You are here

Article Text

Article menu
Letters to JMG
Molecular analysis of 20 patients with 2q37.3 monosomy: definition of minimum deletion intervals for key phenotypes
Free
  1. M A Aldred1,
  2. R O C Sanford2,3,
  3. N S Thomas2,3,
  4. M A Barrow4,
  5. L C Wilson5,
  6. L A Brueton6,
  7. M C Bonaglia7,
  8. R C M Hennekam8,
  9. C Eng9,
  10. N R Dennis2,10,
  11. R C Trembath1,4
  1. 1Division of Medical Genetics, Departments of Genetics and Cardiovascular Sciences, University of Leicester, Leicester, UK
  2. 2Human Genetics Division, University of Southampton, Southampton, UK
  3. 3Wessex Regional Genetics Laboratory, Salisbury District Hospital, Salisbury, UK
  4. 4Leicestershire Genetics Centre, University Hospitals of Leicester NHS Trust, Leicester, UK
  5. 5Clinical and Molecular Genetics Unit, Institute of Child Health and Great Ormond Street Hospital NHS Trust, London, UK
  6. 6West Midlands Genetics Service, Birmingham Women’s Hospital, Birmingham, UK
  7. 7IRCCS E. Medea, Bosisio Parini, Lecco, Italy
  8. 8Department of Paediatrics and Clinical Genetics, Academic Medical Centre, Amsterdam, The Netherlands
  9. 9Human Cancer Genetics Program and Division of Human Genetics, The Ohio State University, Columbus, OH, USA
  10. 10Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton, UK
  1. Correspondence to:
 Dr M A Aldred
 Division of Medical Genetics, Adrian Building, University of Leicester, University Road, Leicester LE1 7RH, UK; maldredhgmp.mrc.ac.uk

http://dx.doi.org/10.1136/jmg.2003.017202

Statistics from Altmetric.com

    Request Permissions

    If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

    Terminal deletions of the long arm of chromosome 2 (2q37) have been recorded in the literature for more than a decade and an associated syndrome first became apparent when nine patients were reported with an Albright hereditary osteodystrophy (AHO)-like metacarpal/metatarsal shortening (brachymetaphalangism).1,2 This is also known as brachydactyly-mental retardation syndrome (BDMR, MIM 600430). To date, some 60 or so cases of 2q37 deletion or monosomy resulting from unbalanced translocations have been reported. Significant variability in clinical presentation is apparent, but almost all patients have some degree of mental retardation and facial dysmorphism. Brachymetaphalangism has been reported in approximately 50% of cases.1–15 Congenital heart anomalies are present in around 20% of patients with 2q37 monosomy,16–22 compared to 1% of the general population. These are predominantly atrial or ventricular septal defects, but more complex problems have been reported.17,22 Additionally, there are two reports of tetralogy of Fallot with monosomy 2q37 resulting from unbalanced translocations,23,24 but both cases were also trisomic for 17q25 and it is not clear which imbalance was causative. Other phenotypes repeatedly associated with 2q37 deletions include Wilms tumor and urogenital anomalies,6,17,19 epilepsy,1,2,7–9,14,16,20,25–27 eczema,2,5–7,16,28,29 and autism or repetitive, hyperkinetic behaviour.1,2,5,7,10,11,15,16,19,25,26,28–32 Situs abnormalities have been reported in two cases9 and holoprosencephaly in one infant.33

    Most 2q37 rearrangements reported to date have been only minimally characterised by conventional cytogenetics or subtelomeric fluorescent in situ hybridisation (FISH). A small number have been subjected to more detailed analysis using multiple FISH clones or microsatellite markers,2,10,15,26 but the ability to assign breakpoints and make genotype–phenotype correlations has been limited. We therefore sought to conduct detailed molecular analyses of a panel of 2q37 deletion patients, focusing on the critical interval distal to D2S3382 and including assessment of individual gene dosage by multiplex amplifiable probe hybridisation (MAPH).34 We define minimal deletion intervals for all of the major phenotypes associated with 2q37 monosomy.

    METHODS

    This study has been approved by the Leicestershire ethics committee. Seven patients have been described previously.2,4,7,16,26 Thirteen additional patients with known 2q37 rearrangements were ascertained through clinical genetics departments in the UK and clinical details are provided as supplementary online information at http://jmg.bmjjournals.com/supplemental/. Informed consent was obtained from parents or guardians. The patient panel comprised 16 deletions, two inverted duplication/deletions, one ring chromosome and one unbalanced translocation. The ring chromosome (patient 53) has virtually no loss of 2p material, being heterozygous for microsatellite D2S2584, ~160 kb from the telomere, and retaining the 2p subtelomeric FISH probe 2052f6. The phenotype is therefore presumed to be due solely to the 2q37 deletion.

    Key points

    • We have conducted detailed dosimetric analysis in 20 patients with monosomy 2q37.

    • No common breakpoints were found, indicating that 2q37 rearrangements are likely not mediated by duplicated low copy repeats.

