Delineation of Subtelomeric Deletion of the Long Arm of Chromosome 6

Authors

  • Ji-Yun Lee,

    Corresponding author
    1. Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
    2. Department of Pathology, College of Medicine, Korea University, Seoul, South Korea
      Ji-Yun Lee, Ph.D., 5-1, Anam-Dong, Seoungbuk-Gu, Seoul, South Korea, 136-705. Tel: 82-2-920-6144; Fax: 82-2-953-3130; E-mail: jiyun-lee@korea.ac.kr, jlee13@ouhsc.edu
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  • Youl-Hee Cho,

    1. Department of Medical Genetics, College of Medicine, Hanyang University, Seoul, South Korea
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  • Gene Hallford

    1. Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
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Ji-Yun Lee, Ph.D., 5-1, Anam-Dong, Seoungbuk-Gu, Seoul, South Korea, 136-705. Tel: 82-2-920-6144; Fax: 82-2-953-3130; E-mail: jiyun-lee@korea.ac.kr, jlee13@ouhsc.edu

Summary

Pure subtelomeric deletion of the long arm of chromosome 6 is rare. The frequency of this deletion accounts for approximately 0.05% of subjects with intellectual disability and developmental delay with or without dysmorphic features. Common phenotypes associated with this deletion include intellectual disability, developmental delay, dysmorphic features, seizure, hypotonia, microcephaly and hypoplasia of the corpus callosum. The smallest overlapped region is approximately 0.4 Mb, and contains three known genes. Of these genes, TBP has been considered as a plausible candidate gene for the phenotype in patients with a subtelomeric 6q deletion. Analysis of the breakpoints in 14 cases revealed a potential common breakpoint interval 8.0–9.0 Mb from the chromosome 6q terminus where the FRA6E fragile site exists and the PARK2 gene is located. This suggests that breakage at the FRA6E fragile site may be the mechanism behind chromosome 6q subtelomeric deletion in some of the cases.

Introduction

Studies have shown subtelomeric changes of chromosomes in a significant proportion of patients with intellectual disability, developmental delay and/or dysmorphic features. Genotype and phenotype correlation studies of common subtelomeric deletions, such as 1p, 9q and 22q, have defined a recognizable syndrome based on these subtelomeric deletions, which has been added to the growing list of syndromes related to chromosomal anomalies.

Here we review published literature related to the subtelomeric deletion of the long arm of chromosome 6 and include a new case which has recently been identified and analyzed by our laboratory. Chromosome 6q subtelomeric deletion is not as common as 1p or 22q subtelomeric deletion (Ravnan et al., 2006). A careful review of the existing scientific literature revealed, 27 cases of pure subtelomeric 6q deletion (Wauters et al., 1993; Batanian & Hussain, 1999; Lorda-Sanchez et al., 2000; Rossi et al., 2001; Anderlid et al., 2002; Rio et al., 2002; Bocian et al., 2004; Kriek et al., 2004; Li & Zhao, 2004; Pickard et al., 2004; Adeyinka et al., 2005; Eash et al., 2005; Kok et al., 2005; Elia et al., 2006; Ravnan et al., 2006; Rooms et al., 2006a and b; Bertini et al., 2006; Striano et al., 2006; Ballif et al., 2007; Shao et al., 2008). In all, 28 cases are considered in the current review. Here, we summarize the frequency of the pure subtelomeric deletion of chromosome 6q in patients with idiopathic intellectual disability, developmental delay and/or dysmorphic features. The clinical phenotype, genotype and phenotype correlation corresponding to the gene content and size, and the possible mechanism of the deletion of chromosome 6q subtelomere are also discussed, based on the published literature.

