Estudo retrospectivo de cariótipo em pacientes com retardo mental

foi realizado um estudo retrospectivo dos resultados de cariótipo com bandas G de 369 pacientes em investigação de RM. A partir dos rearranjos estruturais encontrados, foram levantadas todas as regiões cromossômicas envolvidas nos pontos de quebra e elas foram comparadas com a literatura para RM e bancos de dados.

Resultados:

foram identificados 338 (91,6%) casos normais e 31 (8,4%) com algum tipo de alteração cromossômica. Dentre os casos alterados, 21 pacientes (67,8%) foram identificados com alterações cromossômicas estruturais, 9 (29%) com alterações numéricas e 1 (3,2%) com alteração numérica e estrutural.

Conclusão:

as alterações cromossômicas estruturais foram aquelas observadas com maior frequência. O cariótipo com bandas G contribui para a investigação das causas de RM, mostrando que essa técnica pode ser útil como uma primeira triagem dos pacientes. No entanto, técnicas mais resolutivas como o array based comparative genomic hibridization (aCGH) e o multiplex ligation dependent probe amplification (MLPA) permitem detectar alterações submicroscópicas comumente associadas ao RM.

Palavras-chave
cariótipo; deficiência intelectual; aberrações cromossômicas

Karyotype	Nº of	Chromosomal	Rearrangement	Gene involved	MR syndrome	Reference
	cases	region
46,XY,t(1;11) (p22.3;q23.3)	1	1p22	Duplication; deletion		Kabuki makeup syndrome Goldenhar syndrome	Lo et al. 1998;²²22 Lo IF, Cheung LY, Ng AY, Lam ST. Interstitial Dup(1p) with findings of Kabuki make-up syndrome. Am J Med Genet. 1998; 78(1):55-7.
		1p22	Duplication; deletion		Kabuki makeup syndrome Goldenhar syndrome	Carllier et al. 2008²³23 Callier P, Faivre L, Thauvin-Robinet C, Marle N, Mosca AL, D’Athis P, e tal. Array-CGH in a series of 30 patients with mental retardation, dysmorphic features, and congenital malformations detected an interstitial 1p22.2-p31.1 deletion in a patient with features overlapping the Goldenhar syndrome. Am J Med Genet A. 2008; 146A(16):2109-15.
		11q23.3-qter	Trisomy; deletion; monosomy	-	Dandy Walker variant	Weimer et al. 2006;²⁴24 Ounap K, Bartsch O, Uibo O, Laidre P. Girl with combined cellular immunodeficiency, pancytopenia, malformations, deletion 11q23.3 --> qter, and trisomy 8q24.3 --> qter. Am J Med Genet. 2002; 108(4):322-6.
		11q23.3-qter	Trisomy; deletion; monosomy	-	Dandy Walker variant	Ounap et al. 2002²⁵25 Weimer J, Cohen M, Wiedemann U, Heinrich U, Jonat W, Arnold N. Proof of partial imbalances 6q and 11q due to maternal complex balanced translocation analyzed by microdissection of multicolor labeled chromosomes (FISH-MD) in a patient with Dandy-Walker variant. Cytogenet Genome Res. 2006; 114(3-4):235-9.
46,XX,inv(2)	1	2p24-pter; 2p24;	Trisomy; balanced	-	-	Match et al. 2007;²⁶26 Mach M, Windpassinger C, Wagner K, Kroisel PM, Petek E. Distal monosomy 16p13.3/distal trisomy 2p24.2-pter: molecular-cytogenetic characterisation and phenotype. Genet Couns. 2007; 18(1):9-16.
(p24q22)		2p24.2-p25.1;	translocation			Talisseti et al. 2003;²⁷27 Talisetti A, Forrester SR, Gregory D, Johnson L, Schneider MC, Kimonis VE. Temtamy-like syndrome associated with translocation of 2p24 and 9q32. Clin Dysmorphol. 2003; 12(3):175-7.
		2p24.3-pter				Roggenbuck et al. 2001²⁸28 Roggenbuck JA, Fink JM, Mendelsohn NJ. Unique case of trisomy 2p24.3-pter with no associated monosomy. Am J Med Genet. 2001; 101(1):50-4.
