Retrospective karyotype study in mentally retarded patients

Estudo retrospectivo de cariótipo em pacientes com retardo mental

SUMMARY

Objective:

To describe the chromosomal alterations in patients with mental retardation (MR) using G-banding karyotype analysis.

Method:

A retrospective study of the results G-banding karyotype analysis of 369 patients investigated for MR was performed. Based on the structural rearrangements found, the authors searched all chromosomal regions related with breakpoints, and these were compared with the literature on MR and databases.

Results:

338 (91.6%) normal cases, and 31 (8.4%) with some type of chromosomal abnormality were identified. Among the altered cases, 21 patients (67.8%) were identified with structural chromosomal alterations, nine (29%) with numerical alterations, and one (3.2%) with numerical and structural alterations.

Conclusion:

Structural chromosomal abnormalities were observed more frequently in this study. G-banding karyotyping contributes to the investigation of the causes of MR, showing that this technique can be useful for initial screening of patients. However, higher resolution techniques such as array based comparative genomic hybridization (aCGH) and multiplex ligation-dependent probe amplification (MPLA) can detect submicroscopic alterations commonly associated with MR.

Keywords
karyotype; intellectual disability; chromosome aberrations

RESUMO

Objetivo:

descrever as alterações cromossômicas em pacientes com retardo mental (RM) pela análise do cariótipo com bandas G.

Método:

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

INTRODUCTION

According to the definition of classical cytogenetics, the term aneuploidy corresponds to changes in number of chromosomes, including the presence of an extra copy of a particular chromosome (trisomy) or the absence of one chromosome (monosomy) leading to abnormal karyotype. However, with the advent of new high-resolution molecular technologies, new aneuploidy syndromes have been identified, including deletions and duplications of chromosomal regions.¹ Changes in gene dosage resulting from such deletions and duplications are commonly related to cases of mental retardation. It is estimated that over 15% of cases of severe mental retardation are due to microscopic cytogenetic abnormalities.²

Mental retardation (MR), ethically accepted as intellectual retardation or cognitive delay, is characterized by significant limitations in intellectual functions and adaptive behavior of an individual, with onset of symptoms before the age of 18 years. Adaptive behavior refers to adaptive conceptual, social and practical skills, while intellectual functions are often measured using intelligence test instruments that generate an intelligence quotient (IQ).^2,3

In some cases, MR can be categorized as syndromic, i.e. the child has associated dysmorphic features identifying a genetic syndrome. However, intellectual disability is extremely heterogeneous, a consequence of the large number of different syndromes related to MR, which renders accurate diagnosis impossible based only on the clinical picture.⁴ Accurate diagnosis is essential to provide a specific treatment, to establish a clinical predictor of quality of life, to educate parents on the characteristics and progression of the syndrome, and finally, to define a reproductive prognosis for the family.

Many cases of MR resulting from duplication and recurrent deletions were initially identified by conventional microscopy techniques or banding. G-banding karyotype analysis is a technique used to identify individual human chromosomes in many laboratories. This technique, also known as GTG (G-bands by trypsin using Giemsa), is based on chromosomes digestion with proteolytic enzymes, which are then stained with Giemsa. After staining, each pair of chromosomes exhibits a characteristic pattern of light and dark bands (G bands), which can be individually differentiated under a microscope.

Knowing the importance of accurate diagnosis of MR, and being aware of the extensive clinical use of G-banding as an important method of diagnosis, this study aimed to carry out a retrospective analysis of all the results of G-banding karyotyping of patients with MR, performed in 2009 at Instituto Hermes Pardini, Sector of Human Cytogenetics, in Belo Horizonte, Minas Gerais, Brazil.

METHOD

The present study followed the guidelines of the Brazilian National Health Council – CNS Resolution 196/96, and the identity of all patients was kept confidential. Chromosome study was conducted at the Laboratory of Cytogenetics of Instituto Hermes Pardini using G-banding karyotype analysis.

For each patient, peripheral blood was collected in heparin and from these samples cell cultures were prepared. The cell cultures were treated with colchicine and subjected to hypotonic shock. Then, they were fixed on slides for subsequent staining of G-bands with trypsin and Giemsa.

