play an important role in the care of children with 22q13 deletion syndrome, from suspecting the diagnosis in a developmentally delayed child through the medical, developmental, and behavioral aspects of their care. Furthermore, they serve as a valuable source of support and advocacy for the family and a resource for other care providers. The remainder of this article addresses the current state of knowledge regarding 22q13 deletion syndrome and offers the primary-care physician a framework in which to provide care and information.
... 4 11 Their presence has also been reported in patients with 18p−, 18q−, 22q−, and 1p− deletion syndromes. [12][13][14][15][16][17][18][19][20][21][22][23][24][25] These observations suggest that the telomeric regions of chromosomes might be more prone to cryptic rearrangements and thus might be responsible for mental retardation. As telomeric regions of chromosomes have the highest gene concentration in the human genome, rearrangements involving these regions may have severe phenotypic consequences. ...
Mental retardation (MR), defined as an intelligence quotient (IQ) of less than 70, affects 2-3% of the population and its aetiology and pathogenesis are still poorly understood. The aetiology can be established in only ¬64% of cases with moderate to profound MR and in ¬24% of cases with mild MR.1 Available data indicate that chromosome aberrations are found in 4-28% of affected subjects. However, the yield of these abnormalities is increased when the severity of mental retardation and the presence of congenital anomalies are taken into account.
In the past decade, molecular-cytogenetic methods have documented a number of submicroscopic chromosomal rearrangements involving telomeric regions of chromosomes. They have been implicated in α thalassaemia with MR,2–4 Wolf-Hirschhorn syndrome,4–8, cri du chat syndrome,4,9,10 and Miller-Dieker syndrome.4,11 Their presence has also been reported in patients with 18p−, 18q−, 22q−, and 1p− deletion syndromes.12–25 These observations suggest that the telomeric regions of chromosomes might be more prone to cryptic rearrangements and thus might be responsible for mental retardation. As telomeric regions of chromosomes have the highest gene concentration in the human genome, rearrangements involving these regions may have severe phenotypic consequences. Moreover, the molecular structure of telomeric regions and high frequency of recombination are predisposing factors to the occurrence of such rearrangements.26,27
At present, there is still no single, useful cytogenetic method for screening the entire genome, regardless of the size of suspected chromosomal abnormality. Classical cytogenetic analysis, even with the use of high resolution banding, enables the detection of abnormalities > 3-10 Mb in size. Thus, the resolution of the method is not sensitive enough to identify subtle submicroscopic rearrangements. They are not detected by G banding not only because of their small size but also because of …
... Some were detected while screening for cryptic subtelomeric rearrangements in patients with mental retardation (Knight and Flint 1999). Others (with a generic "chromosomal phenotype") were detected during exclusion of a deletion at the diGeorge/ velocardiofacial region (Goizet et al. 2000;Praphanphoj et al. 2000;Prasad et al. 2000). In fact, commercially available diGeorge probes include 22q distal probes as a control. ...
... In these subjects, expressive language is either absent or severely delayed. Less frequently described traits include epicanthic folds, bulbous nose, dysplastic ears, dolichocephaly, hypotonia, joint laxity, and autism (Goizet et al. 2000;Praphanphoj et al. 2000;Prasad et al. 2000). Although these symptoms are somewhat unspecific, it has been suggested that their association with delayed speech and mild mental retardation should prompt clinicians to search for a 22q distal deletion. ...
The terminal 22q13.3 deletion syndrome is characterized by severe expressive-language delay, mild mental retardation, hypotonia, joint laxity, dolichocephaly, and minor facial dysmorphisms. We identified a child with all the features of 22q13.3 deletion syndrome. The patient's karyotype showed a de novo balanced translocation between chromosomes 12 and 22, with the breakpoint in the 22q13.3 critical region of the 22q distal deletion syndrome [46, XY, t(12;22)(q24.1;q13.3)]. FISH investigations revealed that the translocation was reciprocal, with the chromosome 22 breakpoint within the 22q subtelomeric cosmid 106G1220 and the chromosome 12q breakpoint near STS D12S317. Using Southern blot analysis and inverse PCR, we located the chromosome 12 breakpoint in an intron of the FLJ10659 gene and located the chromosome 22 breakpoint within exon 21 of the human homologue of the ProSAP2 gene. Short homologous sequences (5-bp, CTG[C/A]C) were found at the breakpoint on both derivative chromosomes. The translocation does not lead to the loss of any portion of DNA. Northern blot analysis of human tissues, using the rat ProSAP2 cDNA, showed that full-length transcripts were found only in the cerebral cortex and the cerebellum. The FLJ10659 gene is expressed in various tissues and does not show tissue-specific isoforms. The finding that ProSAP2 is included in the critical region of the 22q deletion syndrome and that our proband displays all signs and symptoms of the syndrome suggests that ProSAP2 haploinsufficiency is the cause of the 22q13.3 deletion syndrome. ProSAP2 is a good candidate for this syndrome, because it is preferentially expressed in the cerebral cortex and the cerebellum and encodes a scaffold protein involved in the postsynaptic density of excitatory synapses.
