Limits...
Complex nature of apparently balanced chromosomal rearrangements in patients with autism spectrum disorder.

Tabet AC, Verloes A, Pilorge M, Delaby E, Delorme R, Nygren G, Devillard F, Gérard M, Passemard S, Héron D, Siffroi JP, Jacquette A, Delahaye A, Perrin L, Dupont C, Aboura A, Bitoun P, Coleman M, Leboyer M, Gillberg C, Benzacken B, Betancur C - Mol Autism (2015)

Bottom Line: Apparently balanced chromosomal rearrangements can be associated with an abnormal phenotype, including intellectual disability and autism spectrum disorder (ASD).We detected clinically significant de novo copy number variants in four patients (22%), including three with de novo rearrangements and one with an inherited abnormality.These findings underscore the utility of SNP arrays for investigating apparently balanced chromosomal abnormalities in subjects with ASD or related neurodevelopmental disorders in both clinical and research settings.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics, AP-HP, Robert Debré University Hospital, 48 boulevard Sérurier, 75019 Paris, France ; INSERM, UMR 1130, Neuroscience Paris Seine, 9 quai Saint Bernard, 75005 Paris, France ; CNRS, UMR 8246, Neuroscience Paris Seine, 9 quai Saint Bernard, 75005 Paris, France ; Sorbonne Universités, UPMC Univ Paris 6, Institut de Biologie Paris-Seine, 9 quai Saint Bernard, 75005 Paris, France.

ABSTRACT

Background: Apparently balanced chromosomal rearrangements can be associated with an abnormal phenotype, including intellectual disability and autism spectrum disorder (ASD). Genome-wide microarrays reveal cryptic genomic imbalances, related or not to the breakpoints, in 25% to 50% of patients with an abnormal phenotype carrying a microscopically balanced chromosomal rearrangement. Here we performed microarray analysis of 18 patients with ASD carrying balanced chromosomal abnormalities to identify submicroscopic imbalances implicated in abnormal neurodevelopment.

Methods: Eighteen patients with ASD carrying apparently balanced chromosomal abnormalities were screened using single nucleotide polymorphism (SNP) arrays. Nine rearrangements were de novo, seven inherited, and two of unknown inheritance. Genomic imbalances were confirmed by fluorescence in situ hybridization and quantitative PCR.

Results: We detected clinically significant de novo copy number variants in four patients (22%), including three with de novo rearrangements and one with an inherited abnormality. The sizes ranged from 3.3 to 4.9 Mb; three were related to the breakpoint regions and one occurred elsewhere. We report a patient with a duplication of the Wolf-Hirschhorn syndrome critical region, contributing to the delineation of this rare genomic disorder. The patient has a chromosome 4p inverted duplication deletion, with a 0.5 Mb deletion of terminal 4p and a 4.2 Mb duplication of 4p16.2p16.3. The other cases included an apparently balanced de novo translocation t(5;18)(q12;p11.2) with a 4.2 Mb deletion at the 18p breakpoint, a subject with de novo pericentric inversion inv(11)(p14q23.2) in whom the array revealed a de novo 4.9 Mb deletion in 7q21.3q22.1, and a patient with a maternal inv(2)(q14.2q37.3) with a de novo 3.3 Mb terminal 2q deletion and a 4.2 Mb duplication at the proximal breakpoint. In addition, we identified a rare de novo deletion of unknown significance on a chromosome unrelated to the initial rearrangement, disrupting a single gene, RFX3.

Conclusions: These findings underscore the utility of SNP arrays for investigating apparently balanced chromosomal abnormalities in subjects with ASD or related neurodevelopmental disorders in both clinical and research settings.

No MeSH data available.


Related in: MedlinePlus

Duplication of the Wolf-Hirschhorn region in patient 1. Map of chromosome 4 (1-6,000,000, hg19) showing the rearrangement detected in patient 1 and previously reported overlapping rearrangements. The region commonly deleted in Wolf-Hirschhorn syndrome and the two proposed critical regions (WHSCR1 and WHSCR2) are represented. Horizontal blue lines represent duplications, and red lines indicate deletions. RefSeq genes are indicated at the bottom of the map.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
getmorefigures.php?uid=PMC4384291&req=5

Fig2: Duplication of the Wolf-Hirschhorn region in patient 1. Map of chromosome 4 (1-6,000,000, hg19) showing the rearrangement detected in patient 1 and previously reported overlapping rearrangements. The region commonly deleted in Wolf-Hirschhorn syndrome and the two proposed critical regions (WHSCR1 and WHSCR2) are represented. Horizontal blue lines represent duplications, and red lines indicate deletions. RefSeq genes are indicated at the bottom of the map.