Subject and Screening Methods for Subtelomeric 6q Deletion

We conducted a systematic literature review through the Public Entrez database searching (http://www.ncbi.nlm.nih.gov/pubmed/) by using the keywords “subtelomere, FISH, array CGH, and intellectual disability” and “6q deletion.” We also searched the references from papers obtained from the on-line search results. We excluded whole genomic imbalance studies that did not specifically focus on the subtelomeric region. From this, we identified 44 cases of subtelomeric 6q deletion that do not overlap with each other that were posted to PubMed prior to September 28th 2010. These cases are reported as part of a subtelomeric screening test that includes a large number of patient groups or an isolated case(s). Of these 44 cases, 27 cases have been identified as a pure terminal deletion, without any additional duplication of another chromosome, and the current case was identified by subtelomeric FISH (TotelVysion assay; Vysis/Abbot, Inc., Downer Grove, IL) and the breakpoint was defined by oligonucleotide array CGH analyses (3×720K Whole-Genome Tiling chip, Roche/NimbleGen System Inc, Madision, WI), carried out during investigation of developmental delay and intellectual disability (Tables 1 and 2) (Lorda-Sanchez et al., 2000; Rossi et al., 2001; Anderlid et al., 2002; Font-Montgomery et al., 2004; Li & Zhao, 2004; Pickard et al., 2004; Stevenson et al., 2004; Adeyinka et al., 2005; Eash et al., 2005; Kok et al., 2005; Bertini et al., 2006; Elia et al., 2006; Ravnan et al., 2006; Rooms et al., 2006a and b; Striano et al., 2006; Ballif et al., 2007; Shao et al., 2008). In this review, cases of unbalanced derivative chromosome 6 resulting in a 6q terminal deletion or pure 6q terminal deletion identified by GTG banding analysis were excluded. This exclusion criterion was used because the focus of this paper is on the pure subtelomeric deletion of chromosome 6q.

Table 1.  Summary of subtelomeric rearrangements in children and adults with idiopathic mental retardation and subtelomeric deletion of chromosome 6q*.
ReferencesTechniqueNumber of cases/familiesNumber of detected abnormalites6q-
  1. Most of subjects tested had normal or ambiguous karyotype by GTG banding analysis at ISCN 500-550.

  2. *No case reports are included.

  3. a2 UPD cases are not included for counting. Four familial rearrangements are published in Colleaux et al. (2001).

  4. bIncluded case with only MR, not psychosis.

  5. cMZ twin.

Flint et al. (1995)VNTR marker analysis9930
Viot et al. (1998)Multiprobe FISH1740
Vorsanova et al. (1998)Multiprobe FISH20980
Knight et al. (1999)Multiprobe FISH466220
Lamb et al. (1999)Multiplex FISH4310
Slavotinek et al. (1999)Microsatellite2720
Ballif et al. (2000)Telomere-specific FISH15440
Bonifacio et al. (2001)PRINS6520
Borgione et al. (2001)Multiprobe FISH/microsatellite3020
Fan et al. (2001)Multiprobe FISH15050
Joyce et al. (2001)Multiprobe FISH20000
Riegel et al. (2001)Multiprobe FISH254130
Rosenberg et al. (2001)Microsatellite markers12050
Rossi et al. (2001)Multiprobe FISH200131
Sismani et al. (2001)Multiprobe FISH+MAPH7010
Anderlid et al. (2002)Multiprobe FISH111111
Baker et al. (2002)Multiprobe FISH25090
Clarkson et al. (2002)Multiprobe FISH+SKY5020
Dawson et al. (2002)Multiprobe FISH4040
Helias-Rodzewicz et al. (2002)Multiprobe FISH3330
Hollox et al. (2002)MAPH3760
Popp et al. (2002)M-TEL2840
Rio et al. (2002)Microsatellite markers15014a0
van Karnebeek et al. (2002)Multiprobe FISH18410
Hulley et al. (2003)Multiprobe FISH1310
Jalal et al. (2003)Multiprobe FISH372130
Bocian et al. (2004)Multiprobe FISH8390
Font-Montgomery et al. (2004)Multiprobe FISH4361
Harada et al. (2004)Subtelomere BAC-array6940
Koolen et al. (2004)MLPA210100
Kriek et al. (2004)MAPH18450
Li and Zhao (2004)Multiprobe FISH4621
Novelli et al. (2004)Multiprobe FISH92150
Pickard et al. (2004)MAPH+Multiprobe FISH70b2b1b
Rodriguez-Revenga et al. (2004)Multiprobe FISH3020
Rooms et al. (2004a)MLPA7540
Rooms et al. (2004b)Microsatellite7000
Walter et al. (2004)Multiprobe FISH50100
Adeyinka et al. (2005)Multiprobe FISH2,1881391
Kok et al. (2005)Subtelomere BAC-array10080
Moog et al. (2005)Multiprobe FISH/total Painting16180
Northrop et al. (2005)Quantitative-MLPA5130
Sogaard et al. (2005)Multiplex FISH13280
Yu et al. (2005)Multiprobe FISH53470
Lam et al. (2006)Multiprobe FISH/MLPA2030
Monfort et al. (2006)MLPA+Multiprobe FISH9580
Palomares et al. (2006)MLPA+Multiprobe FISH5050
Ravnan et al. (2006)Multiprobe FISH11,6883554
Rooms et al. (2006b)MLPA27512c1c
Ballif et al. (2007)Array CGH (BAC)6,9461694
Shao et al. (2008)Array CGH (BAC/PAC)5,3802361
 32,014948 (2.96%)16 (0.05%)
Table 2.  Summary of published 6q terminal deletion cases+.
References6q-
  1. +Published case reports are included.