Slides evaluation was performed using a microscope (NIKON^®, model E 400) coupled to the karyotype analysis software (Applied Spectral Imaging^®, version 6.0). Karyotypes were described according to the standards present in the 2013 International System for Human Cytogenetic Nomenclature (ISCN).⁵

A survey of karyotyping results was carried out, including types of rearrangements, chromosomal region, the possible genes involved, and MR syndromes associated. Based on the structural rearrangements found, we searched all chromosomal regions related with breakpoints, which were then compared with the literature on MR. For this comparison, renowned databases available for public consultation on the international computer network were used, such as the Mapviewer-National Center for Biotechonology Information.⁷² Then, all the specific chromosomal regions were researched in the scientific literature as to their association with MR.

RESULTS

During 2009, we evaluated the karyotyping results of 369 patients with MR, of which 143 (38.8%) were female, and 226 (61.2%) were male. For most of the patients, 338 (91.6%), karyotypes were compatible with normality, while 31 (8.4%) cases had some type of chromosomal abnormality. Of this total of 31 altered cases, 21 patients (67.8%) were identified with structural alterations, 9 (29%) with numerical abnormalities, and 1 (3.2%) with numerical and structural alterations (Figure 1).

FIGURE 1
Distribution of results of 369 patients who underwent G-banding karyotyping for investigation of mental retardation in 2009 at Instituto Hermes Pardini.

Among the patients with identified numerical chromosomal abnormalities, five cases had aneuploidy of sex chromosomes: four cases of 47,XXY karyotype, and one case of X monosomy (45,X karyotype). Regarding autosomal chromosomes, three cases of free trisomy 21 (47,XX,+21 karyotype) were detected. The case of numerical and structural alteration corresponded to a 47,XXY,dup(18)(p12.2 p12.3) karyotype.

As for structural chromosomal abnormalities, reciprocal translocations, inversions, deletions, additional chromosomal segments, and insertions were observed. Based on the comparison of results of karyotypes with structural alterations and their specific chromosomal regions, we were able to identify breakpoints involving 1p22.3; 2p24; 2q22; 3p13; 3q26.2; 3q12; 5p15.1; 5p15.2; 5p15.3; 6q25.3; 7p14; 8p23.1; 8q11.2; 9p24; 10q26.3; 11q23.3; 11q21; 12q24.31; 15q25; 15q26; 17p11.2; 17q21; 18p11.1; 18p11.32; 20q11.2; 22q13. The respective rearrangements as well as the correlation between the genes involved and syndromes related with MR are shown in Table 1. With the exception of the deletion on the short arm of chromosome 5 [46,XX,del(5)(p11.2) karyotype], found in three cases, all other changes occurred once in this study.

TABLE 1
List of breakpoints found in the detected structural alterations and comparison with literature data on mental retardation.