Mentions: This boy was referred for evaluation at the age of 2 years and 9 months because of developmental delay and ASD features. He is the second child of healthy non-consanguineous parents (maternal age 31 years, paternal age 38 years). He was born at 42 weeks after an uneventful pregnancy, weighing 5,280 g (+4.3 SD), probably due to latent diabetes in the mother. He was hypoglycemic during the first days of life, and an inguinal hernia was corrected at the age of two months. There was no delay in motor milestones or language development. He was diagnosed with autism after formal testing at an autism referral center. He had a borderline IQ of 69 (verbal IQ 67, performance IQ 78). There was no history of seizures, and his EEG was normal. His physical and neurological exams were normal except for mild strabismus; in particular, he had no dysmorphic features. At the age of 4 years, he was +2 SD to +3 SD in weight and height. Conventional karyotyping showed a de novo translocation between the telomeric region of the short arm of chromosome 4 and the short arm of an acrocentric chromosome. His karyotype was 46,XY,der(4)t(4;acro p)(p16.3;acro p)dn. Although this translocation is unbalanced, this patient was included in the present study because the excess of heterochromatic material from an acrocentric short arm cannot explain his abnormal phenotype. SNP array analysis revealed a 541 kb deletion in 4p16.3 (17,764-558,839, hg19) and a 4.24 Mb duplication in 4p16.2p16.3 (577,581-4,812,859) in the proband (Figure 1A), absent from the parents. Both rearrangements were confirmed by qPCR and FISH. The deletion was confirmed by FISH with the 4p subtelomeric probe RP11-2H3. Using probes RP11-296G16 (4p16.3) and RP11-265012 (4p16.2), the FISH findings were consistent with an inverted duplication (data not shown), indicating a chromosome 4p inverted duplication deletion. SNP genotyping indicated that both rearrangements occurred on the paternal chromosome. The deletion includes eight RefSeq genes; the duplication encompasses 70 genes and overlaps the Wolf-Hirschhorn critical region (Figure 2).Figure 1


Complex nature of apparently balanced chromosomal rearrangements in patients with autism spectrum disorder.

Tabet AC, Verloes A, Pilorge M, Delaby E, Delorme R, Nygren G, Devillard F, Gérard M, Passemard S, Héron D, Siffroi JP, Jacquette A, Delahaye A, Perrin L, Dupont C, Aboura A, Bitoun P, Coleman M, Leboyer M, Gillberg C, Benzacken B, Betancur C - Mol Autism (2015)

Duplication of the Wolf-Hirschhorn region in patient 1. Map of chromosome 4 (1-6,000,000, hg19) showing the rearrangement detected in patient 1 and previously reported overlapping rearrangements. The region commonly deleted in Wolf-Hirschhorn syndrome and the two proposed critical regions (WHSCR1 and WHSCR2) are represented. Horizontal blue lines represent duplications, and red lines indicate deletions. RefSeq genes are indicated at the bottom of the map.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4384291&req=5

Fig2: Duplication of the Wolf-Hirschhorn region in patient 1. Map of chromosome 4 (1-6,000,000, hg19) showing the rearrangement detected in patient 1 and previously reported overlapping rearrangements. The region commonly deleted in Wolf-Hirschhorn syndrome and the two proposed critical regions (WHSCR1 and WHSCR2) are represented. Horizontal blue lines represent duplications, and red lines indicate deletions. RefSeq genes are indicated at the bottom of the map.
Mentions: This boy was referred for evaluation at the age of 2 years and 9 months because of developmental delay and ASD features. He is the second child of healthy non-consanguineous parents (maternal age 31 years, paternal age 38 years). He was born at 42 weeks after an uneventful pregnancy, weighing 5,280 g (+4.3 SD), probably due to latent diabetes in the mother. He was hypoglycemic during the first days of life, and an inguinal hernia was corrected at the age of two months. There was no delay in motor milestones or language development. He was diagnosed with autism after formal testing at an autism referral center. He had a borderline IQ of 69 (verbal IQ 67, performance IQ 78). There was no history of seizures, and his EEG was normal. His physical and neurological exams were normal except for mild strabismus; in particular, he had no dysmorphic features. At the age of 4 years, he was +2 SD to +3 SD in weight and height. Conventional karyotyping showed a de novo translocation between the telomeric region of the short arm of chromosome 4 and the short arm of an acrocentric chromosome. His karyotype was 46,XY,der(4)t(4;acro p)(p16.3;acro p)dn. Although this translocation is unbalanced, this patient was included in the present study because the excess of heterochromatic material from an acrocentric short arm cannot explain his abnormal phenotype. SNP array analysis revealed a 541 kb deletion in 4p16.3 (17,764-558,839, hg19) and a 4.24 Mb duplication in 4p16.2p16.3 (577,581-4,812,859) in the proband (Figure 1A), absent from the parents. Both rearrangements were confirmed by qPCR and FISH. The deletion was confirmed by FISH with the 4p subtelomeric probe RP11-2H3. Using probes RP11-296G16 (4p16.3) and RP11-265012 (4p16.2), the FISH findings were consistent with an inverted duplication (data not shown), indicating a chromosome 4p inverted duplication deletion. SNP genotyping indicated that both rearrangements occurred on the paternal chromosome. The deletion includes eight RefSeq genes; the duplication encompasses 70 genes and overlaps the Wolf-Hirschhorn critical region (Figure 2).Figure 1

