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Open Access 01-12-2014 | Research article

Familial imbalance in 16p13.11 leads to a dosage compensation rearrangement in an unaffected carrier

Authors: Alicia Delicado, Luis Fernández, María Luisa de Torres, Julián Nevado, Fe Amalia García-Santiago, Roberto Rodríguez, Elena Mansilla, María Palomares, Fernando Santos-Simarro, Elena Vallespín, María Ángeles Mori, Pablo Lapunzina

Published in: BMC Medical Genetics | Issue 1/2014

Abstract

Background

We and others have previously reported that familial cytogenetic studies in apparently de novo genomic imbalances may reveal complex or uncommon inheritance mechanisms.

Methods

A familial, combined genomic and cytogenetic approach was systematically applied to the parents of all patients with unbalanced genome copy number changes.

Results

Discordant array-CGH and FISH results in the mother of a child with a prenatally detected 16p13.11 interstitial microduplication disclosed a balanced uncommon rearrangement in this chromosomal region. Further dosage and haplotype familial studies revealed that both the maternal grandfather and uncle had also the same 16p duplication as the proband. Genomic compensation observed in the mother probably occurred as a consequence of interchromosomal postzygotic nonallelic homologous recombination.

Conclusions

We emphasize that such a dualistic strategy is essential for the full characterization of genomic rearrangements as well as for appropriate genetic counseling.

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Carelle-Calmels N, Saugier-Veber P, Girard-Lemaire F, Rudolf G, Doray B, Guérin E, Kuhn P, Arrivé M, Gilch C, Schmitt E, Fehrenbach S, Schnebelen A, Frébourg T, Flori E: Genetic compensation in a human genomic disorder. N Engl J Med. 2009, 360 (12): 1211-1216. 10.1056/NEJMoa0806544.CrossRefPubMed

Alkalay AA, Guo T, Montagna C, Digilio MC, Dallapiccola B, Marino B, Morrow B: Genetic dosage compensation in a family with velo-cardio-facial/DiGeorge/22q11.2 deletion syndrome. Am J Med Genet A. 2011, 155A (3): 548-554. 10.1002/ajmg.a.33861.CrossRefPubMed

Fernández L, Nevado J, De Torres ML, Mansilla E, Vallespín E, García-Miñaúr S, Palomo R, Deir's L, Cabrera M, Galo ED, Lapunzina P, Delicado A: Additional case of an uncommon 22q11.2 reciprocal rearrangement in a phenotypically normal mother of children with 22q11.2 deletion and 22q11.2 duplication syndromes. Am J Med Genet A. 2012, 158A (11): 2963-2968. 10.1002/ajmg.a.35595.CrossRefPubMed

Nowakowska BA, de Leeuw N, Ruivenkamp CA, Sikkema-Raddatz B, Crolla JA, Thoelen R, Koopmans M, den Hollander N, van Haeringen A, van der Kevie-Kersemaekers AM, Pfundt R, Mieloo H, van Essen T, de Vries BB, Green A, Reardon W, Fryns JP, Vermeesch JR: Parental insertional balanced translocations are an important cause of apparently de novo CNVs in patients with developmental anomalies. Eur J Hum Genet. 2012, 20 (2): 166-170. 10.1038/ejhg.2011.157.CrossRefPubMed

Hannes FD, Sharp AJ, Mefford HC, de Ravel T, Ruivenkamp CA, Breuning MH, Fryns JP, Devriendt K, Van Buggenhout G, Vogels A, Stewart H, Hennekam RC, Cooper GM, Regan R, Knight SJ, Eichler EE, Vermeesch JR: Recurrent reciprocal deletions and duplications of 16p13.11: the deletion is a risk factor for MR/MCA while the duplication may be a rare benign variant. J Med Genet. 2009, 46 (4): 223-232. 10.1136/jmg.2007.055202.CrossRefPubMed

Ullmann R, Turner G, Kirchhoff M, Chen W, Tonge B, Rosenberg C, Field M, Vianna-Morgante AM, Christie L, Krepischi-Santos AC, Banna L, Brereton AV, Hill A, Bisgaard AM, Müller I, Hultschig C, Erdogan F, Wieczorek G, Ropers HH: Array CGH identifies reciprocal 16p13.1 duplications and deletions that predispose to autism and/or mental retardation. Hum Mutat. 2007, 28 (7): 674-682. 10.1002/humu.20546.CrossRefPubMed

Nagamani SC, Erez A, Bader P, Lalani SR, Scott DA, Scaglia F, Plon SE, Tsai CH, Reimschisel T, Roeder E, Malphrus AD, Eng PA, Hixson PM, Kang SH, Stankiewicz P, Patel A, Cheung SW: Phenotypic manifestations of copy number variation in chromosome 16p13.11. Eur J Hum Genet. 2011, 19 (3): 280-286. 10.1038/ejhg.2010.184.CrossRefPubMed