  2. *Parent with chromosome 6q- has intellectual disability.

  3. aThe case with only intellectual disability.

  4. bThe same patient published in Font-Montgomery et al. (2004), case 3.

  5. cThe same patient published in Stevenson et al. (2004).

  6. dVisible at 600 banding level.

  7. eThe same patient published in Rooms et al. (2006a), MZ twin.

Lorda-Sanchez et al. (2000)46,XX, inv(6)(q22.1q27). ish del(6)(q27)dn
Rossi et al. (2001)Case 9. ish del(6)(qter)dn
Anderlid et al. (2002)Case 4. 46,XY.ish del(6)(qter)dn
Li and Zhao (2004)Case 2. 46,XY.ish del(6)(qter)pat*
Pickard et al. (2004)ish del(6)(qter)a
Adeyinka et al. (2005)46, XY.ish del(6)(qter)pat*
Eash et al. (2005)Case 1. 46,XY.ish del(6)(qter)dnb
Case 2. 46,XX.Ish del(6)(qter)dnc
Bertini et al. (2006)Case 1. 46,XY,del(6q)(25).ish del(6)(q26)dnd
Case 2. 46,XY,del(6q)(25).ish del(6)(q26)dnd
Elia et al. (2006)Case 1. 46,XY.ish del(6)(qter)dn
Case 2. 46,XY.ish del(6)(qter)dn
Case 3. 46,XY.ish del(6)(qter)dn
Case 5. 46,XX.ish del(6)(qter)dn
Ravnan et al. (2006)Case 71. 46,XX.ish del(6)(qter) dn
Case 72. 46,XY.ish del(6)(qter)dn
Case 73. 46,XX.ish del(6)(qter)
Case 74. 46,XY.ish del(6)(qter)
Rooms et al. (2006b)Case 6. 46,XY.ish del(6)(qter)mat*e
Striano et al. (2006)Case 2. 46,XX.ish del(6)(qter)dn
Case 3. 46,XX.ish del(6)(qter)dn
Case 4. 46,XY.ish del(6)(qter)dn
Ballif et al. (2007)n/a (4 cases)
Shao et al. (2008)n/a (1 case)
Current case46,XX. ish del(6)(qter)
Total #28

