- Open Access
Molecular cytogenetic characterisation of a mosaic add(12)(p13.3) with an inv dup(3)(q26.31 → qter) detected in an autistic boy
© Carreira et al; licensee BioMed Central Ltd. 2009
Received: 18 May 2009
Accepted: 4 August 2009
Published: 4 August 2009
Inverted duplications (inv dup) of a terminal chromosome region are a particular subset of rearrangements that often results in partial tetrasomy or partial trisomy when accompanied by a deleted chromosome. Associated mosaicism could be the consequence of a post-zygotic event or could result from the correction of a trisomic conception. Tetrasomies of distal segments of the chromosome 3q are rare genetic events and their phenotypic manifestations are diverse. To our knowledge, there are only 12 cases reported with partial 3q tetrasomy. Generally, individuals with this genomic imbalance present mild to severe developmental delay, facial dysmorphisms and skin pigmentary disorders.
We present the results of the molecular cytogenetic characterization of an unbalanced mosaic karyotype consisting of mos 46,XY,add(12)(p13.3) /46,XY  in a previously described 11 years old autistic boy, re-evaluated at adult age. The employment of fluorescence in situ hybridization (FISH) and multicolor banding (MCB) techniques identified the extra material on 12p to be derived from chromosome 3, defining the additional material on 12p as an inv dup(3)(qter → q26.3::q26.3 → qter). Subsequently, array-based comparative genomic hybridization (aCGH) confirmed the breakpoint at 3q26.31, defining the extra material with a length of 24.92 Mb to be between 174.37 and 199.29 Mb.
This is the thirteenth reported case of inversion-duplication 3q, being the first one described as an inv dup translocated onto a non-homologous chromosome. The mosaic terminal inv dup(3q) observed could be the result of two proposed alternative mechanisms. The most striking feature of this case is the autistic behavior of the proband, a characteristic not shared by any other patient with tetrasomy for 3q26.31 → 3qter. The present work further illustrates the advantages of the use of an integrative cytogenetic strategy, composed both by conventional and molecular techniques, on providing powerful information for an accurate diagnosis. This report also highlights a chromosome region potentially involved in autistic disorders.
According to the orientation of the duplicated segment, duplications may be classified either as tandem or inverted, being the last usually associated with deletion of the distal region of the duplicated chromosome . The best studied cases of inverted duplications (inv dup) are the inv dup(8p) [2, 3] and bisatellited inv dup(15) , which are usually non-mosaic. In contrast, mosaic inverted duplications are derived from different post-zygotic mechanisms for which various possible origins have been proposed [5–7]. There is also a particular subset of inv dup in which the duplication ends terminally on the chromosome and which are named terminal inv dup [8, 9].
Tetrasomy of distal 3q segments is associated with adverse phenotypic manifestations, ranging from mild developmental delay to deep facial dysmorphisms, resembling patients with the dup(3q) and Brachmann-de Lange syndromes. Accordingly, some of the patients with 3q tetrasomy show hirsutism, synophrys, broad nasal root, anteverted nares, thin upper lip with downturned mouth corners, craniosynostosis, urinary tract anomalies, micrognathia, cleft palate and malformed ears, characteristics also seen in patients with the dup(3q) syndrome . Brachmann-de Lange syndrome (BDLS) has overlapping features with dup(3q) syndrome, but with apparently normal chromosomes [11, 12].
In this study we characterize by molecular cytogenetics a case of an autistic child previously reported by our group, with a mosaic partial tetrasomy of a distal chromosome 3q segment translocated to the short arm of the chromosome 12 . To our knowledge, this is the first report of a mosaic terminal inv dup(3q) captured in an intact 12p subtelomere. Using fluorescence in situ hybridization (FISH) and array-based comparative genomic hybridization (aCGH) we have better characterized the extra material of chromosome 3 as qter → q26.31::q26.31 → qter. Furthermore, the mechanism of formation for this rearrangement is discussed.
The male child was the first born of non-consanguineous healthy parents and was delivered at term after an uneventful pregnancy. His birth weight was 2850 g (<5th centile) and there were no major neonatal problems, except for the club foot surgically corrected. However, a general developmental delay was noted soon after birth and fever convulsions were observed between the age of 9 and 24 months old.
