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1.  Clinical studies on submicroscopic subtelomeric rearrangements: a checklist 
Journal of Medical Genetics  2001;38(3):145-150.
BACKGROUND—Submicroscopic subtelomeric chromosome defects have been found in 7.4% of children with moderate to severe mental retardation and in 0.5% of children with mild retardation. Effective clinical preselection is essential because of the technical complexities and cost of screening for subtelomere deletions.
METHODS—We studied 29 patients with a known subtelomeric defect and assessed clinical variables concerning birth history, facial dysmorphism, congenital malformations, and family history. Controls were 110 children with mental retardation of unknown aetiology with normal G banded karyotype and no detectable submicroscopic subtelomeric abnormalities.
RESULTS—Prenatal onset of growth retardation was found in 37% compared to 9% of the controls (p<0.0005). A higher percentage of positive family history for mental retardation was reported in the study group than the controls (50% v 21%, p=0.002). Miscarriage(s) were observed in only 8% of the mothers of subtelomeric cases compared to 30% of controls (p=0.028) which was, however, not significant after a Bonferroni correction. Common features (>30%) among subtelomeric deletion cases were microcephaly, short stature, hypertelorism, nasal and ear anomalies, hand anomalies, and cryptorchidism. Two or more facial dysmorphic features were observed in 83% of the subtelomere patients. None of these features was significantly different from the controls. Using the results, a five item checklist was developed which allowed exclusion from further testing in 20% of the mentally retarded children (95% CI 13-28%) in our study without missing any subtelomere cases. As our control group was selected for the "chromosomal phenotype", the specificity of the checklist is likely to be higher in an unselected group of mentally retarded subjects.
CONCLUSIONS—Our results suggest that good indicators for subtelomeric defects are prenatal onset of growth retardation and a positive family history for mental retardation. These clinical criteria, in addition to features suggestive of a chromosomal phenotype, resulted in the development of a five item checklist which will improve the diagnostic pick up rate of subtelomeric defects among mentally retarded subjects.


Keywords: submicroscopic subtelomeric rearrangements; clinical preselection; checklist; chromosome deletion.
doi:10.1136/jmg.38.3.145
PMCID: PMC1734836  PMID: 11238680
2.  Identification of Chromosome Abnormalities in Subtelomeric Regions by Microarray Analysis: A Study of 5,380 Cases 
Subtelomeric imbalances are a significant cause of congenital disorders. Screening for these abnormalities has traditionally utilized GTG-banding analysis, fluorescence in situ hybridization (FISH) assays, and multiplex ligation-dependent probe amplification. Microarray-based comparative genomic hybridization (array-CGH) is a relatively new technology that can identify microscopic and submicroscopic chromosomal imbalances. It has been proposed that an array with extended coverage at subtelomeric regions could characterize subtelomeric aberrations more efficiently in a single experiment. The targeted arrays for chromosome microarray analysis (CMA), developed by Baylor College of Medicine, have on average 12 BAC/PAC clones covering 10 Mb of each of the 41 subtelomeric regions. We screened 5,380 consecutive clinical patients using CMA. The most common reasons for referral included developmental delay (DD), and/or mental retardation (MR), dysmorphic features (DF), multiple congenital anomalies (MCA), seizure disorders (SD), and autistic, or other behavioral abnormalities. We found pathogenic rearrangements at subtelomeric regions in 236 patients (4.4%). Among these patients, 103 had a deletion, 58 had a duplication, 44 had an unbalanced translocation, and 31 had a complex rearrangement. The detection rates varied among patients with a normal karyotype analysis (2.98%), with an abnormal karyotype analysis (43.4%), and with an unavailable or no karyotype analysis (3.16%). Six patients out of 278 with a prior normal subtelomere-FISH analysis showed an abnormality including an interstitial deletion, two terminal deletions, two interstitial duplications, and a terminal duplication. In conclusion, genomic imbalances at subtelomeric regions contribute significantly to congenital disorders. Targeted array-CGH with extended coverage (up to 10 Mb) of subtelomeric regions will enhance the detection of subtelomeric imbalances, especially for submicroscopic imbalances.
doi:10.1002/ajmg.a.32399
PMCID: PMC2680131  PMID: 18663743
array-CGH; subtelomere; chromosomal abnormality; FISH
3.  Screening of Subtelomeric Rearrangements in 100 Korean Pediatric Patients with Unexplained Mental Retardation and Anomalies Using Subtelomeric FISH (Fluorescence In Situ Hybridization) 
Journal of Korean Medical Science  2008;23(4):573-578.
Rearrangements of the subtelomeric regions of chromosomes account for a significant proportion of the underlying genetic defects in both idiopathic mental retardation (MR) and multiple congenital anomalies. To detect the rearrangements, a set of subtelomeric fluorescence in situ hybridization (FISH) probes has been developed. The aim of this study was to reveal the frequency of subtelomeric rearrangements in Korean patients with MR or multiple anomalies. We performed a FISH study using a commercially available subtelomeric FISH probes on a series of unrelated Korean pediatric patients with MR or multiple anomalies without identifiable causes. We used a checklist to evaluate the developmental delay and/or MR. Patients who were shown to have chromosome abnormalities, metabolic disorders, or recognizable dysmorphic syndromes by clinical and laboratory findings were excluded. As a result, 100 patients were eligible for the Subtelomeric FISH study, and a total of 29 patients (29%) were suspected to have subtelomeric rearrangements on initial screening by the multiprobe FISH kit. Among theses, confirmatory FISH studies by using single locus-specific FISH probes were performed in 24 patients. One patient (a 10-yr-old girl) was confirmed to have rearrangement, deletion of the telomeric portion of the short arm of chromosome 4 (4p). Her clinical manifestation was compatible with Wolf-Hirschhorn syndrome, which is known to be caused by 4p deletion. The frequency of subtelomeric rearrangements in this study was 1.1% (1/95), lower than those previously reported (0.5-16.3%). We suggest that subtelomeric FISH test is a useful screening tool for patients with idiopathic MR and/or dysmorphism regardless of its false positive value.
doi:10.3346/jkms.2008.23.4.573
PMCID: PMC2526410  PMID: 18756040
Chromosomal Rearrangement; Idiopathic Mental Retardation; Subtelomeric FISH
4.  High throughput screening of human subtelomeric DNA for copy number changes using multiplex amplifiable probe hybridisation (MAPH) 
Journal of Medical Genetics  2002;39(11):790-795.