Most of the subjects were referred for chromosome subtelomeric screening testing due to presentation of intellectual disability and/or developmental delay with or without dysmorphic features. GTG banding analysis of most of the subjects was normal at ISCN 500-550 band resolution. The methods used to screen for subtelomeric change were fluorescence in situ hybridization (FISH: TotelVysion assay; Vysis/Abbot, Inc., Downer Grove, IL, USA or Chromoprobe Multiprobe-T System; Cytocell Technologies, Ltd., Cambridge, UK), Multiplex Ligation-Dependent Probe Amplification (MLPA), Multiplex Amplifiable Probe Hybridization (MAPH), microsatellite marker analysis, or most recently array CGH (Table 1). In most of the cases, once a subtelomeric rearrangement is identified by MPLA, MAPH, microsatellite marker analysis, or array CGH, the rearrangement is confirmed by FISH.

Inheritance and Frequency of Subtelomeric 6q Deletion

Among these 28 cases with pure 6q terminal deletions, 19 cases were available to do parental follow-up studies to determine whether the deletion was inherited or a de novo event (Table 2). In two of these 19 cases the deletion was inherited from the father (Li & Zhao, 2004; Adeyinka et al., 2005) and in one case it was inherited from the mother (Rooms et al., 2006a and b). The remaining 16 cases were de novo (84.2%; 16/19), and one of these cases was due to a de novo inversion: inv(6)(q22q27).ish del(6)(q27-)dn (Lorda-Sanchez et al., 2000). Parental origin of deleted alleles was also determined in 10 cases. Six cases had the paternal allele deleted and four cases had the maternal allele deleted. Based on available clinical information, none of the four cases with maternal allele deletion had a history of transient neonatal diabetes mellitus (Table 3).

Table 3.  Phenotypic features in individuals with subtelomeric deletion of chromosome 6q.
Cases1a2b3c4d5a6e7e8d9d10f11f12f13f14g15h16i17j18k19l20l21m22l23l24n*25–28o
  1. aEash et al. (2005); bcurrent case; cRooms et al. (2006a and b); dStriano et al. (2006); eBertini et al. (2006); fElia et al. (2006); gRossi et al. (2001);

  2. hLorda-Sanchez et al. (2000); iAnderlid et al. (2002); jLi and Zhao (2004); kAdeyinka et al. (2005); lRavnan et al. (2006); mPickard et al. (2004); nShao et al. (2008); oBallif et al. (2007).

  3. *Listed as multiple congenital anomalies, not specified.

  4. dn: de novo, F: familial, M: Maternal, P: Paternal, +: present, −: not present, blank: no information available.

  5. Abnormal patterns of suture fusion: 1Colpocephaly, 2Brachycephaly, 3Dolichocephaly, 4Scaphocephaly.

Inheritancedn FdndndndndndndndndndndndndnFFdndn     
Parental origin of the deletion  M  PP  PMMPM  PP       
Size of deletion (Mb)0.411.237.58 88 899<11<11          1.5 
Age826/12 49/1221023241219261416/12  16/1298/121 281/12  
SexMFMFFMMFMMMMF FMMMFM FM  
Developmetal delay / Intellectual disability+++++++++++++++++++++++ +
Dysmorphic features+++++++++++++++++ ++ +   
Epicanthal folds + +++  +    +      +   
Strabismus   + + ++++++            
High/cleft palate++++++++ +++            
Micrognathia + + + ++ +++            
Ear anomalies++ ++++++++++ ++         
Short neck  +++ +             
Hypotonia+   ++++  +++++ +        
Borderline /mild microcephaly++++++ +    +++        
Seizures++++++++++++++ +         
Hyperactivity/ADHD+         +    +         
Abnormal corpus callosum+ + ++++ ++++ +          
Abnormal patterns of suture fusion+3  +1+3+2+2+1+1 +1+1+1   +4 +1      
Hydrocephalus+    +        + +       
Joint laxity   + ++ + + + +          
Dimpling on elbows/knee or sacral  + +         +          
Cardiac defects            +     
Genital hypoplasia                   
Retinal anomalies                      
Limb anomalies                     

More than 32,000 subjects have been screened and reported for subtelomeric rearrangements. Of these subjects ∼0.05% appeared to have pure subtelomeric deletion of chromosome 6q (Table 1). This incidence is similar to the Ravnan et al. (2006) study which reported ∼0.04% (5/11,688) cases with pure subtelomeric deletion of chromosome 6q.