As a consequence of suspicions of a pervasive developmental disorder of autistic type, at the age of 3, the proband was referred to a child psychiatrist, who directed him to an autism unit. At 11 years old, his height was between the 25th and 50th centile, weight was on the 90th centile and head circumference was on the 50th centile. Some minor dismorphic features were also observed, such as low set and slightly enlarged ears, high and arched palate and round face. No skin pigmentation disorders were observed. He was submitted to a multidisciplinary neurodevelopmental assessment and showed an adaptive behavior at the 30 month age level and a nonverbal IQ of 61, corresponding to a mild delay, a diagnosis of autism was based on Autism diagnostic interview-revised and the Statistical Mental Disorder IV edition criteria [13–15]. At adult age the proband maintain a clinic of autism and has an adaptative behaviour evaluated with Vineland Adaptative behaviour scales – survey form with a standard score of 30 for communication domain, 59 for daily living skills domain and 63 for socialization domain .
Conventional cytogenetic analysis
Skin fibroblast cultures of the proband confirmed the mosaic, with the abnormal cell line in only 14% of the 50 metaphases studied. As expected, the karyotypes of both parents were normal.
Molecular cytogenetic Studies
FISH and MCB analysis
Further FISH analysis was performed using specific probes for the subtelomeric regions of chromosome 3 (D3S4559, D3S4560; Vysis) which showed that the subtelomeric regions of both chromosomes 3 were intact, and that the 3q subtelomeric probe hybridised at both ends of the extra segment, suggesting an inverted duplication of the terminal 3q (Fig. 2A). To identify a possible loss or cryptic translocation of the 12p sutelomere, the subtelomeric probe for 12pter (GenBank U57865, Vysis) was used. It hybridized as expected in the normal chromosome 12 and an hybridization signal was also seen in the der(12), at the junction point of the additional material (Fig. 2B). The G-banding was revisited, taking into account the FISH findings (Fig. 1), and the additional material on 12p was interpreted as an inverted duplicated segment inv dup(3)(qter → q26.3::q26.3 → qter) being the patient tetrasomic for the region 3q26.3 → 3qter.
To confirm this result described previously by us , multicolor banding (MCB) analysis was performed using a chromosome 3 specific probe set . It was proved that the additional material on 12 resulted from an inverted duplication of the terminal portion of 3q(:qter → q26.3::q26.3 → qter) (Fig. 2C). Altogether these results led to the final karyotype: mos 46,XY,add12(p13.3).ish inv dup(3)(qter → q26.3::q26.3 → qter)(wcp3+,pcp3q+,D3S4560++) /46,XY .
In this work we have characterized by molecular cytogenetics a tetrasomy of a 3qter fragment. The carrier presents minor facial dysmorphisms and general developmental delay associated with an autistic disorder. His karyotype was initially established from peripheral blood lymphocytes as mos 46,XY,add(12)(p13.3) /46,XY  . The use of MCB and aCGH techniques allowed the characterization of the extra material as being derived from chromosome 3, involving an inv dup(3)(qter → q26.3::q26.3 → qter) and with a length of 24.92 Mb.
Vanneste and colleagues have described that post-zygotic chromosome instability is highly frequent in cleavage-stage embryos, leading to segmental chromosomal imbalances and mosaicism, probably a common cause of constitutional chromosomal disorders. In this study, fifty-five percent of embryos carried terminal segmental imbalances, that were the result of DNA double-stranded breaks possibly followed by non-disjunction of the acentric fragment . This study reinforces the theory that mosaic inv dup formation is a post-zygotic event.
There are only twelve reported cases in the literature of inv dup associated with tetrasomy for distal chromosome 3q [10, 23–33]. Of all documented cases, our proband is the only one in which the tetrasomy is not an intrachromosomal triplication [32, 33] or a supernumerary marker chromosome [10, 23–31].
The chromosome region of the present rearrangement has been reported to be involved in both the BDLS (q26.3-q27) and the dup(3q) syndromes (with q26.3 being the critical region) [34–37]. Nonetheless, besides the mental retardation, the low set ears, the arched palate, our patient does not have any of the other 23 physical features compiled for those syndromes by Faas and colleagues .