Background: Subtelomeric regions of the human genome are gene rich, with a high level of sequence polymorphism. A number of clinical conditions, including learning disability, have been attributed to subtelomeric deletions or duplications, but screening for deletion in these regions using conventional cytogenetic methods and fluorescence in situ hybridisation (FISH) is laborious. Here we report that a new method, multiplex amplifiable probe hybridisation (MAPH), can be used to screen for copy number at subtelomeric regions.
Methods: We have constructed a set of MAPH probes with each subtelomeric region represented at least once, so that one gel lane can assay copy number at all chromosome ends in one person. Each probe has been sequenced and, where possible, its position relative to the telomere determined by comparison with mapped clones.
Results: The sensitivity of the probes has been characterised on a series of cytogenetically verified positive controls and 83 normal controls were used to assess the frequency of polymorphic copy number with no apparent phenotypic effect. We have also used MAPH to test a cohort of 37 people selected from males referred for fragile X syndrome testing and found six changes that were confirmed by dosage PCR.
Conclusions: MAPH can be used to screen subtelomeric regions of chromosomes for deletions and duplications before confirmation by FISH or dosage PCR. The high throughput nature of this technique allows it to be used for large scale screening of subtelomeric copy number, before confirmation by FISH. In practice, the availability of a rapid and efficient screen may allow subtelomeric analysis to be applied to a wider selection of patients than is currently possible using FISH alone.
doi:10.1136/jmg.39.11.790
PMCID: PMC1735019  PMID: 12414816
5.  Screening for subtelomeric rearrangements in 210 patients with unexplained mental retardation using multiplex ligation dependent probe amplification (MLPA) 
Journal of Medical Genetics  2004;41(12):892-899.
Background: Subtelomeric rearrangements contribute to idiopathic mental retardation and human malformations, sometimes as distinct mental retardation syndromes. However, for most subtelomeric defects a characteristic clinical phenotype remains to be elucidated.
Objective: To screen for submicroscopic subtelomeric aberrations using multiplex ligation dependent probe amplification (MLPA).
Methods: 210 individuals with unexplained mental retardation were studied. A new set of subtelomeric probes, the SALSA P036 human telomere test kit, was used.
Results: A subtelomeric aberration was identified in 14 patients (6.7%) (10 deletions and four duplications). Five deletions were de novo; four were inherited from phenotypically normal parents, suggesting that these were polymorphisms. For one deletion, DNA samples of the parents were not available. Two de novo submicroscopic duplications were detected (dup 5qter, dup 12pter), while the other duplications (dup 18qter and dup 22qter) were inherited from phenotypically similarly affected parents. All clinically relevant aberrations (de novo or inherited from similarly affected parents) occurred in patients with a clinical score of ⩾3 using an established checklist for subtelomeric rearrangements. Testing of patients with a clinical score of ⩾3 increased the diagnostic yield twofold to 12.4%. Abnormalities with clinical relevance occurred in 6.3%, 5.1%, and 1.7% of mildly, moderately, and severely retarded patients, respectively, indicating that testing for subtelomeric aberrations among mildly retarded individuals is necessary.
Conclusions: The value of MLPA is confirmed. Subtelomeric screening can be offered to all mentally retarded patients, although clinical preselection increases the percentage of chromosomal aberrations detected. Duplications may be a more common cause of mental retardation than has been appreciated.
doi:10.1136/jmg.2004.023671
PMCID: PMC1735655  PMID: 15591274
6.  Screening for submicroscopic chromosome rearrangements in children with idiopathic mental retardation using microsatellite markers for the chromosome telomeres 
Journal of Medical Genetics  1999;36(5):405-411.
Recently much attention has been given to the detection of submicroscopic chromosome rearrangements in patients with idiopathic mental retardation. We have screened 27 subjects with mental retardation and dysmorphic features for such rearrangements using a genetic marker panel screening. The screening was a pilot project using markers from the subtelomeric regions of all 41 chromosome arms. The markers were informative for monosomy in both parents at 366/902 loci (40.6%, 95% confidence interval 37.0-44.2%) in the 22 families where DNA was available from both parents. In two of the 27 subjects, submicroscopic chromosomal aberrations were detected. The first patient had a 5-6 Mb deletion of chromosome 18q and the second patient had a 4 Mb deletion of chromosome 1p. The identification of two deletions in 27 cases gave an aberration frequency of 7.5% without adjustment for marker informativeness (95% confidence interval 1-24%) and an estimated frequency of 18% if marker informativeness for monosomy was taken into account. This frequency is higher than previous estimates of the number of subtelomeric chromosome abnormalities in children with idiopathic mental retardation (5-10%) although the confidence interval is overlapping. Our study suggests that in spite of the low informativeness of this pilot screening, submicroscopic chromosome aberrations may be a common cause of dysmorphic features and mental retardation.


Keywords: idiopathic mental retardation; submicroscopic chromosome rearrangement; chromosome telomeres; 1p monosomy
PMCID: PMC1734367  PMID: 10353788
7.  Subtelomeric Chromosome Rearrangements in Children with Idiopathic Mental Retardation: Applicability of Three Molecular-cytogenetic Methods 
Croatian medical journal  2006;47(6):841-850.
Aim
To identify cryptic subtelomeric rearrangement, a possible cause of idiopathic mental retardation by means of multiprobe telomere fluorescent in situ hybridization (T-FISH).
Methods
Hundred patients (median age 3.0 years) with mental retardation and dysmorphic features were screened using specific T-FISH probes. Multiplex ligation-dependent probe amplification and comparative genomic hybridization were used for the confirmation of results.
Results
Telomere fluorescent in situ hybridization revealed 11 subtelomeric abnormalities in 10 patients (10%; 95% CI, 5.0-17.5). Four of these had only a deletion of subtelomere 2q, which was apparently a normal variant. Among 6 true aberrations (6%; 95% CI, 2.5-12.5) we found 2 de novo subtelomeric deletions and 4 unbalanced subtelomeric rearrangements (one de novo). All clinically significant subtelomeric rearrangements were confirmed by multiplex ligation-dependent probe amplification. Comparative genomic hybridization was used to investigate the whole genome of patients in whom a subtelomeric anomaly was found, confirming some, but not all subtelomeric rearrangements.