Common Clinical Features of Subtelomeric Deletion of 6q

Intellectual disability is the most common feature in patients with any subtelomeric rearrangements. De Vries et al. (2001) developed a “checklist” derived from the common features observed in the subtelomeric rearrangement cases: (1) family history of intellectual disability, (2) prenatal onset of growth retardation, (3) postnatal growth abnormalities (either poor or over-growth), (4) ≥ 2 facial dysmorphic features and/or congenital abnormality. Some of the chromosome regions had consistent, recognizable patterns of clinical features and were suggested clinically as recognizable syndromes by genotype/phenotype correlation studies, such as 1p, 9q and 22q subtelmomeric deletion. However, so far the majority of cases with subtelomeric rearrangements lack a characteristic phenotype.

Hopkins et al. (1997) clearly defined three phenotypic groups associated with chromosome 6q deletions that are visible by GTG banding. Group A individuals have a 6q proximal deletion [del(6)(q11-q16)] that has features including upslanting palpebral fissures, high incidence of hernias and thin lips with lower frequency of microcephaly, micrognathia and heart malformations. Group B individuals have a 6q interstitial deletion [del(6)(q15-q25)] that is associated with increased intrauterine growth retardation, high and arched palate, abnormal respiration, hypertelorism, upper limb malformation, and high infant mortality. Group C individuals have a 6q distal deletion [del(6)(q25-qter)] that is associated with retinal abnormalities, cleft palate, genital hypoplasia, hydrocephalus and seizures.

Several attempts have been made to correlate the terminal deletion of chromosome 6q with distinct phenotypes (Eash et al., 2005; Bertini et al., 2006; Elia et al., 2006; Striano et al., 2006), since Stevenson et al. (2004) questioned its status as a recognizable syndrome. Eash et al. (2005) and Bertini et al. (2006) compared the clinical features of their patients to previously reported cases of cryptic subtelomeric and cytogenetically visible chromosome 6q terminal deletions. Multiple unique features such as cleft palate, limb anomalies, genital hypoplasia, retinal abnormalities, and cardiac defects are frequently present in patients with cytogenetically visible deletions which are possibly >8 Mb away from the 6q terminus. However, both groups share phenotypic abnormalities which are developmental delay, intellectual disability, dysmorphic features, hypotonia, microcephaly, seizure and brain anomalies, suggesting the causative genes for these features may lie in the region of the smallest chromosome 6q subtelomeric deletion, ∼0.4 Mb from the telomere (Eash et al., 2005; case 1). We were able to identify one more 6q subtelomeric deletion case with a deletion approximately 1 Mb from the 6q terminus by array CGH. This case was referred to us for routine chromosome and subtelomeric FISH analyses because of developmental delay, intellectual disability and seizures, and shares phenotypic characteristics with the other published cryptic subtelomeric deletion cases.

We summarized the phenotypes of 28 cases corresponding to the clinical information which has been described previously (Table 3) (Lorda-Sanchez et al., 2000; Anderlid et al., 2002; Li & Zhao, 2004; Pickard et al., 2004; Adeyinka et al., 2005; Eash et al., 2005; Bertini et al., 2006; Elia et al., 2006; Ravnan et al., 2006; Rooms et al., 2006b; Striano et al., 2006). The most frequently observed characteristics of these cases with a subtelomeric deletion of 6q include intellectual disability, developmental delay, dysmorphic features, seizures, hypotonia, anomalies of the corpus callosum, other brain anomalies, high or cleft palate, microcephaly, joint laxity, hydrocephalus, dimpling on elbows and knees, and hyperactivity/ADHD. Most of these characteristics were common to both patients who are carrying a cryptic subtelomeric deletion and those who had a visible chromosome 6q terminal deletion, though smaller deletions tend to cause milder anomalies.