		2q22;	Deletion	ZEB2	Mowat-Wilson	Balasubramanian et al. 2010;²⁹29 Balasubramaniam S, Keng WT, Ngu LH, Goossens MJ, Giurgea I. Mowat-Wilson syndrome: the first two Malaysian cases. Singapore Med J. 2010; 51(3):e54-7. Ballarati et al. 2009;³⁰30 Ballarati L, Recalcati MP, Bedeschi MF, Lalatta F, Valtorta C, Bellini M, et al. Cytogenetic, FISH and array-CGH characterization of a complex chromosomal rearrangement carried by a mentally and language impaired patient. Eur J Med Genet. 2009; 52(4):218-23.
		2q22.2;2q22-q23;			syndrome
		2q22-q24.2				Saunders et al. 2009³¹31 Saunders CJ, Zhao W, Ardinger HH. Comprehensive ZEB2 gene analysis for Mowat-Wilson syndrome in a North American cohort: a suggested approach to molecular diagnostics. Am J Med Genet A. 2009; 149A(11):2527-31.
46,XY,inv(3)	1	3p13; 3p13-p12	Inversion	-	Bardet-Biedl syndrome	Héron et al. 2005;³²32 Héon E, Westall C, Carmi R, Elbedour K, Panton C, Mackeen L, et al. Ocular phenotypes of three genetic variants of Bardet-Biedl syndrome. Am J Med Genet A. 2005; 132A(3):283-7.
(p13q26.2)	1	3p13; 3p13-p12	Inversion	-	Bardet-Biedl syndrome	Ghadami et al. 2000³³33 Ghadami M, Tomita HA, Najafi MT, Damavandi E, Farahvash MS, Yamada K, et al. Bardet-Biedl syndrome type 3 in an Iranian family: clinical study and confirmation of disease localization. Am J Med Genet. 2000; 94(5):433-7.
		3q26.2-q26.31;	Trisomy	-	Chromosome 3q	Abreu-González et al. 2013;³⁴34 Abreu-González M, García-Delgado C, Cervantes A, Aparicio-Onofre A, Guevara-Yáñez R, Sánchez-Urbina R, et al. Clinical, cytogenetic, and biochemical analysis of a family with a t(3;13)(q26.2;p11.2): further delineation of 3q duplication syndrome. Case Rep Genet. 2013; 2013:895259. Faas et al. 2002³⁵35 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(4):315-20.
		3q25.1-26.2			duplication syndrome
46,XX,t(3;8)	1	3q12-q23;	Duplication;	-	-	Gamerding et al. 2006;³⁶36 Gamerdinger U, Bosse K, Eggermann T, Kalscheuer V, Schwanitz G, Engels H. First report of a partial trisomy 3q12-q23 de novo--FISH breakpoint determination and phenotypic characterization. Eur J Med Genet. 2006; 49(3):225-34.
(q12;q11.2)		3q12-q21	deletion			Okada et al. 1987³⁷37 Okada N, Hasegawa T, Osawa M, Fukuyama Y. A case of de novo interstitial deletion 3q. J Med Genet. 1987; 24(5):305-8.
		8q11.2;	Duplication;	CHD7	Charge syndrome	Amouroux et al. 2012;³⁸38 Amouroux C, Vincent M, Blanchet P, Puechberty J, Schneider A, Chaze AM, et al. Duplication 8q12: confirmation of a novel recognizable phenotype with duane retraction syndrome and developmental delay. Eur J Hum Genet. 2012; 20(5):580-3.
		8q11.2-q13	deletion			Verhoeven et al. 2012³⁹39 Verhoeven WM, Egger JI, Feenstra I, de Leeuw N. A de novo 3.57 Mb microdeletion in 8q12.3q13.2 in a patient with mild intellectual disability and epilepsy. Eur J Med Genet. 2012; 55(5):358-61.
46,XY,der(5)del(5) (?p15.1 )add(?p15)	1	5p15.1	Trisomy; duplication	-	Cri-du-Chat syndrome	Balaiardo et al. 2003;⁴⁰40 Baialardo EM, Torrado Mdel V, Barreiro CZ, Gallego MS. Partial distal 5p trisomy resulting from paternal translocation (5;15)(p15.1;p13) in a boy with no mental retardation. Clin Dysmorphol. 2003; 12(4):257-9. Weeb et al. 1988⁴¹41 Webb GC, Voullaire LE, Rogers JG. Duplication of a small segment of 5p due to maternal recombination within a paracentric shift. Am J Med Genet. 1988; 30(4):875-81.