Conclusion
Telomere fluorescent in situ hybridization and multiplex ligation-dependent probe amplification are both very useful and interchangeable methods for the detection of unbalanced chromosome rearrangements, but T-FISH also detects balanced rearrangements. In our experiment, the resolution power of comparative genomic hybridization was too low for subtelomeric screening compared with T-FISH and multiplex ligation-dependent probe amplification.
PMCID: PMC2080485  PMID: 17167856
8.  Genomic imbalances in mental retardation 
Journal of Medical Genetics  2004;41(4):249-255.
Introduction: It has been estimated that cytogenetically visible rearrangements are present in ~1% of newborns. These chromosomal changes can cause a wide range of deleterious developmental effects, including mental retardation (MR). It is assumed that many other cases exist where the cause is a submicroscopic deletion or duplication. To facilitate the detection of such cases, different techniques have been developed, which have differing efficiency as to the number of loci and patients that can be tested.
Methods: We implemented multiplex amplifiable probe hybridisation (MAPH) to test areas known to be rearranged in MR patients (for example, subtelomeric/pericentromeric regions and those affected in microdeletion syndromes) and to look for new regions that might be related to MR.
Results: In this study, over 30 000 screens for duplications and deletions were carried out; 162 different loci tested in each of 188 developmentally delayed patients. The analysis resulted in the detection of 19 rearrangements, of which ~65% would not have been detected by conventional cytogenetic analysis. A significant fraction (46%) of the rearrangements found were interstitial, despite the fact that only a limited number of these loci have so far been tested.
Discussion: Our results strengthen the arguments for whole genome screening within this population, as it can be assumed that many more interstitial rearrangements would be detected. The strengths of MAPH for this analysis are the simplicity, the high throughput potential, and the high resolution of analysis. This combination should help in the future identification of the specific genes that are responsible for MR.
doi:10.1136/jmg.2003.014308
PMCID: PMC1735748  PMID: 15060096
9.  Submicroscopic subtelomeric aberrations in Chinese patients with unexplained developmental delay/mental retardation 
BMC Medical Genetics  2010;11:72.
Background
Subtelomeric imbalance is widely accepted as related to developmental delay/mental retardation (DD/MR). Fine mapping of aberrations in gene-enriched subtelomeric regions provides essential clues for localizing critical regions, and provides a strategy for identifying new candidate genes. To date, no large-scale study has been conducted on subtelomeric aberrations in DD/MR patients in mainland China.
Methods
This study included 451 Chinese children with moderate to severe clinically unexplained DD/MR. The subtelomere-MLPA (multiplex ligation dependent probe amplification) and Affymetrix human SNP array 6.0 were used to determine the subtelomeric copy number variations. The exact size and the breakpoint of each identified aberration were well defined.
Results
The submicroscopic subtelomeric aberrations were identified in 23 patients, with a detection rate of 5.1%. 16 patients had simple deletions, 2 had simple duplications and 5 with both deletions and duplications. The deletions involved 14 different subtelomeric regions (1p, 2p, 4p, 6p, 7p, 7q, 8p, 9p, 10p, 11q, 14q, 15q, 16p and 22q), and duplications involved 7 subtelomeric regions (3q, 4p, 6q, 7p, 8p, 12p and 22q). Of all the subtelomeric aberrations found in Chinese subjects, the most common was 4p16.3 deletion. The sizes of the deletions varied from 0.6 Mb to 12 Mb, with 5-143 genes inside. Duplicated regions were 0.26 Mb to 11 Mb, with 6-202 genes inside. In this study, four deleted subtelomeric regions and one duplicated region were smaller than any other previously reported, specifically the deletions in 11q25, 8p23.3, 7q36.3, 14q32.33, and the duplication in 22q13. Candidate genes inside each region were proposed.
Conclusions
Submicroscopic subtelomeric aberrations were detected in 5.1% of Chinese children with clinically unexplained DD/MR. Four deleted subtelomeric regions and one duplicated region found in this study were smaller than any previously reported, which will be helpful for further defining the candidate dosage sensitive gene associated with DD/MR.
doi:10.1186/1471-2350-11-72
PMCID: PMC2892449  PMID: 20459802
10.  Identification of Chromosome Abnormalities in Subtelomeric Regions Using Multiplex Ligation Dependent Probe Amplification (MLPA) Technique in 100 Iranian Patients With Idiopathic Mental Retardation 
Background
Mental retardation/Developmental delay (MR/DD) is present in 1 - 3% of the general population (1, 2). MR is defined as a significant impairment of both cognitive (IQ < 70) and social adaptive functions, with onset before 18 years of age.
Objectives
The purpose was to determine the results of subtelomeric screening by the Multiplex Ligation Dependent Probe Amplification (MLPA) Technique in 100 selected patients with idiopathic mental retardation (IMR) in Iran.
Materials and Methods
A number of 100 patients with IMR, normal karyotypes and negative fragile-X and metabolic tests were screened for subtelomeric abnormalities using MLPA technique.
Results
Nine of 100 patients showed subtelomeric abnormalities with at least one of the two MLPA kits. Deletion in a single region was found in 3 patients, and in two different subtelomeric regions in 1 patient. Duplication was only single and was present in 2 patients. Three patients were found to have both a deletion and duplication.MLPA testing in the parental samples of 7 patients which was accessible showed that 4 patients were de novo, 2 patients had inherited from a clinically normal mother, and one had inherited from a clinically normal father. Screening with the two MLPA kits (SALSA P036 and SALSA P070) proved abnormality in only five of the 9 patients.
Conclusions
So, the prevalence rate of abnormal subtelomeres using MLPA technique in patients with idiopathic MR in our study was 5 - 9%, the higher limit referring to the positive results of one of the two MLPA kits, and the lower limit representing the results of positive double-checking with the two MLPA kits.
doi:10.5812/ircmj.8221
PMCID: PMC3950786  PMID: 24693374
Ligation; Mental Retardation; Hypersomnolence Idiopathic
11.  Disruption of the gene Euchromatin Histone Methyl Transferase1 (Eu-HMTase1) is associated with the 9q34 subtelomeric deletion syndrome 
Journal of Medical Genetics  2005;42(4):299-306.
Background: A new syndrome has been recognised following thorough analysis of patients with a terminal submicroscopic subtelomeric deletion of chromosome 9q. These have in common severe mental retardation, hypotonia, brachycephaly, flat face with hypertelorism, synophrys, anteverted nares, thickened lower lip, carp mouth with macroglossia, and conotruncal heart defects. The minimum critical region responsible for this 9q subtelomeric deletion syndrome (9q–) is approximately 1.2 Mb and encompasses at least 14 genes.