    • The minimum deleted region in patients with characteristic facial dysmorphism and Albright hereditary osteodystrophy (AHO)-like brachymetaphalangism has been narrowed to approximately 3 Mb.

    • For the first time, preliminary assignments of critical intervals for other features of the syndrome have now been made. All such intervals share a 1.5 Mb overlap.

    • However, considerable clinical variability was apparent and no clear genotype–phenotype correlations could be drawn that would help predict clinical prognosis in a newly-diagnosed young proband.

    DNA was extracted from peripheral blood leukocytes or buccal cells using standard methods. MAPH was conducted essentially as described,34,35 except that probes were cloned into pCR2.1-TOPO using the TOPO-TA cloning kit (Invitrogen, Paisley, UK) and the sequence of the blocking primers was modified accordingly. Probes were designed to the following 2q37 genes: RDC1, RAMP1, ILKAP, MIP-T3, ASB1, TWIST2, HDAC4, NDUFA10, HDLBP, ATSV, GP3ST, PASK, PPP1R7, FARP2, STK25, NEDD5, DTYMK, and to unique sequence adjacent to the polymorphic markers D2S125, D2S140, D2S2585 (2qTEL44), D2S2985 (2qTEL37) and D2S2986 (2qTEL47). Details of probe sequences are available on request. Probes were organised into two multiplex sets for patient analysis and were first tested on DNA from a patient with a large deletion and normal controls to verify their quantitative performance. Results for selected genes were also verified by realtime quantitative PCR (data not shown).

    In some cases it was not possible to perform MAPH, as only small quantities of DNA were available from buccal swab samples. We therefore designed 11 new microsatellite markers, spanning the region from immediately proximal to HDAC4 (BAC AC114788) to the telomere, by in silico screening of publicly-available BAC sequence using the Tandem Repeats Finder program.36 Primer sequences and annealing temperatures are shown in table 1. All new markers proved to be polymorphic. Existing microsatellite markers from the Genethon and Marshfield genetic maps were analysed using primers available from the public genome databases. Singleplex reactions were conducted for 40 cycles using HotStar PCR mastermix (Qiagen, Crawley, UK) supplemented with 1× Q-solution. Multiplex reactions utilised the Multiplex PCR Mastermix (Qiagen, Crawley, UK) supplemented with 0.5× Q-solution, also for 40 cycles following the manufacturer’s recommended thermocycle profile. All microsatellites were labelled with 6-FAM, HEX, or TET fluorophores and analysed on an ABI377 12 cm genotyping gel.

    View this table:
    Table 1

    Primer sequences for SNPs and microsatellites

    RESULTS

    Clinical characteristics

    Clinical features for all cases are summarised in table 2. Consistent with the literature, all except the very youngest patient had mild or moderate developmental delay and some degree of facial dysmorphism. Consent for publication of facial photographs was given in four cases (fig 1) and a further five were published previously (patients 75, 76, 10780, 419 and 622).2,4,7,16 Common features include round face with flattened nasal bridge, frontal bossing, deep-set eyes, up-slanting palpebral fissures, anteverted nares, and thin upper lip. In contrast, the facial dysmorphism in patient 63 was markedly different (see online supplementary information), consistent with her duplication for much of 2q37 and only a very small telomeric deletion (see molecular results below). AHO-like brachymetaphalangism was observed in 11 (55%) of our patients, autism or repetitive, hyperkinetic behaviours in seven (35%), non-febrile seizures also in seven (35%), eczema in five (25%), and heart abnormalities in four (20%). These frequencies are in keeping with those in the wider literature, with the exception of epilepsy, which has been reported in about one-quarter of patients overall. Frequencies for brachymetaphalangism and autism may be underestimates, since some patients, both in this series and the wider literature, are too young to manifest these phenotypes, while eczema might be overlooked unless severe. There was a marked excess of females in our series, but this is much less apparent in the literature as a whole.

    View this table:
    Table 2

    Clinical characteristics of patients

    Figure 1
    Figure 1

    Photographs of four patients with 2q37 deletion illustrate the typical facial appearance in this syndrome.

    Molecular characteristics

    Molecular results are summarised in fig 2. Parental samples were available in 16 of the 19 non-familial cases. All 16 were shown to be de novo rearrangements, none showed co-existence with the known 2q subtelomeric polymorphism37,38 and approximately equal proportions of paternally and maternally-derived rearrangements were observed. A similar lack of bias in parental origin is seen in Williams-Beuren, DiGeorge, and 18p- syndromes,39–41 whereas Sotos, Wolf-Hirschhorn, Cri-du-chat, and 18q- syndromes are predominantly paternal in origin42–45 and 1p36 deletions show a slight maternal bias.46

    Figure 2
    Figure 2

    Results and definition of minimal deletion intervals. Positions of markers are those from Ensembl genome assembly release 17.33.1 M, maternal; P, paternal; (P), assumed paternal origin, as patient and mother had one allele in common for every microsatellite tested but paternal sample was not available; n/a, not applicable to familial translocation; white shading, normal dosage; black shading, duplicated; grey shading, deleted; hatched shading, uninformative or not tested.

