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De novo balanced translocation t (7;16) (p22.1; p11.2) associated with autistic disorder.

ABSTRACT: The high incidence of de novo chromosomal aberrations in a population of persons with autism suggests a causal relationship between certain chromosomal aberrations and the occurrence of isolated idiopathic autism. We report on the clinical and cytogenetic findings in a male patient with autism, no physical abnormalities and a de novo balanced (7;16)(p22.1;p16.2) translocation. G-banded chromosomes and fluorescent in situ hybridization (FISH) were used to examine the patient's karyotype as well as his parents'. FISH with specific RP11-BAC clones mapping near 7p22.1 and 16p11.2 was used to refine the location of the breakpoints. This is, in the best of our knowledge, the first report of an individual with autism and this specific chromosomal aberration.

SUBMITTER: Bayou N

PROVIDER: S-EPMC2373955 | biostudies-literature | 2008

REPOSITORIES: biostudies-literature

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De novo balanced translocation t (7;16) (p22.1; p11.2) associated with autistic disorder.

Bayou Nadia N M'rad Ridha R Belhaj Ahlem A Daoud Hussein H Ben Jemaa Lamia L Zemni Ramzi R Briault Sylvain S Helayem M Bechir MB Chaabouni Habiba H

Journal of biomedicine & biotechnology 20080101

The high incidence of de novo chromosomal aberrations in a population of persons with autism suggests a causal relationship between certain chromosomal aberrations and the occurrence of isolated idiopathic autism. We report on the clinical and cytogenetic findings in a male patient with autism, no physical abnormalities and a de novo balanced (7;16)(p22.1;p16.2) translocation. G-banded chromosomes and fluorescent in situ hybridization (FISH) were used to examine the patient's karyotype as well a ...[more]

PMID: 18475318

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Severe Progressive Autism Associated with Two de novo Changes: A 2.6-Mb 2q31.1 Deletion and a Balanced t(14;21)(q21.1;p11.2) Translocation with Long-Range Epigenetic Silencing of LRFN5 Expression.

Project description:In a 19-year-old severely autistic and mentally retarded girl, a balanced de novo t(14;21)(q21.1;p11.2) translocation was found in addition to a de novo 2.6-Mb 2q31.1 deletion containing 15 protein-encoding genes. To investigate if the translocation might contribute to developmental stagnation at the age of 2 years with later regression of skills, i.e. a more severe phenotype than expected from the 2q31.1 deletion, the epigenetic status and expression of genes proximal and distal to the 14q21.1 breakpoint were investigated in Ebstein Barr Virus-transformed lymphoblast and primary skin fibroblast cells. The 14q21.1 breakpoint was found to be located between a cluster of 7 genes 0.1 Mb upstream, starting with FBXO33, and the single and isolated LRFN5 gene 2.1 Mb downstream. Only expression of LRFN5 appeared to be affected by its novel genomic context. In patient fibroblasts, LRFN5 expression was 10-fold reduced compared to LRFN5 expressed in control fibroblasts. In addition, a relative increase in trimethylated histone H3 lysine 9 (H3K9M3)-associated DNA starting exactly at the translocation breakpoint and going 2.5 Mb beyond the LRFN5 gene was found. At the LRFN5 promoter, there was a distinct peak of trimethylated histone H3 lysine 27 (H3K27M3)-associated DNA in addition to a diminished trimethylated histone H3 lysine 4 (H3K4M3) level. We speculate that dysregulation of LRFN5, a postsynaptic density-associated gene, may contribute to the patient's autism, even though 2 other patients with 14q13.2q21.3 deletions that included LRFN5 were not autistic. More significantly, we have shown that translocations may influence gene expression more than 2 Mb away from the translocation breakpoint.

| S-EPMC2883852 | biostudies-literature

Cytogenetic and molecular analyses of de novo translocation dic(9;13)(p11.2;p12) in an infertile male.