Genes in the Smallest Deleted Region of 6q

It is important to study the extent of genomic imbalances and the genes within those regions to refine the correlation between genotype and phenotype. Recently, the Eu-HMTase1 (EHMT1) gene was identified as the causative gene for the specific phenotype associated with chromosome 9q subtelomeric deletion (Kleefstra et al., 2005; 2006). The phenotype of the patient who has a mutation of this gene shares distinctive phenotype features with patients who have 9q interstitial and terminal deletion, in which several genes are deleted including EHMT1. Disruption of the SHANK3 gene in a t(12;22)(q24.1;q13.3), as well as a recurrent breakpoint within this gene, has been reported in patients with 22q13.3 deletion phenotype (Bonaglia et al., 2001; Bonaglia et al., 2006). This implies the SHANK3 gene may be a plausible candidate gene in the 22q13.3 deletion syndrome.

Figure 1 summarizes the deletion size and number of known genes in the 14 cases, including our unpublished case, that have been reported as a pure deletion, and the molecular studies that have been done for breakpoint mapping. The most common breakpoint found in these 14 cases is in the 8.0–9.0 Mb interval from the 6q terminus, observed in six of the 14 cases. There are approximately 34 known genes and six OMIM morbid genes in this ∼9.0 Mb region (Table S1). A comparison of the case with the smallest deletion (∼0.4 Mb; 3 known genes) reported to date (Eash et al., 2005), and the case that has the largest deletion (<11 Mb; >34 known genes) (Elia et al., 2006) shows no specific phenotype differences, with respect to developmental delay, intellectual disability, dysmorphic features, hypotonia, microcephaly, seizure and brain anomalies (Table 3). Interestingly, the disruption of the gene Quaking (QKI: located ∼7.1 Mb from the 6q terminus) due to the de novo balanced translocation t(5;6)(q23.1;q26) has been revealed in a patient with a clinical phenotype similar to the common 6q- phenotype listed above (Backx et al., 2010). This suggests that haploinsufficiency of the QKI gene may underlie a substantial part of the 6q subtelomeric deletion phenotype. However, the seizures and brain anomalies, which are common features in the 6q terminal deletion cases, including three cases possessing the QKI gene, are absent in the case reported by Backx et al. (2010). This raises the possibility that other gene(s) distal to the QKI gene are responsible for the 6q terminal deletion phenotype. The region of greatest interest is the smallest overlapped portion of the most distal part of chromosome 6q. The genes located in the region within 0.4 Mb of the 6q terminus are PSMB1, TBP and PDCD2.

Figure 1.

The size and the known genes (UCSC Genome Browser Mar. 2006) in the 6q terminal deletion from 13 published cases and the current case. *The same patient published in Rooms et al. (2006b).

The PSMB1 gene encodes a subunit of the proteasome, a multicatalytic proteinase complex that cleaves peptides in an ATP/ubiquitin-dependent process in nonlysosomal pathways. It is tightly linked to the TBP (TATA-binding protein gene) and they are transcribed in the opposite orientation.

The TBP gene has been implicated as a plausible candidate gene for phenotypes in patients with subtelomeric chromosome 6q deletion; however, the possibility of other genes playing a role in the phenotypes resulting from this deleted region cannot be ruled out (Rooms et al., 2006a). TBP contains a long string of glutamines in the N-terminal. This region of the protein modulates the DNA binding activity of the C terminus and modulation of DNA binding affects the rate of transcription complex formation and initiation of transcription. Mutations that expand the number of CAG repeats encoding this polyglutamine tract, thus increasing the length of the polyglutamine string, are associated with spinocerebellar ataxia 17, a neurodegenerative disorder classified as a polyglutamine disease. However, the question of whether a loss of TBP function plays a role in the neurodegenerative disease remains to be addressed.