46,XX,del(5)	3	5p15.2	Translocation and	SRD5A1,POLS		Harvard et al. 2005;¹⁹19 Harvard C, Malefant P, Koochek M, Creighton S, Mickelson EC, Holden JJ, et al. A variant Cri du Chat phenotype and autism spectrum disorder in a subject with de novo cryptic microdeletions involving 5p15.2 and 3p24.3-25 detected using whole genomic array CGH. Clin Genet. 2005; 67(4):341-51. Wu et al. 2005⁴²42 Wu Q, Niebuhr E, Yang H, Hansen L. Determination of the ‘critical region’ for cat-like cry of Cri-du-chat syndrome and analysis of candidate genes by quantitative PCR. Eur J Hum Genet. 2005; 13(4):475-85.
(p15.2)		5p15.2	deletion	SRD5A1,POLS
		5p15.3	Deletion	-		Moreira et al. 2008;⁴³43 Moreira LMA, Carvalho AFL, Borja ALVF, Pinto PSP, Silveira A, de Freitas LM, et al. Mosaic cri-du-chat syndrome in a girl with a mild phenotype. J Appl Genet. 2008; 49(4):415-20.
		5p15.3	Deletion	-		Laczmanska et al. 2006⁴⁴44 Laczmanska I, Stembalska A, Gil J, Czemarmazowicz H, Sasiadek M. Cri du chat syndrome determined by the 5p15.3-->pter deletion-diagnostic problems. Eur J Med Genet. 2006; 49(1):87-92.
46,XX,t(6;11)	1	6q25.3-qter	Deletion	TBP	Chromosome 6q	Abu-Amero et al. 2010;¹⁷17 Abu-Amero KK, Hellani A, Salih MA, Al Hussain A, al Obailan M, Zidan G, et al. Ophthalmologic abnormalities in a de novo terminal 6q deletion. Ophthalmic Genet. 2010; 31(1):1-11.
(q25.3;q21)					deletion syndrome	Lukusa et al. 2001⁴⁵45 Lukusa T, Willekens D, Lukusa N, De Cock F, Fryns JP. Terminal 6q25.3 deletion and abnormal behaviour. Genet Couns. 2001; 12(3):213-21.
		11q14.1-q23.2;	Deletion;	FZD4	Trichorhinophalangeal	Li et al. 2006;⁴⁶46 Li P, Zhang HZ, Huff S, Nimmakayalu M, Qumsiyeh M, Yu J, et al. Karyotype-phenotype insights from 11q14.1-q23.2 interstitial deletions: FZD4 haploinsufficiency and exudative vitreoretinopathy in a patient with a complex chromosome rearrangement. Am J Med Genet A. 2006; 140(24):2721-9. Sanchez et al. 1985⁴⁷47 Sánchez LM, Labarta JD, De Negrotti TC, Migliorini AM. Complex translocation in a boy with trichorhinophalangeal syndrome. J Med Genet. 1985; 22(4):314-6.
		11q21	translocation		syndrome
46,XX,ins(7;?)	1	7p14.3;	Deletion	GLI3	Greig	Debeer et al. 2007;⁴⁸48 Debeer P, Devriendt K, De Smet L, deRavel T, Gonzalez-Meneses A, Grzeschik KH, et al. The spectrum of hand and foot malformations in patients with Greig cephalopolysyndactyly. J Child Orthop. 2007; 1(2):1143-50. Duno et al. 2004⁴⁹49 Dunø M, Hove H, Kirchhoff M, Devriendt K, Schwartz M. Mapping genomic deletions down to the base: a quantitative copy number scanning approach used to characterise and clone the breakpoints of a recurrent 7p14.2p15.3 deletion. Hum Genet. 2004; 115(6):459-67.