Bottom Line: Apparently balanced chromosomal rearrangements can be associated with an abnormal phenotype, including intellectual disability and autism spectrum disorder (ASD).We detected clinically significant de novo copy number variants in four patients (22%), including three with de novo rearrangements and one with an inherited abnormality.These findings underscore the utility of SNP arrays for investigating apparently balanced chromosomal abnormalities in subjects with ASD or related neurodevelopmental disorders in both clinical and research settings.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics, AP-HP, Robert Debré University Hospital, 48 boulevard Sérurier, 75019 Paris, France ; INSERM, UMR 1130, Neuroscience Paris Seine, 9 quai Saint Bernard, 75005 Paris, France ; CNRS, UMR 8246, Neuroscience Paris Seine, 9 quai Saint Bernard, 75005 Paris, France ; Sorbonne Universités, UPMC Univ Paris 6, Institut de Biologie Paris-Seine, 9 quai Saint Bernard, 75005 Paris, France.

ABSTRACT

Background: Apparently balanced chromosomal rearrangements can be associated with an abnormal phenotype, including intellectual disability and autism spectrum disorder (ASD). Genome-wide microarrays reveal cryptic genomic imbalances, related or not to the breakpoints, in 25% to 50% of patients with an abnormal phenotype carrying a microscopically balanced chromosomal rearrangement. Here we performed microarray analysis of 18 patients with ASD carrying balanced chromosomal abnormalities to identify submicroscopic imbalances implicated in abnormal neurodevelopment.

Methods: Eighteen patients with ASD carrying apparently balanced chromosomal abnormalities were screened using single nucleotide polymorphism (SNP) arrays. Nine rearrangements were de novo, seven inherited, and two of unknown inheritance. Genomic imbalances were confirmed by fluorescence in situ hybridization and quantitative PCR.

Results: We detected clinically significant de novo copy number variants in four patients (22%), including three with de novo rearrangements and one with an inherited abnormality. The sizes ranged from 3.3 to 4.9 Mb; three were related to the breakpoint regions and one occurred elsewhere. We report a patient with a duplication of the Wolf-Hirschhorn syndrome critical region, contributing to the delineation of this rare genomic disorder. The patient has a chromosome 4p inverted duplication deletion, with a 0.5 Mb deletion of terminal 4p and a 4.2 Mb duplication of 4p16.2p16.3. The other cases included an apparently balanced de novo translocation t(5;18)(q12;p11.2) with a 4.2 Mb deletion at the 18p breakpoint, a subject with de novo pericentric inversion inv(11)(p14q23.2) in whom the array revealed a de novo 4.9 Mb deletion in 7q21.3q22.1, and a patient with a maternal inv(2)(q14.2q37.3) with a de novo 3.3 Mb terminal 2q deletion and a 4.2 Mb duplication at the proximal breakpoint. In addition, we identified a rare de novo deletion of unknown significance on a chromosome unrelated to the initial rearrangement, disrupting a single gene, RFX3.

Conclusions: These findings underscore the utility of SNP arrays for investigating apparently balanced chromosomal abnormalities in subjects with ASD or related neurodevelopmental disorders in both clinical and research settings.

No MeSH data available.


Related in: MedlinePlus