Taking into account the twelve cases previously reported and the present one, it becomes evident that the phenotypes associated with tetrasomy of distal 3q segments are heterogeneous [10, 23–33]. As a consequence, we failed to establish any genotype-phenotype correlation once neither the region involved nor the degree of the mosaicism could be correlated with a consistent pattern. Nevertheless, the presence of skin pigmentary disorders is a particular feature that connects the majority of the cases reported [23, 25, 27–32]. Indeed, hyperpigmentation is present in 8 of the reported patients, with a pattern concordant with lines of Blaschko in 5 patients. Correlating these cases, Gimelli and colleagues proposed the presence of a gene involved in skin pigmentation defects located at 3q27.1-qter region . However, hypopigmentation and hyperpigmentation following the Blaschko's lines are relatively common in individuals with chromosomal mosaicism. In the present case, although involving the 3q27.1-qter region, there are no skin pigmentary alterations.
The autistic behavior observed in our patient, and not reported in any other case with distal 3q tetrasomy, is an interesting feature. According to the results of a genome-wide screen performed by Auranen and colleagues, there is evidence for a major susceptibility locus on chromosome 3q25-q27 for the autism-spectrum disorders . Accordingly, a study of the same group revealed the existence of an allelic association on chromosome 3q25-q27 in families with autism spectrum disorders originating from a sub-isolate of Finland [38, 39]. Since no other reported patient with 3qter tetrasomy demonstrated autistic behavior, we could be facing a random occurrence. However, it would be interesting to evaluate children with autistic behavior for micro-rearrangements in this region of chromosome 3.
To the best of our knowledge, this is the first study describing a mosaic interchromosomal inverted duplication of a 3qter segment captured in a non-homologous intact subtelomere (12pter). Also new is the fact that the proband presents an autistic behavior, not observed in any other patients with the same genomic imbalance. The concomitant employment of aCGH and multicolor FISH techniques contributed to the understanding of this unusual rearrangement.
Cytogenetic and FISH studies
Cytogenetic analysis was carried out on GTG-banded chromosomes (650 bands per haploid genome) prepared from peripheral blood lymphocytes and fibroblast cultures according to the standard protocols .
FISH studies were performed on metaphase spreads according to the standard procedures. M-multiprobe system (Cytocell Ltd, Adderbury, UK) was used to paint all chromosomes. For chromosome 3 individual wcp with a chromosome 3-specific library (Vysis Abbott Molecular, Inc., Des Plaines, IL) was used as well as specific subtelomeric probes for chromosomes 3 and 12 (Vysis). The derivative chromosome 12 was also studied by MCB applying the probe sets for chromosome 3 and 12, as described by Liehr and colleagues . FISH results were analyzed using a Nikon Eclipse fluorescence microscope (Nikon Instruments Europe B.V., Badhoevedorp, The Netherlands) coupled with a Cytovision system (Applied Imaging International Lda, Newcastle upon Tyne, UK). MCB was analysed using a Zeiss Axioplan fluorescence microscope (Zeiss; Jena, Germany) with MetaSystems (Isis) software (Altlussheim, Germany).
BAC aCGH was performed for all genome screening using a 1 Mb clone set. Control and patients' DNA were labelled with Cy5 and Cy3 dCTP's (Amersham Pharmacia Biotech, Piscataway, New Jersey) using a random prime labelling system (Bioprime DNA Labelling System, Invitrogen, Carlsbad, CA) according to established protocols . Scanning of the array was performed at 532 nm and 635 nm using a GenePix4000B scanner (Axon Instruments) and images were analyzed with the GenePix Pro 6.0 software. Correction of spot intensities for the local background followed previously described protocols .
We wish to thank the patient and his family for their participation. Supportted in parts by the Erwin-Riesch Stiftung.
