Insertional translocation of 15q25‐q26 into 11p13 and duplication at 8p23.1 characterized by high resolution arrays in a boy with congenital malformations and aniridia

Simioni, Milena; Vieira, Társis Paiva; Sgardioli, Ilária Cristina; Freitas, Edmílson Dias de; Rosenberg, Carla; Maurer-Morelli, Cláudia Vianna; Lopes-Cendes, Íscia; Fett‐Conte, Agnes Cristina

doi:10.1002/ajmg.a.35603

Cited by 19 publications

(9 citation statements)

References 29 publications

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“…Likewise, Cheng et al [] published a case report of a Chinese family with several members with aniridia due to a 566‐kb deletions spanning the DCDC1 , DNAJC24 , IMMP1L , and ELP4 genes at a point 123 kb from the 3′ end of PAX6 . The most recent article presenting a deletion directly downstream of PAX6 was written by Simioni et al [], reporting a boy with an insertional duplication of 15q25–q26 into 11p13 including a 49‐kb deletion of ELP4 , 8 kb from the 3′ end of PAX6 exhibiting symptoms of developmental delay, bilateral aniridia, strabismus, and nystagmus. While this paper reported a much smaller deletion, like our patient, this deletion included an additional rearrangement leading us to hypothesize that his ocular phenotype is caused by the fact that the portion of 11p distal to the deletion is physically removed from the PAX6 region so even if the DRR is present, it is probably too far away to exert any regulatory effect [Simioni et al, ].…”

Section: Discussionmentioning

confidence: 99%

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A familial pericentric inversion of chromosome 11 associated with a microdeletion of 163kb and microduplication of 288kb at 11p13 and 11q22.3 without aniridia or eye anomalies

Balay

Totten

Okada

et al. 2015

American J of Med Genetics Pt A

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Interstitial deletions of 11p13 involving MPPED2, DCDC5, DCDC1, DNAJC24, IMMP1L, and ELP4 are previously reported to have downstream transcriptional effects on the expression of PAX6, due to a downstream regulatory region (DRR). Currently, no clear genotype-phenotype correlations have been established allowing for conclusive information regarding the exact location of the PAX6 DRR, though its location has been approximated in mouse models to be within the Elp4 gene. Of the clinical reports currently published examining patients with intact PAX6 genes but harboring deletions identified in genes downstream of PAX6, 100% indicate phenotypes which include aniridia, whereas approximately half report additional eye deformities, autism, or intellectual disability. In this clinical report, we present a 12-year-old male patient, his brother, and mother with pericentric inversions of chromosome 11 associated with submicroscopic interstitial deletions of 11p13 and duplications of 11q22.3. The inversions were identified by standard cytogenetic analysis; microarray and FISH detected the chromosomal imbalance. The patient's phenotype includes intellectual disability, speech abnormalities, and autistic behaviors, but interestingly neither the patient, his brother, nor mother have aniridia or other eye anomalies. To the best of our knowledge, these findings in three family members represent the only reported cases with 11p13 deletions downstream of PAX6 not demonstrating phenotypic characteristics of aniridia or abnormal eye development. Although none of the deleted genes are obvious candidates for the patient's phenotype, the absence of aniridia in the presence of this deletion in all three family members further delineates the location of the DRR for PAX6.

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Section: Discussionmentioning

confidence: 99%

“…Diagram of 11p13 deletions downstream of PAX6 present in recent case reports [Davis et al, ; Bayrakli et al, ; Cheng et al, ; Zhang et al, ; Simioni et al, ]. Arrows represent downstream regulatory region suggested in mouse models by McBride et al [].…”

Section: Discussionmentioning

confidence: 99%

A familial pericentric inversion of chromosome 11 associated with a microdeletion of 163kb and microduplication of 288kb at 11p13 and 11q22.3 without aniridia or eye anomalies

Balay

Totten

Okada

et al. 2015

American J of Med Genetics Pt A

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“…The aGH analysis detected two duplications: a 17.09-Mb segment at the chromosomal region 15q25-q26 (nt 81 869 248-98 962 477 bp (hg18)) and a 3.8-Mb duplication at the chromosomal region 8p23.1 (nt 8 129 435-11 934 586 bp (hg18)). The complete report of this patient has been published elsewhere, 21 although the present study highlights the 15q-15q26 region that involves KIF7 ( Figure 3). Patient 11, who showed a karyotype of 46,XX,t(4;5)(p10;p10), had no alterations involving breakpoint regions that would further characterize it as a balanced translocation.…”