    As suggested by the original cytogenetic analyses, all patients were found to have terminal deletions with the exception of patient 75 (AW, Fisher et al16), who showed an interstitial deletion with the distal breakpoint localised between D2S140 (deleted) and AC005237CA (retained). Microsatellite analysis in patient 63 showed that the inverted duplication detected cytogenetically was accompanied by a previously undetected small terminal deletion. The duplicated and deleted regions were apparently separated by a small region of normal gene dosage, as judged by relative peak heights of the microsatellites. This has not yet been verified by alternative methods, but would be in keeping with the mechanism proposed by Bonaglia et al26 for the causation of inverted duplications.

    Breakpoint mapping and minimum deletion intervals

    Since we wished to focus on the critical interval for AHO-like phenotype, distal to D2S338, breakpoints in the larger deletions were not characterised in detail. Breakpoints in the nine smallest terminal deletions, the translocation, and one duplication/deletion all localised within a 3.8 Mb region bounded by D2S338 proximally and AC013469CA distally. Two of these breakpoints, patients 10780 and 122, were precisely localised to non-overlapping intervals of 169 and 33.8 kb, respectively, within the HDAC4 gene. Taken as a whole, these data define the most distal breakpoints so far characterised for both interstitial and terminal 2q37 deletions.

    We then attempted to define the minimal deleted interval for each of the major features of the syndrome (fig 2). Due to the apparent reduced penetrance, this was done on an inclusion-only basis, that is, the absence of a clinical characteristic was not used as a criterion for excluding that genomic region. The critical interval for the AHO-like brachymetaphalangism extends from HDAC4 to the telomere, a region of approximately 3 Mb, as defined by patients 10780 and 122. These patients also both show the characteristic facial dysmorphism. The interstitial nature of the deletion in patient 75, who clinically showed an atrial septal defect, eczema, epilepsy, and autism,16 potentially excludes a number of the most telomeric 2q genes as candidates for these phenotypes. Thus, the minimum deleted region amongst our patients with autistic or hyperkinetic behaviour and/or epilepsy is ~2.1 Mb between HDAC4 and AC005237CA. An overlapping 1.5 Mb region is deleted in patients with eczema, while RAMP1 and AC005237CA bound a ~3.4 Mb region common to patients with cardiac septal defects (fig 2).

    DISCUSSION

    Genotype–phenotype correlations have been instructive in a number of other deletion syndromes to define discrete clinical subgroups, leading to more accurate prognostication and identification of candidate genes for specific phenotypes.44,46–50 In conducting this detailed analysis of 20 patients with 2q37 rearrangements, our aims were threefold: (a) to refine the minimal deleted region for the AHO-like brachymetaphalangism; (b) to determine whether genotype–phenotype correlations could be drawn for other features of the syndrome; and (c) to precisely map the breakpoints as possible clues to the rearrangement mechanism.

    Brachymetaphalangism

    The critical interval for the AHO-like brachymetaphalangism is unequivocally assigned to the 3 Mb region from HDAC4 to the telomere. This represents a refinement of approximately 2 Mb compared to the previous minimum interval.15 It has previously been suggested that much of this interval could be excluded due to arachnodactyly in patient 8493.26 However, the duplicated region in this patient extends just proximal of the Indian hedgehog gene (IHH). Mutations of IHH are now known to cause brachydactyly type A.51 Therefore, duplication of the gene might result in the reverse phenotype, unusually long fingers, which would account for the arachnodactyly phenotype in this patient and would likely override any subtle abnormality due to the terminal 2q deletion. Three genes previously proposed as candidates for the brachymetaphalangism phenotype, GPC1, HDLBP, and STK25,10,12,52 are localised within the 3 Mb minimal region and remain candidates. Conversely, TWIST2, which we considered a candidate gene on the basis of its proposed role in regulating osteoblast development,53 is not deleted in patient 10780 and can therefore be excluded. Brachymetaphalangism is partially penetrant and is present in approximately half of the patients deleted for this minimum region. Some patients show additional, more serious, skeletal abnormalities but, due to the small number characterised to date, it is unclear whether these represent pleiotropic effects of the same underlying gene.

    Additional clinical features

    Several other features of 2q37 deletions, such as congenital heart anomalies, eczema, autism, and epilepsy, have potentially greater morbidity and thus are clinically more significant. We therefore sought to make genotype–phenotype correlations and investigate whether these are discrete features of a contiguous gene deletion syndrome or pleiotropic effects of haplo-insufficiency for a single gene. Minimum intervals, ranging from 1.5 to 3.4 Mb, could be defined for each of these features. However, these phenotypes are less specific than brachymetaphalangism and, being more common in the general population, phenocopies will also exist. Thus, our assignment of critical intervals for these phenotypes, which is based on a small number of patients, should be regarded as preliminary and requires verification in a larger panel of patients. Some additional support for an autism susceptibility locus at 2q37.3 is already available from a small terminal deletion in a patient with isolated autism32 and from a weak suggestion of linkage in one genome scan.54 As presently defined, all minimum intervals share a 1.5 Mb region of overlap. Thus it remains to be determined whether the 2q37 deletion phenotype represents a contiguous gene deletion syndrome and it is possible that developmental abnormalities of several organ systems might result from haplo-insufficiency of a single gene.