- Van Dyke DL, Miller MJ, Weiss L: The origin of inverted tandem duplications, and phenotypic effects of tandem duplication of the X chromosome long arm. Am J Med Genet 1983, 15: 441–450. 10.1002/ajmg.1320150309PubMedView ArticleGoogle Scholar
- Floridia G, Piantanida M, Minelli A, et al.: The same molecular mechanism at the maternal meiosis I produces mono and dicentric 8p duplications. Am J Hum Genet 1996, 58: 785–796.PubMed CentralPubMedGoogle Scholar
- Giglio S, Broman KW, Matsumoto N, et al.: Olfactory receptor-gene clusters, genomic-inversion polymorphisms, and common chromosome rearrangements. Am J Hum Genet 2001, 68: 874–883. 10.1086/319506PubMed CentralPubMedView ArticleGoogle Scholar
- Leana-Cox J, Jenkins L, Palmer CG, Plattner R, Sheppard L, Flejter WL, Zackowski J, Tsien F, Schwartz S: Molecular cytogenetic analysis of inv dup(15) chromosomes, using probes specific for the Prader-Willi/Angelman syndrome region: clinical implications. Am J Hum Genet 1994, 54: 748–756.PubMed CentralPubMedGoogle Scholar
- Kotzot D, Martinez MJ, Bagci G, Basaran S, Baumer A, Binkert F, Brecevic L, Castellan C, Chrzanowska K, Dutly F, Gutkowska A, Karaüzüm SB, Krajewska-Walasek M, Luleci G, Miny P, Riegel M, Schuffenhauer S, Seidel H, Schinzel A: Parental origin and mechanisms of formation of cytogenetically recognisable de novo direct and inverted duplications. J Med Genet 2000, 37: 281–286. 10.1136/jmg.37.4.281PubMed CentralPubMedView ArticleGoogle Scholar
- Pramparo T, Giglio S, Gregato G, de Gregori M, Patricelli MG, Ciccone R, Scappaticci S, Mannino G, Lombardi C, Pirola B, Giorda R, Rocchi M, Zuffardi O: Inverted duplications: how many of them are mosaic? Eur J Hum Genet 2004, 12: 713–717. 10.1038/sj.ejhg.5201240PubMedView ArticleGoogle Scholar
- Chabchoub E, Rodríguez L, Galán E, Mansilla E, Martínez-Fernandez ML, Martínez-Frías ML, Fryns JP, Vermeesch JR: Molecular characterisation of a mosaicism with a complex chromosome rearrangement: evidence for coincident chromosome healing by telomere capture and neo-telomere formation. J Med Genet 2007, 44: 250–256. 10.1136/jmg.2006.045476PubMed CentralPubMedView ArticleGoogle Scholar
- Hoo JJ, Chao M, Szego K, Rauer M, Echiverri SC, Harris C: Four new cases of inverted terminal duplication: a modified hypothesis of mechanism of origin. Am J Med Genet 1995, 58: 299–304. 10.1002/ajmg.1320580402PubMedView ArticleGoogle Scholar
- Cotter PD, Kaffe S, Li L, Gershin IF, Hirschhorn K: Loss of subtelomeric sequence associated with a terminal inversion duplication of the short arm of chromosome 4. Am J Med Genet 2001, 102: 76–80. [http://www3.interscience.wiley.com/journal/84504012/abstract] 10.1002/1096-8628(20010722)102:1<76::AID-AJMG1389>3.0.CO;2-4PubMedView ArticleGoogle Scholar
- Izumi K, Yamashita Y, Aramaki M, Kosaki R, Hosokai N, Takahashi T, Kosaki K: Neocentromere marker chromosome of distal 3q mimicking dup(3q) syndrome phenotype. Am J Med Genet 2008, 146A: 1967–1971. 10.1002/ajmg.a.32120PubMedView ArticleGoogle Scholar
- Opitz JM: The Brachmann – de Lange Syndrome. Am J Med Genet 1985, 22: 89–102. 10.1002/ajmg.1320220110PubMedView ArticleGoogle Scholar
- Opitz JM: The Brachmann – de Lange Syndrome, a continuing enigma. Arch Pediatr Adolesc Med 1994, 148: 1206–68.PubMedView ArticleGoogle Scholar
- Oliveira G, Matoso E, Vicente A, Ribeiro P, Marques C, Ataíde A, Miguel T, Saraiva J, Carreira I: Partial tetrasomy of chromosome 3q and mosaicism in a child with autism. J Aut Develp Disord 2003, 33: 177–185. 10.1023/A:1022943627660View ArticleGoogle Scholar