Project description:BackgroundWhole arm t(9;13)(p11;p12) translocations are rare and have been described only a few times; all of the previously reported cases were familial.ResultsWe present here an infertile male carrier with a whole-arm reciprocal translocation dic(9;13)(p11.2;p12) revealed by GTG-, C-, and NOR-banding karyotypes with no mature sperm cells in his ejaculate. FISH and genome-wide 400 K CGH microarray (Agilent) analyses demonstrated a balanced chromosome complement and further characterised the abnormality as a dicentric chromosome (9;13): dic(9;13)(pter→p11.2::p12→qter),neo(9)(pter→p12→neo→p11.2). An analysis of the patient's ejaculated cells identified immature germ cells at different phases of spermatogenesis but no mature spermatozoa. Most (82.5%) of the germ cells were recognised as spermatocytes at stage I, and the cell nuclei were most frequently found in pachytene I (41.8%). We have also undertaken FISH analysis and documented an increased rate of aneuploidy of chromosomes 15, 18, X and Y in the peripheral blood leukocytes of our patient. To study the aneuploidy risk in leukocytes, we have additionally included 9 patients with non-obstructive azoospermia with normal karyotypes.ConclusionsWe propose that the azoospermia observed in the patient with the dic(9;13)(p11.2;p12) translocation was most likely a consequence of a very high proportion (90%) of association between XY bivalents and quadrivalent formations in prophase I.

| S-EPMC3944724 | biostudies-literature

A de novo apparently balanced translocation [46,XY,t(2;9)(p13;p24)] interrupting RAB11FIP5 identifies a potential candidate gene for autism spectrum disorder.

Project description:Autism spectrum disorder (ASD) is a severe developmental disorder of the central nervous system characterized by impairments in social interaction, communication, and range of interests and behaviors. The syndrome's prevalence is estimated to be as high as 1 in 150 American children yet its etiology remains largely unknown. Examination of observed cytogenetic variants in individuals with ASD may identify genes involved in its pathogenesis. As part of a multidisciplinary study, an apparently balanced de novo translocation between chromosomes 2 and 9 [46,XY,t(2;9)(p13;p24)] was identified in a subject with pervasive developmental disorder not otherwise specified (PDD-NOS), and no distinctive dysmorphic features. Molecular characterization of the rearrangement revealed direct interruption of the RAB11 family interacting protein 5 (RAB11FIP5) gene. RAB11FIP5 is a Rab effector involved in protein trafficking from apical recycling endosomes to the apical plasma membrane. It is ubiquitously expressed and reported to contribute to both neurotransmitter release and neurotransmitter uptake at the synaptic junction. Detailed analysis of the rearrangement breakpoints suggests that the reciprocal translocation may have formed secondary to incorrect repair of double strand breaks (DSBs) by nonhomologous end-joining (NHEJ).

| S-EPMC4355399 | biostudies-literature

A Novel <i>SETBP1</i> Gene Disruption by a De Novo Balanced Translocation in a Patient with Speech Impairment, Intellectual, and Behavioral Disorder.

Project description:Balanced chromosomal abnormalities (BCAs) can disrupt gene function resulting in disease. To date, BCA disrupting the SET binding protein 1 ( SETBP1 ) gene has not been reported. On the other hand, de novo heterozygous variants in the highly conserved 11-bp region in SETBP1 can result in the Schinzel-Giedion syndrome. This condition is characterized by severe intellectual disability, a characteristic face, and multiple-system anomalies. Further other types of mutations involving SETBP1 are associated with a different phenotype, mental retardation, autosomal dominant 29 (MRD29), which has mild dysmorphic features, developmental delay, and behavioral disorders. Here we report a male patient who has moderate intellectual disability, mild behavioral difficulties, and severe expressive speech impairment resulting from a de novo balanced chromosome translocation, t(12;18)(q22;q12.3). By whole genome sequencing, we determined the breakpoints at the nucleotide level. The 18q12.3 breakpoint was located between exons 2 and 3 of SETBP1 . Phenotypic features of our patient are compatible with those with MRD29. This is the first reported BCA disrupting SETBP1 .

| S-EPMC9236750 | biostudies-literature

Position effect, cryptic complexity, and direct gene disruption as disease mechanisms in de novo apparently balanced translocation cases.