    Genotype–phenotype correlations

    Amongst this panel of 2q37 deletion patients, we found no clear relationship between clinical features and the size or position of the monosomic region. Patients with very similar deletion breakpoints showed markedly different phenotypes, for example 10780 and 122, or 127 and 389. The same is true in translocation families, where individuals with identical 2q37 deletions have been reported with discordant phenotypes.12,14 This represents a significant challenge in predicting phenotype for this deletion, since the likely clinical outcome in a young proband cannot be determined from the deletion breakpoints. Variable expressivity is common in deletion syndromes and may be due to reduced penetrance of the haplo-insufficient genes, epigenetic factors, modifying effects of other genes, as recently proposed for VEGF and cardiovascular defects in DiGeorge (del22q11) syndrome,55 or multigenic inheritance.56 An additional factor might be recessive phenotypes that are only uncovered in a minority of deletion patients.

    Mechanism of rearrangement

    Elucidating chromosomal breakpoints can provide clues as to the underlying mechanism of rearrangement. Several interstitial deletion syndromes, including Williams-Beuren (7q), Smith-Magenis (17p) and DiGeorge (22q), show clustered breakpoints and are commonly mediated by low copy repeat sequences and inversion polymorphisms.57–59 Clusters of olfactory receptor (OR) genes have also been implicated in recurrent rearrangements involving chromosomes 4p and 8p.60,61 OR-like genes have also been mapped to 2q37.3, but they do not co-localise with the deletion breakpoints in our patients. Furthermore, a recent study suggests that duplicated segments are not involved in mediating the majority of terminal deletions and translocations.62 Our data, which show a lack of identical breakpoint locations, support this finding.

    Summary

    This detailed analysis of 20 patients with 2q37.3 monosomy has, for the first time, allowed minimal deletion intervals to be defined for all the major phenotypes of the syndrome. However, there is striking phenotypic variability and it is clear that the size and extent of the deleted region cannot be used as a predictor of the likely phenotype in the patient. As increasing numbers of small deletions are detected by more widespread use of subtelomeric FISH, this presents a challenge for clinicians in trying to determine the likely prognosis for a young proband. Ultimately, therefore, the real challenge is to identify not only the gene(s) on 2q37 responsible for the phenotypes in these patients, but also the modifiers, be they genetic, epigenetic, or environmental, that contribute to the phenotypic variability between patients with similar breakpoints. Only then can we begin to give more precise prognostic information to the parents of a child newly-diagnosed with a 2q37.3 deletion.

    Acknowledgments

    We are indebted to Patricia Jacobs for forging this collaboration and to the families for their cooperation in this study. We thank Sue Price and Sheila Youings for additional clinical input and sample collection, John Armour for advice in setting up MAPH, the clinical cytogenetics staff in Salisbury, Leicester, Birmingham, and Manchester for their expertise, and Berendine van Zyl for additional mapping work. CE is a Doris Duke Distinguished Clinical Scientist.