Objective: To characterise the breakpoints of a de novo balanced translocation t(X;9)(p11.23;q34.3) in a mentally retarded female patient with clinical features similar to the 9q– syndrome.
Results: Sequence analysis of the break points showed that the translocation was fully balanced and only one gene on chromosome 9 was disrupted—Euchromatin Histone Methyl Transferase1 (Eu-HMTase1)—encoding a histone H3 lysine 9 methyltransferase (H3-K9 HMTase). This indicates that haploinsufficiency of Eu-HMTase1 is responsible for the 9q submicroscopic subtelomeric deletion syndrome. This observation was further supported by the spatio-temporal expression of the gene. Using tissue in situ hybridisation studies in mouse embryos and adult brain, Eu-HMTase1 was shown to be expressed in the developing nervous system and in specific peripheral tissues. While expression is selectively downregulated in adult brain, substantial expression is retained in the olfactory bulb, anterior/ventral lateral ventricular wall, and hippocampus and weakly in the piriform cortex.
Conclusions: The expression pattern of this gene suggests a role in the CNS development and function, which is in line with the severe mental retardation and behaviour problems in patients who lack one copy of the gene.
doi:10.1136/jmg.2004.028464
PMCID: PMC1736026  PMID: 15805155
12.  A Genotype-First Approach for the Molecular and Clinical Characterization of Uncommon De Novo Microdeletion of 20q13.33 
PLoS ONE  2010;5(8):e12462.
Background
Subtelomeric deletions of the long arm of chromosome 20 are rare, with only 11 described in the literature. Clinical features of individuals with these microdeletions include severe limb malformations, skeletal abnormalities, growth retardation, developmental and speech delay, mental retardation, seizures and mild, non-specific dysmorphic features.
Methodology/Principal Findings
We characterized microdeletions at 20q13.33 in six individuals referred for genetic evaluation of developmental delay, mental retardation, and/or congenital anomalies. A comparison to previously reported cases of 20q13.33 microdeletion shows phenotypic overlap, with clinical features that include mental retardation, developmental delay, speech and language deficits, seizures, and behavior problems such as autistic spectrum disorder. There does not appear to be a clinically recognizable constellation of dysmorphic features among individuals with subtelomeric 20q microdeletions.
Conclusions/Significance
Based on genotype-phenotype correlation among individuals in this and previous studies, we discuss several possible candidate genes for specific clinical features, including ARFGAP1, CHRNA4 and KCNQ2 and neurodevelopmental deficits. Deletion of this region may play an important role in cognitive development.
doi:10.1371/journal.pone.0012462
PMCID: PMC2929201  PMID: 20805988
13.  Array comparative genomic hybridisation-based identification of two imbalances of chromosome 1p in a 9-year-old girl with a monosomy 1p36 related phenotype and a family history of learning difficulties: a case report 
Introduction
Monosomy 1p36 is one of the most common terminal deletion syndromes, with an approximate incidence of 1 in every 5000 live births. This syndrome is associated with several pronounced clinical features including characteristic facial features, cardiac abnormalities, seizures and mental retardation, all of which are believed to be due to haploinsufficiency of genes within the 1p36 region. The deletion size varies from approximately 1.5 Mb to 10 Mb with the most common breakpoints located at 1p36.13 to 1p36.33. Over 70% of 1p36 deletion patients have a true terminal deletion. A further 7% have interstitial deletions and a proportion have a derivative chromosome 1 where the 1p telomere is replaced by material from another chromosome, either as a result of a de-novo rearrangement or as a consequence of malsegregation of a balanced parental translocation at meiosis.
Case presentation
Array comparative genomic hybridisation analysis of a 9-year-old Caucasian girl presenting with dysmorphic facial features and learning difficulties, for whom previous routine karyotyping had been normal, identified two submicroscopic rearrangements within chromosome 1p. Detection of both an insertional duplication of a region of 1p32.3 into the subtelomeric region of the short arm of a chromosome 1 homologue and a deletion within 1p36.32 of the same chromosome instigated a search for candidate genes within these regions which could be responsible for the clinical phenotype of the patient. Several genes were identified by computer-based annotation, some of which have implications in neurological and physical development.
Conclusion
Array comparative genomic hybridisation is providing a robust method for pinpointing regions of candidate genes associated with clinical phenotypes that extend beyond the resolution of the light microscope. This case report provides an example of how this method of analysis and the subsequent reporting of findings have proven useful in collaborative efforts to elucidate multiple gene functions from a clinical perspective.
doi:10.1186/1752-1947-2-355
PMCID: PMC2596801  PMID: 19019217
14.  Subtelomeric study of 132 patients with mental retardation reveals 9 chromosomal anomalies and contributes to the delineation of submicroscopic deletions of 1pter, 2qter, 4pter, 5qter and 9qter 
BMC Medical Genetics  2005;6:21.
Background
Cryptic chromosome imbalances are increasingly acknowledged as a cause for mental retardation and learning disability. New phenotypes associated with specific rearrangements are also being recognized. Techniques for screening for subtelomeric rearrangements are commercially available, allowing the implementation in a diagnostic service laboratory. We report the diagnostic yield in a series of 132 subjects with mental retardation, and the associated clinical phenotypes.
Methods
We applied commercially available subtelomeric fluorescence in situ hybridization (FISH). All patients referred for subtelomeric screening in a 5-year period were reviewed and abnormal cases were further characterized clinically and if possible molecularly.
Results
We identified nine chromosomal rearrangements (two of which were in sisters) corresponding to a diagnostic yield of approx. 7%. All had dysmorphic features. Five had imbalances leading to recognizable phenotypes.