- Lord C, Rutter M, LeCouteur A: Autism Diagnostic Interview-Revised: a revised version of a diagnostic interview for caregivers of individuals with possible pervasive developmental disorders. J Autism Dev Disord 1994, 24: 659–685. 10.1007/BF02172145PubMedView ArticleGoogle Scholar
- American Psychiatric Association: Diagnostic and statistical manual of mental disorders. Washington, D.C 4th edition. 1994. 10.1093/jpepsy/10.2.215Google Scholar
- Sparrow SS, Cicchetti DV: Diagnostic uses of the Vineland Adaptive Behavior Scales. Journal of Pediatric Psychology 1985, 10: 215–225. 10.1093/jpepsy/10.2.215PubMedView ArticleGoogle Scholar
- Liehr T, Heller A, Starke H, Rubtsov N, Trifonov V, Mrasek K, Weise A, Kuechler A, Claussen U: Microdissection based high resolution multicolour banding for all 24 chromosomes. Int J Mol Med 2002, 9: 335–339. 10.1186/1475-9268-7-1PubMedGoogle Scholar
- Daniel A, St Heaps L, Sylvester D, Diaz S, Peters G: Two mosaic terminal inverted duplications arising post-zygotically: Evidence for possible formation of neo-telomeres. Cell Chromosome 2008, 7: 1. 10.1136/jmg.2008.058016PubMed CentralPubMedView ArticleGoogle Scholar
- Kotzot D: Complex and segmental uniparental disomy updated. Journal of Medical Genetics 2008, 45: 545–556. 10.1093/hmg/6.8.1195PubMedView ArticleGoogle Scholar
- Depinet TW, Zackowski JL, Earnshaw WC, Kaffe S, Sekhon GS, Stallard R, Sullivan BA, Vance GH, Van Dyke DL, Willard HF, Zinn AB, Schwartz S: Characterization of neo-centromeres in marker chromosomes lacking detectable alpha-satellite DNA. Hum Mol Genet 1997, 6: 1195–1204. 10.1002/1096-8628(20010722)102:1<86::AID-AJMG1390>3.0.CO;2-TPubMedView ArticleGoogle Scholar
- Voullaire L, Saffery R, Earle E, Irvine DV, Slater H, Dale S, du Sart D, Fleming T, Choo KH: Mosaic inv dup(8p) marker chromosome with stable neocentromere suggests neocentromerization is a post-zygotic event. Am J Med Genet 2001, 102: 86–94. [http://www3.interscience.wiley.com/journal/84504001/abstract] 10.1002/1096-8628(20010722)102:1<86::AID-AJMG1390>3.0.CO;2-TPubMedView ArticleGoogle Scholar
- Vanneste E, Voet T, Le Caignec C, Ampe M, Konings P, Melotte C, Debrock S, Amyere M, Vikkula M, Schuit F, Fryns JP, Verbeke G, D'Hooghe T, Moreau Y, Vermeesch JR: Chromosome instability is common in human cleavage-stage embryos. Nat Med 2009, 15: 577–83. 10.1038/nm.1924PubMedView ArticleGoogle Scholar
- Portnoi MF, Boutchnei S, Bouscarat F, Morlier G, Nizard S, Dersarkissian H, Crickx B, Nouchy M, Taillemite JL, Belaich S: Skin pigmentary anomalies and mosaicism for an acentric marker chromosome originating from 3q. J Med Genet 1999, 36: 246–250. 10.1136/jmg.37.10.807PubMed CentralPubMedGoogle Scholar
- Cockwell A, Gibbons B, Moore I, Crolla JA: An analphoid supernumerary marker chromosome derived from chromosome 3 ascertained in a fetus with multiple malformations. J Med Genet 2000, 37: 807–809. 10.1002/1096-8628(20000911)94:2<113::AID-AJMG3>3.0.CO;2-QPubMed CentralPubMedView ArticleGoogle Scholar
- Teshima T, Bawle M, Weksberg R, Shuman C, Van Dyke DL, Schwartz S: Analphoid 3qter markers. Am J Med Genet 2000, 94: 113–119. [http://www3.interscience.wiley.com/cgi-bin/fulltext/73001349/PDFSTART] 10.1002/1096-8628(20000911)94:2<113::AID-AJMG3>3.0.CO;2-QPubMedView ArticleGoogle Scholar
- Barbi G, Spaich C, Adolph S, Kehrer-Sawatzki H: Analphoid de novo marker chromosome inv dup(3)(q28qter) with neocentromere in a dysmorphic and developmentally retarded girl. J Med Genet 2003, 40: e27. 10.1136/jmg.40.3.e27PubMed CentralPubMedView ArticleGoogle Scholar
- Yu J, Qi Z, Thompson K, Modaff P, Wells W, Meisner L, Pauli R: Characterization of a rare neocentric marker chromosome using chromosome microdissection. 54th annual meeting of the American Society of Human Genetics 2004, 192.Google Scholar