    REFERENCES

    1. ↵
      Phelan M C, Rogers RC, Clarkson KB, Bowyer FP, Levine MA, Estabrooks LL, Severson MC, Dobyns WB. Albright hereditary osteodystrophy and del(2)(q37.3) in four unrelated individuals. Am J Med Genet1995;58:1–7.
      OpenUrlCrossRefPubMedWeb of Science
    2. ↵
      Wilson LC, Leverton K, Oude Luttikhuis MEM, Oley CA, Flint J, Wolstenholme J, Duckett DP, Barrow MA, Leonard JV, Read AP, Trembath RC. Brachydactyly and mental retardation: an Albright hereditary osteodystrophy-like syndrome localised to 2q37. Am J Hum Genet1995;56:400–7.
      OpenUrlPubMedWeb of Science
    3. Haag M, Gilfillan T, Berry R, Hull C, Stewart J, Manchester DK, McGavran L. Microdeletion in chromosome 2qter in two unrelated children with characteristic facies and mental retardation. Am J Hum Genet1993;53:A1571.
      OpenUrl
    4. ↵
      Power MM, James RS, Barber JCK, Fisher AM, Wood PJ, Leatherdale BA, Flanagan DEH, Hatchwell E. RDC1, the vasoactive intestinal peptide receptor: a candidate gene for the features of Albright hereditary osteodystrophy associated with deletion of 2q37. J Med Genet1997;34:287–90.
      OpenUrlAbstract/FREE Full Text
    5. ↵
      Friedman BD, Gorski JL, Hall BD, Brothman A, Carey JC, Arbor WL. Deletion of chromosomal region 2q37: clinical phenotype in eight cases. Am J Hum Genet1997;61:A545.
      OpenUrl
    6. ↵
      Viot-Szoboszlai G, Amiel J, Doz F, Prieur M, Couturier J, Zucker JN, Henry I, Munnich A, Vekemans M, Lyonnet S. Wilms’ tumor and gonadal dysgenesis in a child with the 2q37.1 deletion syndrome. Clin Genet1998;53:278–80.
      OpenUrlPubMedWeb of Science
    7. ↵
      Bijlsma EK, Aalfs CM, Sluijter S, Oude Luttikhuis MEM, Trembath RC, Hoovers JMN, Hennekam RCM. Familial cryptic translocation between chromosomes 2qter and 8qter: further delineation of the Albright hereditary osteodystrophy-like phenotype. J Med Genet1999;36:604–9.
      OpenUrlAbstract/FREE Full Text
    8. Braddock BR, Shrimpton AE, Stein CS, Hoo JJ. Two distinctively different phenotypes of 2q37 terminal deletion: location of a gene on telomeric 2q37 mimicking Albright hereditary osteodystrophy/pseudohypoparathyroidism. Am J Hum Genet1999;65:A861.
    9. ↵
      Reddy KS, Flannery D, Farrer RJ. Microdeletion of chromosome sub-band 2q37.3 in two patients with abnormal situs visceram. Am J Med Genet1999;84:460–8.
      OpenUrlCrossRefPubMedWeb of Science
    10. ↵
      Smith M, Escamilla JR, Filipek P, Bocian ME, Modahl C, Flodman P, Spence MA. Molecular genetic delineation of 2q37.3 deletion in autism and osteodystrophy: report of a case and of new markers for deletion screening by PCR. Cytogenet Cell Genet2001;94:15–22.
      OpenUrlCrossRefPubMedWeb of Science
    11. ↵
      Rio M, Molinari F, Heuertz S, Ozilou C, Gosset P, Raoul O, Cormier-Daire V, Amiel J, Lyonnet S, Le Merrer M, Turleau C, de Blois MC, Prieur M, Romana S, Vekemans M, Munnich A, Colleaux L. Automated fluorescent genotyping detects 10% of cryptic subtelomeric rearrangements in idiopathic syndromic mental retardation. J Med Genet2002;39:266–70.
      OpenUrlAbstract/FREE Full Text
    12. ↵
      Syrrou M, Keymolen K, Devriendt K, Holvoet M, Thoelen R, Verhofstadt K, Fryns J-P. Glypican 1 gene: good candidate for brachydactyly type E. Am J Med Genet2002;108:310–4.
      OpenUrlPubMed
    13. Weise A, Starke H, Heller A, Tonnies H, Volleth M, Stumm M, Gabriele S, Nietzel A, Claussen U, Liehr T. Chromosome 2 aberrations in clinical cases characterised by high resolution multicolour banding and region specific FISH probes. J Med Genet2002;39:434–9.
      OpenUrlFREE Full Text
    14. ↵
      Batstone PJ, Simpson S, Bonthron DT, Keng WT, Hamilton D, Forsyth L, Sales M, Pratt N, Goudie D. Effective monosomy or trisomy of chromosome band 2q37.3 due to the unbalanced segregation of a 2;11 translocation. Am J Med Genet2003;118A:241–6.
    15. ↵
      Giardino D, Finelli P, Gottardi G, De Canal G, Monica MD, Lonardo F, Scarano G, Larizza L. Narrowing the candidate region of Albright hereditary osteodystrophy-like syndrome by deletion mapping in a patient with an unbalanced cryptic translocation t(2;6)(q37.3;q26). Am J Med Genet2003;122A:261–5.
    16. ↵