Conclusion
Subtelomeric screening is a useful adjunct to conventional cytogenetic analyses, and should be considered in mentally retarded subjects with dysmorphic features and unknown cause.
doi:10.1186/1471-2350-6-21
PMCID: PMC1174871  PMID: 15904506
15.  Renal Failure Associated with APECED and Terminal 4q Deletion: Evidence of Autoimmune Nephropathy 
Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare autosomal recessive disorder caused by mutations in the autoimmune regulator gene (AIRE). Terminal 4q deletion is also a rare cytogenetic abnormality that causes a variable syndrome of dysmorphic features, mental retardation, growth retardation, and heart and limb defects. We report a 12-year-old Saudi boy with mucocutaneous candidiasis, hypoparathyroidism, and adrenocortical failure consistent with APECED. In addition, he has dysmorphic facial features, growth retardation, and severe global developmental delay. Patient had late development of chronic renal failure. The blastogenesis revealed depressed lymphocytes' response to Candida albicans at 38% when compared to control. Chromosome analysis of the patient revealed 46,XY,del(4)(q33). FISH using a 4p/4q subtelomere DNA probe assay confirmed the deletion of qter subtelomere on chromosome 4. Parental chromosomes were normal. The deleted array was further defined using array CGH. AIRE full gene sequencing revealed a homozygous mutation namely 845_846insC. Renal biopsy revealed chronic interstitial nephritis with advanced fibrosis. In addition, there was mesangial deposition of C3, C1q, and IgM. This is, to the best of our knowledge, the first paper showing evidence of autoimmune nephropathy by renal immunofluorescence in a patient with APECED and terminal 4q deletion.
doi:10.1155/2010/586342
PMCID: PMC3010696  PMID: 21197407
16.  The use of array-CGH in a cohort of Greek children with developmental delay 
Background
The genetic diagnosis of mental retardation (MR) is difficult to establish and at present many cases remain undiagnosed and unexplained. Standard karyotyping has been used as one of the routine techniques for the last decades. The implementation of Array Comparative Genomic Hybridization (array-CGH) has enabled the analysis of copy number variants (CNVs) with high resolution. Major cohort studies attribute 11% of patients with unexplained mental retardation to clinically significant CNVs. Here we report the use of array-CGH for the first time in a Greek cohort. A total of 82 children of Greek origin with mean age 4.9 years were analysed in the present study. Patients with visible cytogenetic abnormalities ascertained by standard karyotyping as well as those with subtelomeric abnormalities determined by Multiplex Ligation-dependent Probe Amplification (MLPA) or subtelomeric FISH had been excluded.
Results
Fourteen CNVs were detected in the studied patients. In nine patients (11%) the chromosomal aberrations were inherited from one of the parents. One patients showed two duplications, a 550 kb duplication in 3p14.1 inherited from the father and a ~1.1 Mb duplication in (22)(q13.1q13.2) inherited from the mother. Although both parents were phenotypically normal, it cannot be excluded that the dual duplication is causative for the patient's clinical profile including dysmorphic features and severe developmental delay. Furthermore, three de novo clinically significant CNVs were detected (3.7%). There was a ~6 Mb triplication of 18q21.1 in a girl 5 years of age with moderate MR and mild dysmorphic features and a ~4.8 Mb duplication at (10)(q11.1q11.21) in a 2 years old boy with severe MR, multiple congenital anomalies, severe central hypotonia, and ataxia. Finally, in a 3 year-old girl with microcephaly and severe hypotonia a deletion in (2)(q31.2q31.3) of about ~3.9 Mb was discovered. All CNVs were confirmed by Fluorescence in situ hybridization (FISH). For the remaining 9 patients the detected CNVs (inherited duplications or deletions of 80 kb to 800 kb in size) were probably not associated with the clinical findings.
Conclusions
Genomic microarrays have within the recent years proven to be a highly useful tool in the investigation of unexplained MR. The cohorts reported so far agree on an around 11% diagnostic yield of clinically significant CNVs in patients with unexplained MR. Various publicly available databases have been created for the interpretation of identified CNVs and parents are analyzed in case a rare CNV is identified in the child. We have conducted a study of Greek patients with unexplained MR and confirmed the high diagnostic value of the previous studies. It is important that the technique becomes available also in less developed countries when the cost of consumables will be reduced.
doi:10.1186/1755-8166-3-22
PMCID: PMC2987877  PMID: 21062444
17.  Prospective screening for subtelomeric rearrangements in children with mental retardation of unknown aetiology: the Amsterdam experience 
Journal of Medical Genetics  2002;39(8):546-553.
Objective: The frequency of subtelomeric rearrangements in patients with unexplained mental retardation (MR) is uncertain, as most studies have been retrospective and case retrieval may have been biased towards cases more likely to have a chromosome anomaly. To ascertain the frequency of cytogenetic anomalies, including subtelomeric rearrangements, we prospectively screened a consecutive cohort of cases with unexplained MR in an academic tertiary centre.
Methods: Inclusion criteria were: age <18 years at referral, IQ<85, no aetiological diagnosis after complete examination, which included karyotyping with high resolution banding (HRB).
Results: In 266 karyotyped children, anomalies were detected in 20 (7.5%, seven numerical, 13 structural); 39 cases were analysed by FISH for specific interstitial microdeletions, and anomalies were found in nine (23%). FISH analyses for subtelomeric microdeletions were performed in 184 children (44% moderate-profound MR, 51% familial MR), and one rearrangement (0.5%) was identified in a non-familial MR female with mild MR (de novo deletion 12q24.33-qter). The number of probable polymorphisms was considerable: 2qter (n=7), Xpter (n=3), and Ypter (n=1). A significantly higher total number of malformations and minor anomalies was present in the cytogenetic anomaly group compared to the group without cytogenetic anomalies.
Conclusions: The total frequency of cytogenetic anomalies in this prospective study was high (1:10), but the frequency of subtelomeric rearrangements was low. The most likely explanations are the high quality of HRB cytogenetic studies and the lack of clinical selection bias. Conventional cytogenetic analyses, combined with targeted microdeletion testing, remain the single most effective way of additional investigation in mentally retarded children, also in a tertiary centre.
doi:10.1136/jmg.39.8.546
PMCID: PMC1735204  PMID: 12161591
18.  Lifetime Prevalence of Mental Disorders in Lebanon: First Onset, Treatment, and Exposure to War  
PLoS Medicine  2008;5(4):e61.
Background
There are no published data on national lifetime prevalence and treatment of mental disorders in the Arab region. Furthermore, the effect of war on first onset of disorders has not been addressed previously on a national level, especially in the Arab region. Thus, the current study aims at investigating the lifetime prevalence, treatment, age of onset of mental disorders, and their relationship to war in Lebanon.