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;22
												Carllier et al. 200823
				11q23.3-qter		Trisomy; deletion; monosomy		-		Dandy Walker variant		Weimer et al. 2006;24
												Ounap et al. 200225
46,XX,inv(2)		1		2p24-pter; 2p24;		Trisomy; balanced		-		-		Match et al. 2007;26
(p24q22)				2p24.2-p25.1;		translocation						Talisseti et al. 2003;27
				2p24.3-pter								Roggenbuck et al. 200128
				2q22;		Deletion		ZEB2		Mowat-Wilson		Balasubramanian et al. 2010;29 Ballarati et al. 2009;30
				2q22.2;2q22-q23;						syndrome
				2q22-q24.2								Saunders et al. 200931
46,XY,inv(3)		1		3p13; 3p13-p12		Inversion		-		Bardet-Biedl syndrome		Héron et al. 2005;32
(p13q26.2)												Ghadami et al. 200033
				3q26.2-q26.31;		Trisomy		-		Chromosome 3q		Abreu-González et al. 2013;34 Faas et al. 200235
				3q25.1-26.2						duplication syndrome
46,XX,t(3;8)		1		3q12-q23;		Duplication;		-		-		Gamerding et al. 2006;36
(q12;q11.2)				3q12-q21		deletion						Okada et al. 198737
				8q11.2;		Duplication;		CHD7		Charge syndrome		Amouroux et al. 2012;38
				8q11.2-q13		deletion						Verhoeven et al. 201239
46,XY,der(5)del(5) (?p15.1 )add(?p15)		1		5p15.1		Trisomy; duplication		-		Cri-du-Chat syndrome		Balaiardo et al. 2003;40 Weeb et al. 198841
46,XX,del(5)		3		5p15.2		Translocation and		SRD5A1,POLS				Harvard et al. 2005;19 Wu et al. 200542
(p15.2)						deletion
				5p15.3		Deletion		-				Moreira et al. 2008;43
												Laczmanska et al. 200644
46,XX,t(6;11)		1		6q25.3-qter		Deletion		TBP		Chromosome 6q		Abu-Amero et al. 2010;17
(q25.3;q21)										deletion syndrome		Lukusa et al. 200145
				11q14.1-q23.2;		Deletion;		FZD4		Trichorhinophalangeal		Li et al. 2006;46 Sanchez et al. 198547
				11q21		translocation				syndrome
46,XX,ins(7;?)		1		7p14.3;		Deletion		GLI3		Greig		Debeer et al. 2007;48 Duno et al. 200449
(p14;?)				7p14-p15; 7p14						cephalopolysyndactyly syndrome
46,XY,del(8)		1		8p23.1; 8p22-		Deletion;		-		Kabuki syndrome		Wu et al. 2010;50 Sanlaville et al. 2005;51 Zafra et al. 200552
(p23.1)				8p23.1; 8p23.1-		duplication
				pter
46,XY,add(9)(p24)		1		9p23-pter;		Deletion;		DMRT		Chromosome 9p		Barbaro et al. 2009;53
				9p24.2-pter; 9p24.3		duplication				deletion syndrome		Yang et al. 201254
46,XX,der(10)		1		10q26-qter		Deletion		-		-		Lam et al. 200655
t(10;?15)				15q25.3;		Trisomy; deletion		-		-		Kim et al. 2009;56
(q26.3;?q25)				15q25.2; 15q25-								Wagenstaler et al. 200757
				qter
46,XY,t(12;20)		1		12q24.31-qter		Translocation/		-		-		Callier et al. 2007;58
(q24.31;q11.2)						microdeletion						Bao et al. 200559
				20q11.2		Duplication		ASXL1		-		Ávila et al. 201360
46,XY,add(15)		1		15q26.1-26.2;		Deletion		MEF2A,CHD2		-		Davidson et al. 2008;61
(q26)				15q26.2-qter								Capelli et al. 201262
46,XX,inv(17)		1		17p11.2		Deletion		TNFRSF1		Smith-Magenis		Boudreau et al. 2009;63
(p11.2q21)								3B,FAM27L		syndrome		Partida -Pérez et al. 201264
				17q21.31;		Deletion;		CRHR1,MAPT		17q21.31		Koolen et al. 2006;65
				17q21.32		duplication				microdeletion		Grisart et al. 2009;66
										syndrome		Partida-Pérez et al. 201264
46,XY,inv(18)		1		18p11.1		Deletion		-		Chromosome 18p		Portnoi et al. 2007;67
(p11.1p11.32)										deletion syndrome		Wester et al. 200668
				18p11.2;		Deletion, trisomy		-				Portinoi et al. 2007;67
				18p11.32								Moog et al. 199469
46,XX,r(22)		1		22q13; 22q13.3;		Deletion;		SHANK3		22q13 deletion		Demirhan e Tunc, 2010;70
(p13q13)				22q13.31;		translocation;				syndrome		Koç et al. 200871
[17]/46,XX[13]				22q13.1-q13.2		duplication

• add: additional segment; del: deletion; der: derivative chromosome; ins: insertion; inv: inversion; r: ring chromosome; t: reciprocal translocation; p: short arm; q: long arm; ter: terminal.

Considering the structural alterations, three cases revealed additional marker chromosomes of unknown origin, two of which were mosaic marker chromosomes. The cases of mosaic presented 47,XX,+mar[13]/46,XX[17] karyotype (mosaicism for one lineage with presence of an additional marker chromosome, and another lineage with normal complement) and 47,XY,+r[8]/46,XY[22] karyotype (mosaicism for one lineage with an additional marker chromosome ring, and another lineage with normal complement). In one case, the additional marker chromosome was seen in all cells analyzed (47,XX,+mar).

DISCUSSION

This study presents a retrospective analysis of the results of G-banding karyotyping of individuals with MR assessed at Instituto Hermes Pardini in 2009, and the comparison of these results with literature data. Based on this evaluation, we were able to identify chromosomal alterations in 8.4% of patients only. Although this method is important either to explain or rule out causes of MR, it has limitations, especially in relation to the identification of submicroscopic alterations. Thus, other techniques such as fluorescent in situ hybridization (FISH),⁶ comparative genomic hybridization (CGH), array based comparative genomic hybridization (aCGH),⁷ and multiplex ligation-dependent probe amplification (MLPA),⁸ are more suitable to detect submicroscopic rearrangements responsible for most cases of MR, especially in cases of idiopathic MR.