      Fisher AM, Ellis KH, Browne CE, Barber JCK, Barker M, Kennedy CR, Foley H, Patton MA. Small terminal deletions of the long arm of chromosome 2: two new cases. Am J Med Genet1994;53:366–9.
      OpenUrlCrossRefPubMedWeb of Science
    17. ↵
      Wang TH, Johnston K, Hsieh CL, Dennery PA. Terminal deletion of the long arm of chromosome 2 in a premature infant with karyotype: 46,XY,del(2)(q37). Am J Med Genet1994;49:399–401.
      OpenUrlCrossRefPubMedWeb of Science
    18. Stratton RF, Tolworthy JA, Young RS. Deletion (2)(q37). Am J Med Genet1994;51:153–5.
      OpenUrlPubMed
    19. ↵
      Conrad B, Dewald G, Christensen E, Lopez M, Higgins J, Pierpoint ME. Clinical phenotype associated with terminal 2q37 deletion. Clin Genet1995;48:134–9.
      OpenUrlPubMedWeb of Science
    20. ↵
      Ardinger HH, Persons DL, Lutz RE, Beattie MA. Significant hypotonia and developmental delay: hallmarks of a terminal deletion of chromosome 2q. Am J Hum Genet1999;65:A853.
      OpenUrl
    21. Giardino D, Finelli P, Gottardi G, Clerici D, Mosca F, Briscioli V, Larizza L. Cryptic subtelomeric translocation t(2;16)(q37;q24) segregating in a family with unexplained stillbirths and a dysmorphic, slightly retarded child. Eur J Hum Genet2001;9:881–6.
      OpenUrlCrossRefPubMed
    22. ↵
      Temple IK, Browne C, Hodgkins P. Anterior chamber eye anomalies, redundant skin and syndactyly—a new syndrome associated with breakpoints at 2q37.2 and 7q36.3. Clin Dysmorphol1999;8:157–63.
      OpenUrlPubMed
    23. ↵
      Ghaffari SR, Boyd E, Tolmie JL, Crow YJ, Trainer AH, Connor JM. A new strategy for cryptic telomeric translocation screening in patients with idiopathic mental retardation. J Med Genet1998;35:225–33.
      OpenUrlAbstract/FREE Full Text
    24. ↵
      Bruyere H, Rajcan-Separovic E, Doyle J, Pantzar T, Langlois S. Familial cryptic translocation (2;17) ascertained through recurrent spontaneous abortions. Am J Med Genet2003;123A:285–9.
    25. ↵
      Stein CK, Del Signore C, Bellinger M, Bryke CR. Deletion of 2q37—a new syndrome? Am J Hum Genet1992;51:A1223.
      OpenUrl
    26. ↵
      Bonaglia MC, Giorda R, Poggi G, Raggi ME, Rossi E, Baroncini A, Giglio S, Borgatti R, Zuffardi O. Inverted duplications are recurrent rearrangements always associated with a distal deletion: description of a new case involving 2q. Eur J Hum Genet2000;8:597–603.
      OpenUrlCrossRefPubMedWeb of Science
    27. ↵
      Bacino CA, Kashork CD, Davino NA, Shaffer LG. Detection of a cryptic translocation in a family with mental retardation using FISH and telomere region-specific probes. Am J Med Genet2000;92:250–5.
      OpenUrlCrossRefPubMedWeb of Science
    28. ↵
      Gorski JL, Cox BA, Kyine M, Uhlmann W, Glover TW. Terminal deletion of the long arm of chromosome 2 in a mildly dysmorphic hypotonic infant with karyotype 46,XY,del(2)(q37). Am J Med Genet1989;32:350–2.
      OpenUrlCrossRefPubMedWeb of Science
    29. ↵
      Daniel A, Baker E, Chia N, Haan E, Malafiej P, Hinton L, Clarke N, Ades L, Darmanian A, Callen D. Recombinants of intrachromosomal transposition of subtelomeres in chromosomes 1 and 2: a cause of minute terminal chromosomal imbalances. Am J Med Genet2003;117A:57–64.
    30. Burd L, Martsolf JT, Kerbeshian J, Jalal SM. Partial 6p trisomy associated with infantile autism. Clin Genet1988;33:356–9.
      OpenUrlPubMedWeb of Science
    31. Speleman F, Callens B, Logghe K, Van Roy N, Horsley SW, Jauch A, Verschraegen-Spae MR, Leroy JG. Subtelomeric familial translocation t(2;7)(q37;q35) leading to partial trisomy 7q35→qter: molecular cytogenetic analysis and clinical phenotype in two generations. Am J Med Genet2000;93:349–54.
      OpenUrlCrossRefPubMed
    32. ↵
      Wolff DJ, Clifton K, Karr C, Charles J. Pilot assessment of the subtelomeric regions of children with autism: detection of a 2q deletion. Genet Med2002;4:10–4.
      OpenUrlPubMedWeb of Science
    33. ↵
      Lehman NL, Zaleski DH, Sanger WG, Adickes E, eds. Holoprosencephaly associated with an apparent isolated 2q37. 1→2q37. 3 deletion. Am J Med Genet2001;100:179–81.
      OpenUrlCrossRefPubMedWeb of Science
    34. ↵