Methods and Findings
The Lebanese Evaluation of the Burden of Ailments and Needs Of the Nation study was carried out on a nationally representative sample of the Lebanese population (n = 2,857 adults). Respondents were interviewed using the fully structured WHO Composite International Diagnostic Interview 3.0. Lifetime prevalence of any Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) disorder was 25.8%. Anxiety (16.7%) and mood (12.6%) were more common than impulse control (4.4%) and substance (2.2%) disorders. Only a minority of people with any mental disorder ever received professional treatment, with substantial delays (6 to 28 y) between the onset of disorders and onset of treatment. War exposure increased the risk of first onset of anxiety (odds ratio [OR] 5.92, 95% confidence interval [CI] 2.5–14.1), mood (OR 3.32, 95% CI 2.0–5.6), and impulse control disorders (OR 12.72, 95% CI 4.5–35.7).
Conclusions
About one-fourth of the sample (25.8%) met criteria for at least one of the DSM-IV disorders at some point in their lives. There is a substantial unmet need for early identification and treatment. Exposure to war events increases the odds of first onset of mental disorders.
In a survey of 2,857 adults in Lebanon, Elie Karam and colleagues found a lifetime prevalence of any DSM-IV psychiatric disorder of 25.8%.
Editors' Summary
Background.
Mental illnesses—persistent problems with thinking, with feelings, with behavior, and with coping with life—are very common. In the UK about a quarter, and in the US, almost half, of people have a mental illness at some time during their life. Depression, for example, persistently lowers a person's mood and can make them feel hopeless and unmotivated. Anxiety—constant, unrealistic worries about daily life—can cause sleep problems and physical symptoms such as stomach pains. People with impulse-control disorders, have problems with controlling their temper or their impulses which may sometimes lead to hurting themselves or other people. These and other mental illnesses seriously affect the work, relationships, and quality of life of the ill person and of their family. However, most people with mental illnesses can lead fulfilling and productive lives with the help of appropriate medical and nonmedical therapies.
Why Was This Study Done?
Recent epidemiological surveys (studies that investigate the factors that affect the health of populations) have provided important information about the burden of mental disorders in some industrialized countries. However, little is known about the global prevalence of mental disorders (the proportion of people in a population with each disorder at one time) or about how events such as wars affect mental health. This information is needed so that individual countries can provide effective mental-health services for their populations. To provide this information, the World Mental Health (WMH) Survey Initiative is undertaking large-scale psychiatric epidemiological surveys in more than 29 countries. As part of this Initiative, researchers have examined the prevalence and treatment of mental disorders in Lebanon and have asked whether war in this country has affected the risk of becoming mentally ill.
What Did the Researchers Do and Find?
The researchers randomly selected a sample of nearly 3,000 adults living in Lebanon and interviewed them using an Arabic version of the World Health Organization's “Composite International Diagnostic Interview” (CIDI 3.0). This interview tool generates diagnoses of mental disorders in the form of “DSM-IV codes,” the American Psychiatric Association's standard codes for specific mental disorders. The researchers also asked the study participants about their experience of war-related traumatic events such as being a civilian in a war zone or being threatened by a weapon. The researchers found that one in four Lebanese had had one or more DSM-IV disorder at some time during their life. Major depression was the single most common disorder. The researchers also calculated that by the age of 75 years, about one-third of the Lebanese would probably have had one or more DSM-IV disorder. Only half of the Lebanese with a mood disorder ever received professional help; treatment rates for other mental disorders were even lower. The average delay in treatment ranged from 6 years for mood disorders to 28 years for anxiety disorders. Finally, exposure to war-related events increased the risk of developing an anxiety, mood, or impulse-control disorder by about 6-fold, 3-fold, and 13-fold, respectively.
What Do These Findings Mean?
These findings indicate that the prevalence of mental illness in Lebanon is similar to that in the UK and the US, the first time that this information has been available for an Arabic-speaking country. Indeed, the burden of mental illness in Lebanon may actually be higher than these findings suggest, because the taboos associated with mental illness may have stopped some study participants from reporting their problems. The findings also show that in Lebanon exposure to war-related events greatly increases the risk of developing for the first time several mental disorders. Further studies are needed to discover whether this finding is generalizable to other countries. Finally, these findings indicate that many people in Lebanon who develop a mental illness never receive appropriate treatment. There is no shortage of health-care professionals in Lebanon, so the researchers suggest that the best way to improve the diagnosis and treatment of mental disorders in this country might be to increase the awareness of these conditions and to reduce the taboos associated with mental illness, both among the general population and among health-care professionals.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050061.
Read a related PLoS Medicine Perspective article
IDRAAC has a database that provides access to all published research articles related to mental health in the Arab World
The UK charity Mind provides information on understanding mental illness
The US National Institute of Mental Health provides information on understanding, treating, and preventing mental disorders (mainly in English but some information in Spanish)
MedlinePlus provides a list of useful links to information about mental health
Wikipedia has a page on DSM-IV codes (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
The World Mental Health Survey Initiative and the Lebanese WHM study are described on the organizations' Web pages
doi:10.1371/journal.pmed.0050061
PMCID: PMC2276523  PMID: 18384228
19.  Identification of subtelomeric genomic imbalances and breakpoint mapping with quantitative PCR in 296 individuals with congenital defects and/or mental retardation 
Background
Submicroscopic imbalances in the subtelomeric regions of the chromosomes are considered to play an important role in the aetiology of mental retardation (MR). The aim of the study was to evaluate a quantitative PCR (qPCR) protocol established by Boehm et al. (2004) in the clinical routine of subtelomeric testing.
Results
296 patients with MR and a normal karyotype (500–550 bands) were screened for subtelomeric imbalances by using qPCR combined with SYBR green detection. In total, 17 patients (5.8%) with 20 subtelomeric imbalances were identified. Six of the aberrations (2%) were classified as causative for the symptoms, because they occurred either de novo in the patients (5 cases) or the aberration were be detected in the patient and an equally affected parent (1 case). The extent of the deletions ranged from 1.8 to approximately 10 Mb, duplications were 1.8 to approximately 5 Mb in size. In 6 patients, the copy number variations (CNVs) were rated as benign polymorphisms, and the clinical relevance of these CNVs remains unclear in 5 patients (1.7%). Therefore, the overall frequency of clinically relevant imbalances ranges between 2% and 3.7% in our cohort.