(p14;?)		7p14-p15; 7p14			cephalopolysyndactyly syndrome
46,XY,del(8)	1	8p23.1; 8p22-	Deletion;	-	Kabuki syndrome	Wu et al. 2010;⁵⁰50 Wu Y, Ji T, Wang J, Xiao J, Wang H, Li J, et al. Submicroscopic subtelomeric aberrations in Chinese patients with unexplained developmental delay/mental retardation. BMC Med Genet. 2010; 11:72. Sanlaville et al. 2005;⁵¹51 Sanlaville D, Genevieve DD, Bernardin C, Amiel J, Baumann C, Blois MC, et al. Failure to detect an 8p22-8p23.1 duplication in patients with Kabuki (Niikawa-Kuroki) syndrome. Eur J Hum Genet. 2005; 13(5):690-93. Zafra et al. 2005⁵²52 Zafra de la Rosa G, Venegas-Vega CA, Monroy N, Contreras-Bucio G, Friedrich U, Houman M, et al. Trisomy 3q25.1-qter and monosomy 8p23.1-pter in a patient: cytogenetic and molecular analysis with delineation of the phenotype. Am J Med Genet A. 2005; 136(3):259-64.
(p23.1)		8p23.1; 8p23.1-	duplication
		pter
46,XY,add(9)(p24)	1	9p23-pter;	Deletion;	DMRT	Chromosome 9p	Barbaro et al. 2009;⁵³53 Barbaro M, Balsamo A, Anderlid BM, Myhre AG, Gennari M, Nicoletti A, et al. Characterization of deletions at 9p affecting the candidate regions for sex reversal and deletion 9p syndrome by MLPA. Eur J Hum Genet. 2009; 17(11):1439-47.
		9p24.2-pter; 9p24.3	duplication		deletion syndrome	Yang et al. 2012⁵⁴54 Yang Y, Wang C, Wang F, Zhu L, Liu H, He X. Novel chromosomal translocation t(11;9)(p15;p23) involving deletion and duplication of 9p in a girl associated with autism and mental retardation. Gene. 2012; 502(2):154-8.
46,XX,der(10)	1	10q26-qter	Deletion	-	-	Lam et al. 2006⁵⁵55 Lam AC, Lam ST, Lai KK, Tong TM, Chau TC. High rate of detection of subtelomeric aberration by using combined MLPA and subtelomeric FISH approach in patients with moderate to severe mental retardation. Clin Biochem. 2006; 39(3):196-202.
t(10;?15)		15q25.3;	Trisomy; deletion	-	-	Kim et al. 2009;⁵⁶56 Kim JH, Lee WM, Ryoo NH, Ha JS, Jeon DS, Kim JR, et al. [A case of partial trisomy 15q25.3-qter]. Korean J Lab Med. 2009; 29(1):66-70.
(q26.3;?q25)		15q25.2; 15q25-				Wagenstaler et al. 2007⁵⁷57 Wagenstaller J, Spranger S, Lorenz-Depiereux B, Kazmierczak B, Nathrath M, Wahl D, et al. Copy-number variations measured by single-nucleotide-polymorphism oligonucleotide arrays in patients with mental retardation. Am J Hum Genet. 2007; 81(4):768-79.
		qter
46,XY,t(12;20)	1	12q24.31-qter	Translocation/	-	-	Callier et al. 2007;⁵⁸58 Callier P, Faivre L, Marle N, Thauvin-Robinet C, Mosca AL, Masurel-Paulet A, et al. Untreated growth hormone deficiency with extremely short stature, bone dysplasia, cleft lip-palate and severe mental retardation in a 26-year-old man with a de novo unbalanced translocation t(1;12)(q24;q24). Eur J Med Genet. 2007; 50(6):455-64.
(q24.31;q11.2)			microdeletion			Bao et al. 2005⁵⁹59 Bao L, Schorry EK. A girl with partial trisomy 12q24.31 inherited from her father and a possible novel syndrome transmitted from her mother. Am J Med Genet A. 2005; 138(4):361-4.
(q24.31;q11.2)		20q11.2	Duplication	ASXL1	-	Ávila et al. 2013⁶⁰60 Ávila M, Kirchhoff M, Marle N, Hode HD, Chouchane M, Thauvin-Robinet C, et al. Delineation of a new chromosome 20q11.2 duplication syndrome including the ASXL1 gene. Am J Med Genet A. 2013; 161A(7):1594-8.
46,XY,add(15)	1	15q26.1-26.2;	Deletion	MEF2A,CHD2	-	Davidson et al. 2008;⁶¹61 Davidsson J, Collin A, Björkhem G, Soller M. Array based characterization of a terminal deletion involving chromosome subband 15q26.2: an emerging syndrome associated with growth retardation, cardiac defects and developmental delay. BMC Med Genet. 2008; 9:2.