Ramalingam A, Zhou XG, Fiedler SD, Brawner SJ, Joyce JM, Liu HY, Yu S: 16p13.11 duplication is a risk factor for a wide spectrum of neuropsychiatric disorders. J Hum Genet. 2011, 56 (7): 541-544. 10.1038/jhg.2011.42.CrossRefPubMed

Vallespín E, Palomares Bralo M, Mori M, Martín R, García-Miñaúr S, Fernández L, de Torres ML, García-Santiago F, Mansilla E, Santos F, M-Montaño VE, Crespo MC, Martín S, Martínez-Glez V, Delicado A, Lapunzina P, Nevado J: Customized high resolution CGH-array for clinical diagnosis reveals additional genomic imbalances in previous well-defined pathological samples. Am J Med Genet A. 2013, 161A (8): 1950-1960. 10.1002/ajmg.a.35960.CrossRefPubMed

10.

Kato T, Kurahashi H, Emanuel BS: Chromosomal translocations and palindromic AT-rich repeats. Curr Opin Genet Dev. 2012, 22 (3): 221-228. 10.1016/j.gde.2012.02.004.CrossRefPubMedPubMedCentral

11.

Loftus BJ, Kim UJ, Sneddon VP, Kalush F, Brandon R, Fuhrmann J, Mason T, Crosby ML, Barnstead M, Cronin L, Deslattes Mays A, Cao Y, Xu RX, Kang HL, Mitchell S, Eichler EE, Harris PC, Venter JC, Adams MD: Genome duplications and other features in 12 Mb of DNA sequence from human chromosome 16p and 16q. Genomics. 1999, 60 (3): 295-308. 10.1006/geno.1999.5927.CrossRefPubMed

12.

Martin J, Han C, Gordon LA, Terry A, Prabhakar S, She X, Xie G, Hellsten U, Chan YM, Altherr M, Couronne O, Aerts A, Bajorek E, Black S, Blumer H, Branscomb E, Brown NC, Bruno WJ, Buckingham JM, Callen DF, Campbell CS, Campbell ML, Campbell EW, Caoile C, Challacombe JF, Chasteen LA, Chertkov O, Chi HC, Christensen M, Clark LM, et al: The sequence and analysis of duplication-rich human chromosome 16. Nature. 2004, 432 (7020): 988-994. 10.1038/nature03187.CrossRefPubMed

13.

Mefford HC, Cooper GM, Zerr T, Smith JD, Baker C, Shafer N, Thorland EC, Skinner C, Schwartz CE, Nickerson DA, Eichler EE: A method for rapid, targeted CNV genotyping identifies rare variants associated with neurocognitive disease. Genome Res. 2009, 19 (9): 1579-1585. 10.1101/gr.094987.109.CrossRefPubMedPubMedCentral

14.

Kariminejad R, Lind-Thomsen A, Tümer Z, Erdogan F, Ropers HH, Tommerup N, Ullmann R, Müller RS: High frequency of rare copy number variants affecting functionally related genes in patients with structural brain malformations. Hum Mutat. 2011, 32 (12): 1427-1435. 10.1002/humu.21585.CrossRefPubMed

15.

Feng Y, Walsh CA: Mitotic spindle regulation by Nde1 controls cerebral cortical size. Neuron. 2004, 44 (2): 279-293. 10.1016/j.neuron.2004.09.023.CrossRefPubMed

16.

Neill NJ, Ballif BC, Lamb AN, Parikh S, Ravnan JB, Schultz RA, Torchia BS, Rosenfeld JA, Shaffer LG: Recurrence, submicroscopic complexity, and potential clinical relevance of copy gains detected by array CGH that are shown to be unbalanced insertions by FISH. Genome Res. 2011, 21 (4): 535-544. 10.1101/gr.114579.110.CrossRefPubMedPubMedCentral

Title: Familial imbalance in 16p13.11 leads to a dosage compensation rearrangement in an unaffected carrier
Authors: Alicia Delicado
Luis Fernández
María Luisa de Torres
Julián Nevado
Fe Amalia García-Santiago
Roberto Rodríguez
Elena Mansilla
María Palomares
Fernando Santos-Simarro
Elena Vallespín
María Ángeles Mori
Pablo Lapunzina
Publication date: 01-12-2014
Publisher: BioMed Central
Published in: BMC Medical Genetics / Issue 1/2014
Electronic ISSN: 1471-2350
DOI: https://doi.org/10.1186/s12881-014-0116-3

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Springer Medicine

Familial imbalance in 16p13.11 leads to a dosage compensation rearrangement in an unaffected carrier

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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