Deletion of the long arm of chromosome 6 is common in patients with lymphoid neoplasms. Specifically, deletions in the 6q26–27 region – a possible region of minimal deletion – have been associated with both lymphoid and multiple tumor type neoplasms (Hauptschein et al., 1998). The PDCD2 (programmed cell death 2) gene, located within the 6q26–27 region, is targeted by the BCL6 repression gene (Baron et al., 2002). It has been suggested that the combined effect of PDCD2 halpoinsufficiency and its down-regulation by BCL6 may be responsible for accelerating tumor progression (Steinemann et al., 2003). The effect of this mechanism on cancer susceptibility in patients with constitutional 6q deletion, however, is currently unknown.

Possible Mechanism of Subtelomeric Deletion of 6q

Hecht & Hecht (1992) defined 6q25 as the most common breakpoint by identifying the breakpoints in patients with cytogenetically visible chromosome 6q terminal deletions; however, it is possible that, at least in some reports, this breakpoint could be misinterpreted without detailed molecular cytogenetic studies.

Review of the 13 published cases and the current case that have been subjected to detailed mapping, reveals the most common deletion site is 8–9 Mb from the 6q terminus (6/14). FRA6E, the third most frequently observed common fragile site (CFS) in the human population, is located in this region (6q26) of ∼3.6 Mb which includes eight genes: IGF2R, SLC22A1, SLC22A2, SLC22A3, PLG, LPA, MAP3K4, and PARK2. (Fig. 1) (Denison et al., 2003). CFSs are highly unstable genomic regions under specific tissue culture conditions and are predisposed to chromosomal gap, break, and rearrangement in cancer cells. The relationship between fragile sites and constitutional chromosome rearrangements is not fully understood. However, FRAXA (Xq27.3) and FRAXE (Xq28) are known sites that are associated with fragile X syndrome. FRA11B (11q23.3) has also been implicated in physical linkage in the chromosomal deletion of Jacobsen syndrome (Jones et al., 1994). The role of replication delay and premature chromosome condensation in causing chromosome deletion has been described for FRA3B (Le Beau et al., 1998; El Achkar et al., 2005). These unstable fragile sites with incomplete chromatin condensation are caused by late replication and/or incomplete replication, which itself leads to gaps and breaks at these sites during the subsequent mitosis. This feature may be related to their potential role in causing chromosome 6q terminal deletion in some cases, although random breakage must also be considered as a possible mechanism.

Conclusion

Subtelomeric deletion of the long arm of chromosome 6 is rare. It is shown to be present in ∼0.05% of patients with intellectual disability and/or development delay. The most common finding among all patients with a subtelomeric deletion of chromosome 6q is intellectual disability and developmental delay. Other commonly reported findings are dysmorphic features, seizures, hypotonia, hypoplasia of the corpus callosum, other brain anomalies, high or cleft palate, microcephaly, joint laxity, hydrocephalus, dimpling on elbows and knees, and hyperactivity/ADHD. The minimal deletion interval associated with intellectual disability has been narrowed to within ∼0.4 Mb of the chromosome 6q terminus; the TBP gene located in this region has been implicated as a possible cause of the common phenotype. In comparing the findings of the common breakpoint with defined mapping of 14 cases, the mechanism of chromosome 6q terminal deletion, in some cases, may be related to the fragile site, FRA6E. It is critical that further studies of this region be done to better understand the deletion mechanism.

As more cases are reported, we will be able to establish discrete phenotypes and natural histories that can aid in counseling families and understanding the mechanism of a subtelomeric deletion of chromosome 6q.

Acknowledgements

The authors express special thanks to Dr. Shibo Li at OUHSC and Dr. Christa L. Martin at Emory University and for her scientific mentorship.

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