Conclusion
This study illustrates that the qPCR/SYBR green technique represents a rapid and versatile method for the detection of subtelomeric imbalances and the option to map the breakpoint. Thus, this technique is highly suitable for genotype/phenotype studies in patients with MR/developmental delay and/or congenital defects.
doi:10.1186/1755-8166-2-10
PMCID: PMC2660352  PMID: 19284615
20.  Clinical utility of multiplex ligation-dependent probe amplification technique in identification of aetiology of unexplained mental retardation: A study in 203 Indian patients 
Background & objectives:
Developmental delay (DD)/mental retardation also described as intellectual disability (ID), is seen in 1-3 per cent of general population. Diagnosis continues to be a challenge at clinical level. With the advancement of new molecular cytogenetic techniques such as cytogenetic microarray (CMA), multiplex ligation-dependent probe amplification (MLPA) techniques, many microdeletion/microduplication syndromes with DD/ID are now delineated. MLPA technique can probe 40-50 genomic regions in a single reaction and is being used for evaluation of cases with DD/ID. In this study we evaluated the clinical utility of MLPA techniques with different probe sets to identify the aetiology of unexplained mental retardation in patients with ID/DD.
Methods:
A total of 203 randomly selected DD/ID cases with/without malformations were studied. MLPA probe sets for subtelomeric regions (P070/P036) and common microdeletions/microduplications (P245-A2) and X-chromosome (P106) were used. Positive cases with MLPA technique were confirmed using either fluorescence in situ hybridization (FISH) or follow up confirmatory MLPA probe sets.
Results:
The overall detection rate was found to be 9.3 per cent (19 out of 203). The detection rates were 6.9 and 7.4 per cent for common microdeletion/microduplication and subtelomeric probe sets, respectively. No abnormality was detected with probe set for X-linked ID. The subtelomeric abnormalities detected included deletions of 1p36.33, 4p, 5p, 9p, 9q, 13q telomeric regions and duplication of 9pter. The deletions/duplications detected in non telomeric regions include regions for Prader Willi/Angelman regions, Williams syndrome, Smith Magenis syndrome and Velocardiofacial syndrome.
Interpretation & conclusions:
Our results show that the use of P245-A2 and P070/P036-E1 probes gives good diagnostic yield. Though MLPA cannot probe the whole genome like cytogenetic microarray, due to its ease and relative low cost it is an important technique for evaluation of cases with DD/ID.
PMCID: PMC3994742  PMID: 24604040
Common microdeletion/microduplication syndromes; developmental delay; intellectual disability; India; MLPA; subtelomeric abnormalities
21.  Microdeletion 15q13.3: a locus with incomplete penetrance for autism, mental retardation, and psychiatric disorders 
Journal of medical genetics  2009;46(6):382-388.
Background
Microdeletions within chromosome 15q13.3 are associated both with a recently recognised syndrome of mental retardation, seizures, and dysmorphic features, and with schizophrenia.
Methods and results
Based on routine diagnostic testing of ~8200 samples using array comparative genomic hybridisation, we identified 20 individuals (14 children and six parents in 12 families) with microdeletions of 15q13.3. Phenotypes in the children included developmental delay, mental retardation, or borderline IQ in most and autistic spectrum disorder (6/14), speech delay, aggressiveness, attention deficit hyperactivity disorder, and other behavioural problems. Both parents were available in seven families, and the deletion was de novo in one, inherited from an apparently normal parent in four, and inherited from a parent with learning disability and bipolar disorder in two families. Of the 14 children, six in five families were adopted, and DNA was available for only one of these 10 biological parents; the deletion was very likely inherited for one of these families with two affected children. Among the unavailable parents, two mothers were described as having mental retardation, another mother as having “mental illness”, and one father as having schizophrenia. We hypothesise that some of the unavailable parents have the deletion.
Conclusions
The occurrence of increased adoption, frequent autism, bipolar disorder, and lack of penetrance are noteworthy findings in individuals with deletion 15q13.3. A high rate of adoption may be related to the presence of the deletion in biological parents.
Unconfirmed histories of antisocial behaviours in unavailable biological parents raise the concern that future research may show that deletion 15q13.3 is associated with such behaviours.
doi:10.1136/jmg.2008.064378
PMCID: PMC2776649  PMID: 19289393
22.  Molecular-cytogenetic detection of a deletion of 1p36.3. 
Journal of Medical Genetics  1997;34(4):314-317.
We report a deletion of 1p36.3 in a child with microcephaly, mental retardation, broad forehead, deep set eyes, depressed nasal bridge, flat midface, relative prognathism, and abnormal ears. The phenotype is consistent with that described for partial monosomy for 1p36.3. Reverse chromosome painting and microsatellite and Southern blot analyses were used to map the extent of the deletion. Fluorescence in situ hybridisation (FISH) analysis using probes from every telomere indicates that the rearrangement is likely to be a chromosomal truncation or rearrangement involving subtelomeric repetitive DNA. The deletion was identified by screening a sample of children and adults with idiopathic mental retardation. In conjunction with previous work on this sample, we estimate that 7.4% of the group have subtelomeric rearrangements.
Images
PMCID: PMC1050919  PMID: 9138156
23.  Disease Biomarkers in Cerebrospinal Fluid of Patients with First-Onset Psychosis 
PLoS Medicine  2006;3(11):e428.
Background
Psychosis is a severe mental condition that is characterized by a loss of contact with reality and is typically associated with hallucinations and delusional beliefs. There are numerous psychiatric conditions that present with psychotic symptoms, most importantly schizophrenia, bipolar affective disorder, and some forms of severe depression referred to as psychotic depression. The pathological mechanisms resulting in psychotic symptoms are not understood, nor is it understood whether the various psychotic illnesses are the result of similar biochemical disturbances. The identification of biological markers (so-called biomarkers) of psychosis is a fundamental step towards a better understanding of the pathogenesis of psychosis and holds the potential for more objective testing methods.
Methods and Findings
Surface-enhanced laser desorption ionization mass spectrometry was employed to profile proteins and peptides in a total of 179 cerebrospinal fluid samples (58 schizophrenia patients, 16 patients with depression, five patients with obsessive-compulsive disorder, ten patients with Alzheimer disease, and 90 controls). Our results show a highly significant differential distribution of samples from healthy volunteers away from drug-naïve patients with first-onset paranoid schizophrenia. The key alterations were the up-regulation of a 40-amino acid VGF-derived peptide, the down-regulation of transthyretin at ~4 kDa, and a peptide cluster at ~6,800–7,300 Da (which is likely to be influenced by the doubly charged ions of the transthyretin protein cluster). These schizophrenia-specific protein/peptide changes were replicated in an independent sample set. Both experiments achieved a specificity of 95% and a sensitivity of 80% or 88% in the initial study and in a subsequent validation study, respectively.