Among the numerical chromosomal abnormalities identified in this study, the 47,XXY karyotype was most frequent. This abnormality causes Klinefelter syndrome, the most common numerical chromosomal disorder among men. The estimated frequency of this disorder is between 1:500 and 1:1,000 live births. Men with Klinefelter syndrome usually have delayed auditory processing, language dysfunction and, in rare cases, severe intellectual retardation.²

Turner syndrome is less common than other sex chromosome aneuploidies, and its most important chromosome constitution is 45,X, found in one case in this study. Some patients, in addition to the unique physical characteristics of this syndrome, have a non-verbal IQ significantly lower than their verbal IQ; many require educational intervention, especially in mathematics.^9,10

The only numerical alteration of autosomal chromosome found in this study was trisomy 21 (47,XX,+21). This chromosome constitution is observed in patients with Down syndrome, an example of neurogenetic disorder related to aneuploidy,¹ and corresponds to the most common genetic cause of moderate mental retardation^11,12 and intellectual disability.¹³

In this study we also identified three cases of additional marker chromosomes, two with mosaic karyotype (47,XX,+mar[13]/46,XX[17] and 47,XY,+r[8]/46,XY[22]). Supernumerary marker chromosomes are a heterogeneous group of structurally abnormal chromosomes derived from any of the 24 chromosomes, but they cannot be identified using conventional cytogenetic techniques.¹⁴ They are found in clinically normal individuals, but are often reported in patients with mental retardation and infertility.¹⁵ Mosaicism associated with marker chromosomes is a well-known finding, observed in approximately 50% of cases. Different types of mosaicism can be found, the most common being 47,XX,+mar/46,XX.¹⁴

The analysis of chromosomal abnormalities and comparison with literature data revealed that the alterations identified in this study occur in regions determined by breakpoints also described in previous studies with patients with MR. In the 46,XX,inv(2)(p24q22) inversion, for example, there is the q22 breakpoint located close to the ZEB2 gene. Deletions involving this gene are responsible for Mowat-Wilson syndrome, and MR is one of its main clinical manifestations.¹⁶ The 6q25.3 point of 46,XX,t(6;11)(q25.3;q21) translocation is associated with a deletion syndrome with moderate MR.¹⁷

The present study found three patients with terminal deletion in the short arm of chromosome 5 and p15.2 breakpoint [46,XX,del(5)(p15.2)]. Most deletions in the short arm of chromosome 5 are related to Cri-du-Chat syndrome, which is a genetic disease caused by deletion of variable size, with breakpoints ranging from p13 to p15.2.¹⁸ A distinctive cry (similar to that of a meowing kitten), dysmorphisms, psychomotor delay, and MR are some of the clinical manifestations of the syndrome. Studies confirm the critical region of the syndrome, mapped in 5p15, with genes related to Cri-du-Chat in p15.3, and dysmorphisms and MR in p15.2.^18,19

With the aid of websites GenScript⁷³ and ClinVar,⁷⁴ we were able to identify genes within the chromosome regions involved with the identified structural alterations, and evaluate which of them have already been reported in relation with MR. We found reports on all of the regions identified in our study as containing genes that due to loss or gain in the number of copies resulted in developmental delay; or significant speech delay; or growth delay; or intellectual delay.^20,21

CONCLUSIONS

Genetics is one of the areas of expertise that has most contributed to the elucidation of the causes of MR, with various possibilities for diagnosis. This study illustrates the contribution of G-banding karyotype analysis for investigation of the causes of MR, since our results are in line with those reported in the literature. Structural chromosomal abnormalities were observed more frequently in this study. Knowing the critical regions on chromosomes is very important to correlate genotype and phenotype, and karyotype studies may help determine such regions. Therefore, although G-banding karyotype analysis may not be the most suitable test for syndromes related to mental retardation, since a large number of these syndromes are due to submicroscopic deletions and duplications, this technique proves to be useful for initial screening of affected individuals, and negative results should be evaluated using more accurate techniques such as aCGH and MLPA.

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Publication Dates

• Publication in this collection
  May 2016

History

• Received
  24 Oct 2014
• Accepted
  04 Nov 2014