Section: Resultsmentioning

confidence: 68%

Investigation of genetic factors underlying typical orofacial clefts: mutational screening and copy number variation

et al. 2014

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Typical orofacial clefts (OFCs) comprise cleft lip, cleft palate and cleft lip and palate. The complex etiology has been postulated to involve chromosome rearrangements, gene mutations and environmental factors. A group of genes including IRF6, FOXE1, GLI2, MSX2, SKI, SATB2, MSX1 and FGF has been implicated in the etiology of OFCs. Recently, the role of the copy number variations (CNVs) has been studied in genetic defects and diseases. CNVs act by modifying gene expression, disrupting gene sequence or altering gene dosage. The aims of this study were to screen the above-mentioned genes and to investigate CNVs in patients with OFCs. The sample was composed of 23 unrelated individuals who were grouped according to phenotype (associated with other anomalies or isolated) and familial recurrence. New sequence variants in GLI2, MSX1 and FGF8 were detected in patients, but not in their parents, as well as in 200 control chromosomes, indicating that these were rare variants. CNV screening identified new genes that can influence OFC pathogenesis, particularly highlighting TCEB3 and KIF7, that could be further analyzed. The findings of the present study suggest that the mechanism underlying CNV associated with sequence variants may play a role in the etiology of OFC.

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“…In the latter, the diagnosis was considered nonconclusive, because the origin of the marker chromosome was not identified. In the other two nondeleted individuals, the following chromosomal abnormalities were detected: one with 46,XY,der(11)ins(11;15)(p13; q24q26) (previously published as a case report), 22 and one with 46,XYder(9)ins(9;15)(q33;q21.1-q22.31). These two cases were further characterized by aGH and the final karyotype was defined, respectively, as follow: 46,XY,der(11)ins(11;15)(p13; q24q26).arr8p23.1 (8,129,934,586)x3,11p13 (31,706,16031,755,245)x1, 15q25q26 (81,869,962,477) x3; 46,XYder(9)ins(9;15)(q33;q21.1-q22.31).arr15q21.1q22.…”

Section: Resultsmentioning

confidence: 88%

“…Nondeleted individuals were reevaluated and only individuals who remained with a suspicion of 22q11.2 DS, and with no other diagnostic hypothesis were selected for TBX1 and FGF8 gene sequencing analysis. Primers used for both genes have been previously reported by Simioni et al 22 and Freitas, 23 respectively. The fragments obtained by polymerase chain reaction were directly sequenced using the BigDye terminator v3.1 cycle sequencing kit (Applied Biosystems, Foster City, California, United States) and the capillary electrophoresis system (Applied Biosystems 3130xl Genetic Analyzer) was used for fragment reading.…”

Section: Laboratory Investigationmentioning

confidence: 99%

22q11.2 Deletion Syndrome: Laboratory Diagnosis and TBX1 and FGF8 Mutation Screening

et al. 2015

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Velocardiofacial syndrome is one of the recognized forms of chromosome 22q11.2 deletion syndrome (22q11.2 DS) and has an incidence of 1 of 4,000 to 1 of 6,000 births. Nevertheless, the 22q11 deletion is not found in several patients with a 22q11.2 DS phenotype. In this situation, other chromosomal aberrations and/or mutations in the T-box 1 transcription factor C (TBX1) gene have been detected in some patients. A similar phenotype to that of the 22q11.2 DS has been reported in animal models with mutations in fibroblast growth factor 8 (Fgf8) gene. To date, FGF8 mutations have not been investigated in humans. We tested a strategy to perform laboratory testing to reduce costs in the investigation of patients presenting with the 22q11.2 DS phenotype. A total of 109 individuals with clinical suspicion were investigated using GTG-banding karyotype, fluorescence in situ hybridization, and/or multiplex ligation-dependent probe amplification. A conclusive diagnosis was achieved in 33 of 109 (30.2%) cases. In addition, mutations in the coding regions of TBX1 and FGF8 genes were investigated in selected cases where 22q11.2 deletion had been excluded, and no pathogenic mutations were detected in both genes. This study presents a strategy for molecular genetic characterization of patients presenting with the 22q11.2 DS using different laboratory techniques. This strategy could be useful in different countries, according to local resources. Also, to our knowledge, this is the first investigation of FGF8 gene in humans with this clinical suspicion.

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Insertional translocation of 15q25‐q26 into 11p13 and duplication at 8p23.1 characterized by high resolution arrays in a boy with congenital malformations and aniridia

Cited by 19 publications

References 29 publications

A familial pericentric inversion of chromosome 11 associated with a microdeletion of 163kb and microduplication of 288kb at 11p13 and 11q22.3 without aniridia or eye anomalies

A familial pericentric inversion of chromosome 11 associated with a microdeletion of 163kb and microduplication of 288kb at 11p13 and 11q22.3 without aniridia or eye anomalies

Investigation of genetic factors underlying typical orofacial clefts: mutational screening and copy number variation

22q11.2 Deletion Syndrome: Laboratory Diagnosis and TBX1 and FGF8 Mutation Screening

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