      Armour JA, Sismani C, Patsalis PC, Cross G. Measurement of locus copy number by hybridisation with amplifiable probes. Nucleic Acids Res2000;28:605–9.
      OpenUrlAbstract/FREE Full Text
    35. ↵
      White S, Kalf M, Liu Q, Villerius M, Engelsma D, Kriek M, Vollebregt E, Bakker B, van Ommen GJ, Breuning MH, den Dunnen JT. Comprehensive detection of genomic duplications and deletions in the DMD gene, by use of multiplex amplifiable probe hybridization. Am J Hum Genet2002;71:365–74.
      OpenUrlCrossRefPubMedWeb of Science
    36. ↵
      Benson G. Tandem repeats finder: a program to analyze DNA sequences. Nucleic Acids Res1999;27:573–80.
      OpenUrlAbstract/FREE Full Text
    37. ↵
      Knight SJ, Lese CM, Precht KS, Kuc J, Ning Y, Lucas S, Regan R, Brenan M, Nicod A, Lawrie NM, Cardy DL, Nguyen H, Hudson TJ, Riethman HC, Ledbetter DH, Flint J. An optimized set of human telomere clones for studying telomere integrity and architecture. Am J Hum Genet2000;67:320–32.
      OpenUrlCrossRefPubMedWeb of Science
    38. ↵
      Ballif BC, Kashork CD, Shaffer LG. The promise and pitfalls of telomere region-specific probes. Am J Hum Genet2000;67:1356–9.
      OpenUrlPubMedWeb of Science
    39. ↵
      Nickerson E, Greenberg F, Keating MT, McCaskill C, Shaffer LG. Deletions of the elastin gene at 7q11.23 occur in approximately 90% of patients with Williams syndrome. Am J Hum Genet1995;56:1156–61.
      OpenUrlPubMedWeb of Science
    40. Baumer A, Dutly F, Balmer D, Riegel M, Tukel T, Krajewska-Walasek M, Schinzel AA. High level of unequal meiotic crossovers at the origin of the 22q11. 2 and 7q11.23 deletions. Hum Mol Genet1998;7:887–94.
      OpenUrlAbstract/FREE Full Text
    41. ↵
      Schaub RL, Reveles XT, Baillargeon J, Leach RJ, Cody JD. Molecular characterization of 18p deletions: evidence for a breakpoint cluster. Genet Med2002;4:15–9.
      OpenUrlPubMed
    42. ↵
      Cody JD, Pierce JF, Brkanac Z, Plaetke R, Ghidoni PD, Kaye CI, Leach RJ. Preferential loss of the paternal alleles in the 18q- syndrome. Am J Med Genet1997;69:280–6.
      OpenUrlCrossRefPubMed
    43. Wieczorek D, Krause M, Majewski F, Albrecht B, Horn D, Riess O, Gillessen-Kaesbach G. Effect of the size of the deletion and clinical manifestation in Wolf-Hirschhorn syndrome: analysis of 13 patients with a de novo deletion. Eur J Hum Genet2000;8:519–26.
      OpenUrlCrossRefPubMedWeb of Science
    44. ↵
      Mainardi PC, Perfumo C, Cali A, Coucourde G, Pastore G, Cavani S, Zara F, Overhauser J, Pierluigi M, Bricarelli FD. Clinical and molecular characterisation of 80 patients with 5p deletion: genotype-phenotype correlation. J Med Genet2001;38:151–8.
      OpenUrlAbstract/FREE Full Text
    45. ↵
      Miyake N, Kurotaki N, Sugawara H, Shimokawa O, Harada N, Kondoh T, Tsukahara M, Ishikiriyama S, Sonoda T, Miyoshi Y, Sakazume S, Fukushima Y, Ohashi H, Nagai T, Kawame H, Kurosawa K, Touyama M, Shiihara T, Okamoto N, Nishimoto J, Yoshiura K, Ohta T, Kishino T, Niikawa N, Matsumoto N. Preferential paternal origin of microdeletions caused by prezygotic chromosome or chromatid rearrangements in Sotos syndrome. Am J Hum Genet2003;72:1331–7.
      OpenUrlCrossRefPubMedWeb of Science
    46. ↵
      Heilstedt HA, Ballif BC, Howard LA, Lewis RA, Stal S, Kashork CD, Bacino CA, Shapira SK, Shaffer LG. Physical map of 1p36, placement of breakpoints in monosomy 1p36, and clinical characterization of the syndrome. Am J Hum Genet2003;72:1200–12.
      OpenUrlCrossRefPubMedWeb of Science
    47. Zollino M, Lecce R, Fischetto R, Murdolo M, Faravelli F, Selicorni A, Butte C, Memo L, Capovilla G, Neri G. Mapping the Wolf-Hirschhorn syndrome phenotype outside the currently accepted WHS critical region and defining a new critical region, WHSCR-2. Am J Hum Genet2003;72:590–7.
      OpenUrlCrossRefPubMedWeb of Science
    48. Endele S, Fuhry M, Pak SJ, Zabel BU, Winterpacht A. LETM1, a novel gene encoding a putative EF-hand Ca(2+)-binding protein, flanks the Wolf-Hirschhorn syndrome (WHS) critical region and is deleted in most WHS patients. Genomics1999;60:218–25.
      OpenUrlCrossRefPubMedWeb of Science
    49. Green EK, Priestley MD, Waters J, Maliszewska C, Latif F, Maher ER. Detailed mapping of a congenital heart disease gene in chromosome 3p25. J Med Genet2000;37:581–7.