- Sullivan CM, Mountford ST, Emmerson JM, Ellis RJ, Turmbull C, Waters KS: A mosaic karyotype with an additional inv dup(3)(qter-q26.2::q26.2-qter), containing a neocentromere, detected in a skin biopsy from a girl with skeletal abnormalities, abnormal skin pigmentation and developmental delay. J Med Genet 2005,42(Suppl 1):S71.Google Scholar
- Liehr T: Small supernumerary marker chromosome (sSMC). [http://www.med.uni-jena.de/fish/sSMC/03.htm]
- Gimelli G, Giorda R, Beri S, Gimelli S, Zuffardi O: A large analphoid invdup(3)(q22.3qter) marker chromosome characterized by array-CGH in a child with malformations, mental retardation, ambiguous genitalia and Blaschko's lines. Eur J Med Genet 2007, 50: 264–273. 10.1016/j.ejmg.2007.04.003PubMedView ArticleGoogle Scholar
- Murthy SK, Malhotra AK, Jacob PS, Naveed S, Al-Rowaished EE, Mani S, Padariyakam S, Pramathan R, Nath R, Al-Ali MT, Al-Gazali L: Analphoid supernumerary marker chromosome characterized by aCGH and FISH as inv dup(3)(q25.33qter) de novo in a child with dysmorphic features and streaky pigmentation: case report. Mol Cytogenet 2008, 1: 19.PubMed CentralPubMedView ArticleGoogle Scholar
- Kroisel PM, Petek E, Wagner K: Skin pigmentary anomalies in a mosaic form of partial tetrasomy 3q. J Med Genet 2000, 37: 723–725. 10.1002/ajmg.a.30134PubMed CentralPubMedView ArticleGoogle Scholar
- Õunap K, Ilus T, Bartsch O: A girl with inverted triplication of chromosome 3q25.3 → q29 and multiple congenital anomalies consistent with 3q duplication syndrome. Am J Med Genet 2005, 134A: 434–438. 10.1002/ajmg.a.30134View ArticleGoogle Scholar
- Faas BH, De Vries BB, Van Es-Van Gaal J, Merkx G, Draaisma JM, Smeets DF: A new case of dup(3q) syndrome due to a pure duplication of 3qter. Clin Genet 2002, 62: 315–320. 10.1034/j.1399-0004.2002.620411.xPubMedView ArticleGoogle Scholar
- McKusick VA: On line Mendelian inheritance in man (OMIM). The Johns Hopkins Univ Press 1995.Google Scholar
- Ireland M, English C, Cross I, Lindsay S, Strachan T: Partial trisomy 3q and the mild Cornelia de Lange syndrome phenotype. J Med Genet 1995, 32: 837–838. 10.1136/jmg.32.10.837PubMed CentralPubMedView ArticleGoogle Scholar
- Falek A, Schmidt R, Jervis G: Familial de Lange Syndrome with chromosomal abnormalities. Pediatrics 1996, 37: 92–101.Google Scholar
- Auranen M, Vanhala R, Varilo T, Ayers K, Kempas E, Ylisaukko-Oja T, Sinsheimer JS, Peltonen L, Järvelä I: A Genomewide Screen for Autism-Spectrum Disorders: Evidence for a Major Susceptibility Locus on Chromosome 3q25–27. Am J Hum Genet 2002, 71: 777–790.PubMed CentralPubMedView ArticleGoogle Scholar
- Auranen M, Varilo T, Alen R, Vanhala R, Ayers K, Kempas E, Ylisaukko-Oja T, Peltonen L, Järvelä I: Evidence for allelic association on chromosome 3q25–27 in families with autism spectrum disorders originating from a subisolate of Finland. Mol Psychiatry 2003, 8: 879–884. 10.1038/ejhg.2008.180PubMedView ArticleGoogle Scholar
- Rooney DE, Czepulkowski BH: Human Cytogenetics: A Practical Approach. New York: Oxford University Press; 1992.Google Scholar
- Backx L, Ceulemans B, Vermeesch JR, Devriendt K, Esch HV: Early myoclonic encephalopathy caused by a disruption of the neuregulin-1 receptor ErbB4. Eur J Hum Genet 2009, 17: 378–382. 10.1369/jhc.4A6436.2005PubMed CentralPubMedView ArticleGoogle Scholar
- Vermeesch JR, Melotte C, Froyen G, Van Vooren S, Dutta B, Maas N, Vermeulen S, Menten B, Speleman F, De Moor B, Van Hummelen P, Marynen P, Fryns JP, Devriendt K: Molecular karyotyping: array CGH quality criteria for constitutional genetic diagnosis. J Histochem Cytochem 2005, 53: 413–422. 10.1369/jhc.4A6436.2005PubMedView ArticleGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.