(q26)		15q26.2-qter				Capelli et al. 2012⁶²62 Capelli LP, Krepischi AC, Gurgel-Guianetti J, Mendes MF, Rodrigues T, Varela MC, et al. Deletion of the RMGA and CHD2 genes in a child with epilepsy and mental deficiency. Eur J Med Genet. 2012; 55(2):132-4.
46,XX,inv(17)	1	17p11.2	Deletion	TNFRSF1	Smith-Magenis	Boudreau et al. 2009;⁶³63 Boudreau EA, Johnson KP, Jackman AR, Blancato J, Huizing M, Bendavid C, et al. Review of disrupted sleep patterns in Smith-Magenis syndrome and normal melatonin secretion in a patient with an atypical interstitial 17p11.2 deletion. Am J Med Genet A. 2009; 149A(7):1382-91.
(p11.2q21)		17p11.2	Deletion	3B,FAM27L	syndrome	Partida -Pérez et al. 2012⁶⁴64 Partida-Pérez M, Dominguez MG, Neira VA, Figuera LS, Rivera H. De novo inv(17)(p11.2q21.3) in an intellectually disabled girl: appraisal of 21 inv(17) constitutional instances. J Genet. 2012; 91(2):241-4.
		17q21.31;	Deletion;	CRHR1,MAPT	17q21.31	Koolen et al. 2006;⁶⁵65 Koolen DA, Vissers LE, Pfundt R, de Leeuw N, Knight SJ, Regan R, et al. A new chromosome 17q21.31 microdeletion syndrome associated with a common inversion polymorphism. Nat Genet. 2006; 38(9):999-1001.
		17q21.32	duplication		microdeletion	Grisart et al. 2009;⁶⁶66 Grisart B, Willat L, Destrée A, Fryns JP, Rack K, de Ravel T, et al. 17q21.31 microduplication patients are characterized by behavioural problems and poor social interaction. J Med Genet. 2009; 46(8):524-30.
					syndrome	Partida-Pérez et al. 2012⁶⁴64 Partida-Pérez M, Dominguez MG, Neira VA, Figuera LS, Rivera H. De novo inv(17)(p11.2q21.3) in an intellectually disabled girl: appraisal of 21 inv(17) constitutional instances. J Genet. 2012; 91(2):241-4.
46,XY,inv(18)	1	18p11.1	Deletion	-	Chromosome 18p	Portnoi et al. 2007;⁶⁷67 Portnoï MF, Gruchy N, Marlin S, Finkel L, Denoyelle F, Dubourg C, et al. Midline defects in deletion 18p syndrome: clinical and molecular characterization of three patients. Clin Dysmorphol. 2007; 16(4):247-52.
(p11.1p11.32)		18p11.1	Deletion	-	deletion syndrome	Wester et al. 2006⁶⁸68 Wester U, Bondenson ML, Edeby C, Annerén G. Clinical and molecular characterization of individuals with 18p deletion: a genotype-phenotype correlation. Am J Med Genet A. 2006; 140(11):1164-71.
		18p11.2;	Deletion, trisomy	-		Portinoi et al. 2007;⁶⁷67 Portnoï MF, Gruchy N, Marlin S, Finkel L, Denoyelle F, Dubourg C, et al. Midline defects in deletion 18p syndrome: clinical and molecular characterization of three patients. Clin Dysmorphol. 2007; 16(4):247-52.
		18p11.32				Moog et al. 1994⁶⁹69 Moog U, Engelen JJ, de Die-Smulders CE, Albrechts JC, Loneus WH, Haagen AA, et al. Partial trisomy of the short arm of chromosome 18 due to inversion duplication and direct duplication. Clin Genet. 1994; 46(6):423-9.
46,XX,r(22)	1	22q13; 22q13.3;	Deletion;	SHANK3	22q13 deletion	Demirhan e Tunc, 2010;⁷⁰70 Dermirhan O, Tunç E. Phenotypic correlations in a patient with ring chromosome 22. Indian J Hum Genet. 2010; 16(2):97-9.
(p13q13)		22q13.31;	translocation;		syndrome	Koç et al. 2008⁷¹71 Koç A, Karaer K, Ergün MA, Yirmibeş-Karaoğuz M, Kan D, Cansu A, et al. A case with a ring chromosome 22. Turk J Pedriatr. 2008; 50(2):193-6.
[17]/46,XX[13]		22q13.1-q13.2	duplication

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