      OpenUrlAbstract/FREE Full Text
    50. ↵
      Robinson SW, Morris CD, Goldmuntz E, Reller MD, Jones MA, Steiner RD, Maslen CL. Missense mutations in CRELD1 are associated with cardiac atrioventricular septal defects. Am J Hum Genet2003;72:1047–52.
      OpenUrlCrossRefPubMedWeb of Science
    51. ↵
      Gao B, Guo J, She C, Shu A, Yang M, Tan Z, Yang X, Guo S, Feng G, He L. Mutations in IHH, encoding Indian hedgehog, cause brachydactyly type A-1. Nat Genet2001;28:386–8.
      OpenUrlCrossRefPubMedWeb of Science
    52. ↵
      Davids MS, Crawford E, Weremowicz S, Morton CC, Copeland NG, Gilbert DJ, Jenkins NA, Phelan MC, Comb MJ, Melnick MB. STK25 is a candidate gene for pseudopseudohypoparathyroidism. Genomics2001;77:2–4.
      OpenUrlPubMed
    53. ↵
      Lee MS, Lowe G, Flanagan S, Kuchler K, Glackin CA. Human Dermo-1 has attributes similar to twist in early bone development. Bone2000;27:591–602.
      OpenUrlPubMed
    54. ↵
      Yonan AL, Alarcon M, Cheng R, Magnusson PK, Spence SJ, Palmer AA, Grunn A, Juo SH, Terwilliger JD, Liu J, Cantor RM, Geschwind DH, Gilliam TC. A genome wide screen of 345 families for autism-susceptibility loci. Am J Hum Genet2003;73:886–97.
      OpenUrlCrossRefPubMedWeb of Science
    55. ↵
      Stalmans I, Lambrechts D, De Smet F, Jansen S, Wang J, Maity S, Kneer P, von der Ohe M, Swillen A, Maes C, Gewillig M, Molin DG, Hellings P, Boetel T, Haardt M, Compernolle V, Dewerchin M, Plaisance S, Vlietinck R, Emanuel B, Gittenberger-de Groot AC, Scambler P, Morrow B, Driscol DA, Moons L, Esguerra CV, Carmeliet G, Behn-Krappa A, Devriendt K, Collen D, Conway SJ, Carmeliet P. VEGF: a modifier of the del22q11 (DiGeorge) syndrome? Nat Med2003;9:173–82.
      OpenUrlCrossRefPubMedWeb of Science
    56. ↵
      Ming JE, Muenke M. Multiple hits during early embryonic development: digenic diseases and holoprosencephaly. Am J Hum Genet2002;71:1017–32.
      OpenUrlCrossRefPubMedWeb of Science
    57. ↵
      Ji Y, Eichler EE, Schwartz S, Nicholls RD. Structure of chromosomal duplicons and their role in mediating human genomic disorders. Genome Res2000;10:597–610.
      OpenUrlAbstract/FREE Full Text
    58. Osborne LR, Li M, Pober B, Chitayat D, Bodurtha J, Mandel A, Costa T, Grebe T, Cox S, Tsui LC, Scherer SW. A 1.5 million-base pair inversion polymorphism in families with Williams-Beuren syndrome. Nat Genet2001;29:321–5.
      OpenUrlCrossRefPubMedWeb of Science
    59. ↵
      Stankiewicz P, Lupski JR. Molecular-evolutionary mechanisms for genomic disorders. Curr Opin Genet Dev2002;12:312–9.
      OpenUrlCrossRefPubMedWeb of Science
    60. ↵
      Giglio S, Broman KW, Matsumoto N, Calvari V, Gimelli G, Neumann T, Ohashi H, Voullaire L, Larizza D, Giorda R, Weber JL, Ledbetter DH, Zuffardi O. Olfactory receptor-gene clusters, genomic-inversion polymorphisms, and common chromosome rearrangements. Am J Hum Genet2001;68:874–83.
      OpenUrlCrossRefPubMedWeb of Science
    61. ↵
      Giglio S, Calvari V, Gregato G, Gimelli G, Camanini S, Giorda R, Ragusa A, Guerneri S, Selicorni A, Stumm M, Tonnies H, Ventura M, Zollino M, Neri G, Barber J, Wieczorek D, Rocchi M, Zuffardi O. Heterozygous submicroscopic inversions involving olfactory receptor-gene clusters mediate the recurrent t(4;8)(p16;p23) translocation. Am J Hum Genet2002;71:276–85.
      OpenUrlCrossRefPubMedWeb of Science
    62. ↵
      Schwartz S, Astbury C, Bailey J, Crowe C, Eichler EE, Eichenmiller M, Graf M. Delineation of genomic breakpoints in chromosomal rearrangements: lack of involvement of duplicated segments. Am J Hum Genet2003;73:A206.
      OpenUrl

    Supplementary materials

    • Web-only Appendix

      The appendix is available as a downloadable PDF (printer friendly file).

      If you do not have Adobe Reader installed on your computer,
      you can download this free-of-charge, please Click here

       

      Files in this Data Supplement:

      • [View PDF] - Clinical descriptions of previously unpublished patients

    Footnotes

    • This work was supported by the Wellcome Trust through a grant to PJ and an Advanced Training Fellowship to MAA (ref: 064271/Z/01/Z).

    • Conflict of interest: none declared.