Conclusions
Our results suggest that the application of modern proteomics techniques, particularly mass spectrometric approaches, holds the potential to advance the understanding of the biochemical basis of psychiatric disorders and may in turn allow for the development of diagnostics and improved therapeutics. Further studies are required to validate the clinical effectiveness and disease specificity of the identified biomarkers.
Protein profiles from 179 cerebrospinal fluid samples yield differences between patients with psychotic disorders and healthy volunteers, suggesting that such biomarkers could assist in the early diagnosis of mental illness.
Editors' Summary
Background.
Psychosis is an abnormal mental state characterized by loss of contact with reality, often associated with hallucinations, delusions, personality changes, and disorganized thinking. Psychotic symptoms occur in several psychiatric disorders, including schizophrenia, bipolar disorder, and psychotic depression. It is not clear what the underlying biological abnormalities in the brain are, and whether they are the same for the different psychotic illnesses. The hope is that recent advances in brain imaging and systematic characterization of genetic activity and protein composition in the brain might help to shed light on mental diseases, eventually leading to better diagnosis, treatment, and possibly even prevention.
Why Was This Study Done?
This study was carried out in order to search for biomarkers for psychosis and schizophrenia by comparing the protein composition in the cerebrospinal fluid (the clear body fluid that surrounds the brain and the spinal cord) of patients with different psychotic disorders and normal individuals who served as controls.
What Did the Researchers Do and Find?
The researchers used a technique called surface-enhanced laser desorption ionization mass spectrometry, which allows a comprehensive analysis of the protein composition of a particular sample, on a total of 179 cerebrospinal fluid samples. The samples came from 90 individuals without mental illness who served as controls, 58 people with schizophrenia who were very recently diagnosed and had not yet taken any medication, 16 patients with depression, five patients with obsessive-compulsive disorder, and ten patients with Alzheimer disease. All of the patients gave their informed consent to participate in the study. The researchers found that samples from treatment-naïve schizophrenic patients had a number of characteristic changes compared with samples from control individuals, and that those changes were not found in the patients with other mental illnesses. The researchers then wanted to test whether they would see the same pattern in a separate set of patients with schizophrenia versus controls, which turned out to be the case. Two of the changes in the cerebrospinal fluid that were associated with schizophrenia, namely higher levels of parts of a protein called VGF and lower levels of a protein called transthyretin, were also found in post-mortem brain samples of patients with schizophrenia compared with samples from controls. Lower levels of transthyretin were also found in serum (blood) of first-onset drug naïve schizophrenia patients.
What Do These Findings Mean?
These results suggest that this approach has the potential to find biomarkers for psychosis and, possibly, schizophrenia that might help in the understanding of the molecular basis for these conditions. If shown, in future studies, to be directly involved in causing the disease symptoms, they would be important targets for treatment and prevention efforts, and might also be useful for diagnostic purposes. Overall, there are promising examples, such as this study, suggesting that new molecular techniques can yield fresh insights into psychiatric illnesses such as schizophrenia and other psychotic disorders. Additional studies are needed to confirm the findings presented here and to address many open questions, and would seem well justified given these results.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030428.
MedlinePlus entries on psychosis and schizophrenia
The National Alliance for Research on Schizophrenia and Depression
The National Alliance for the Mentally Ill
The Schizophrenia Society of Canada
Wikipedia entries on psychosis and schizophrenia (note that Wikipedia is an online encyclopedia that anyone can edit)
doi:10.1371/journal.pmed.0030428
PMCID: PMC1630717  PMID: 17090210
24.  Detection of chromosomal imbalances in children with idiopathic mental retardation by array based comparative genomic hybridisation (array-CGH) 
Journal of Medical Genetics  2005;42(9):699-705.
Chromosomal aberrations are a common cause of multiple anomaly syndromes that include growth and developmental delay and dysmorphism. Novel high resolution, whole genome technologies, such as array based comparative genomic hybridisation (array-CGH), improve the detection rate of submicroscopic chromosomal abnormalities allowing re-investigation of cases where conventional cytogenetic techniques, Spectral karyotyping (SKY), and FISH failed to detect abnormalities. We performed a high resolution genome-wide screening for submicroscopic chromosomal rearrangements using array-CGH on 41 children with idiopathic mental retardation (MR) and dysmorphic features. The commercially available microarray from Spectral Genomics contained 2600 BAC clones spaced at approximately 1 Mb intervals across the genome. Standard chromosome analysis (>450 bands per haploid genome) revealed no chromosomal rearrangements. In addition, multi-subtelomeric FISH screening in 30 cases and SKY in 11 patients did not detect any abnormality. Using array-CGH we detected chromosomal imbalances in four patients (9.8%) ranging in size from 2 to 14 Mb. Large scale copy number variations were frequently observed. Array-CGH has become an important tool for the detection of chromosome aberrations and has the potential to identify genes involved in developmental delay and dysmorphism. Moreover, the detection of genomic imbalances of clinical significance will increase knowledge of the human genome by performing genotype-phenotype correlation.
doi:10.1136/jmg.2004.029637
PMCID: PMC1736138  PMID: 16141005
25.  Dedicator of cytokinesis 8 is disrupted in two patients with mental retardation and developmental disabilities 
Genomics  2007;91(2):195-202.
We have identified disruptions of the dedicator of cytokinesis 8 gene, DOCK8, in two unrelated patients with mental retardation. In one patient, a male with MR and no speech, we mapped a genomic deletion of approximately 230 kb in subtelomeric 9p. In the second patient, a female with mental retardation and ectodermal dysplasia and a balanced translocation t(X;9)(q13.1;p24), we mapped the 9p24 breakpoint to a region overlapping with the centromeric end of the 230 kb subtelomeric deletion. We characterized the DOCK8 gene from the critical 9p deletion region and determined the longest isoform of the DOCK8 gene is truncated in both patients. Furthermore, the DOCK8 gene is expressed in several human tissues including adult and fetal brain. Recently, a role for DOCK8 in processes that affect organization of filamentous actin has been suggested. Several genes influencing actin cytoskeleton have been implicated in human cognitive function and thus a possibility exists that the rare mutations of the DOCK8 gene may contribute to some cases of autosomal dominant mental retardation.
doi:10.1016/j.ygeno.2007.10.011
PMCID: PMC2245991  PMID: 18060736
Subtelomere; Mental retardation; Chromosome translocation; DOCK8; Autosome

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