Project description:The majority of apparently balanced translocation (ABT) carriers are phenotypically normal. However, several mechanisms were proposed to underlie phenotypes in affected ABT cases. In the current study, whole-genome mate-pair sequencing (WG-MPS) followed by Sanger sequencing was applied to further characterize de novo ABTs in three affected individuals. WG-MPS precisely mapped all ABT breakpoints and revealed three possible underlying molecular mechanisms. Firstly, in a t(X;1) carrier with hearing loss, a highly skewed X-inactivation pattern was observed and the der(X) breakpoint mapped ~87kb upstream an X-linked deafness gene namely POU3F4, thus suggesting an underlying long-range position effect mechanism. Secondly, cryptic complexity and a chromothripsis rearrangement was identified in a t(6;7;8;12) carrier with intellectual disability. Two translocations and a heterozygous deletion disrupted SOX5; a dominant nervous system development gene previously reported in similar patients. Finally, a direct gene disruption mechanism was proposed in a t(4;9) carrier with dysmorphic facial features and speech delay. In this case, the der(9) breakpoint directly disrupted NFIB, a gene involved in lung maturation and development of the pons with important functions in main speech processes. To conclude, in contrast to familial ABT cases with identical rearrangements and discordant phenotypes, where translocations are considered coincidental, translocations seem to be associated with phenotype presentation in affected de novo ABT cases. In addition, this study highlights the importance of investigating both coding and non-coding regions to decipher the underlying pathogenic mechanisms in these patients, and supports the potential introduction of low coverage WG-MPS in the clinical investigation of de novo ABTs.

| S-EPMC6173455 | biostudies-literature

Shwachman syndrome associated with de novo reciprocal translocation t(6;12)(q16.2;q21.2).

Project description:We describe a de novo apparently balanced reciprocal translocation t(6;12)(q16.2; q21.2) in an 18 month old girl with Shwachman syndrome, characterised by exocrine pancreatic insufficiency and bone marrow dysfunction. The cause of this syndrome is unknown, although autosomal recessive inheritance has been proposed. The translocation breakpoints in the present patient may be candidate regions for a gene responsible for Shwachman syndrome.

| S-EPMC1051744 | biostudies-other

Genetic variation affects de novo translocation frequency.

Project description:Translocation is one of the most frequently occurring human chromosomal aberrations. The constitutional t(11;22)(q23;q11), which is the only known recurrent non-Robertsonian translocation, represents a good model for studying translocations in humans. Here we demonstrate polymorphisms of the palindromic sequence at the t(11;22) breakpoint that affect the frequency of de novo translocations in sperm from normal males. A typical allele consists of a perfect palindrome, producing ~10-5 de novo t(11;22) translocations. Alleles with an asymmetric center do not form the t(11;22). Our data show the importance of genome sequence on chromosomal rearrangements, a class of human mutation that is thought to be random.

| S-EPMC2818512 | biostudies-literature

Case Report: Balanced Reciprocal Translocation t (17; 22) (p11.2; q11.2) and 10q23.31 Microduplication in an Infertile Male Patient Suffering From Teratozoospermia.

Project description:Two chromosomal abnormalities are described in an infertile man suffering from teratozoospermia: balanced reciprocal translocation t (17; 22) (p11.2; q11.2) and a microduplication in the region 10q23.31. Twenty genes located on the breakpoints of translocation (e.g., ALKBH5, TOP3A, SPECC1L, and CDC45) are selected due to their high expression in testicular tissues and might be influenced by chromosome translocation. Four genes located on the breakpoints of microduplication including FLJ37201, KIF20B, LINC00865, and PANK1 result in an increased dosage of genes, representing an imbalance in the genome. These genes have been reported to be associated with developmental disorders/retardation and might be risk factors affecting spermatogenesis. Bioinformatics analysis is carried out on these key genes, intending to find the pathogenic process of reproduction in the context of the translocation and microduplication encountered in the male patient. The combination of the two chromosomal abnormalities carries additional risks for gametogenesis and genomic instability and is apparently harmful to male fertility. Overall, our findings could contribute to the knowledge of male infertility caused by genetic factors.

| S-EPMC9204271 | biostudies-literature

De novo balanced reciprocal translocation mosaic t(1;3)(q42;q25) detected by prenatal genetic diagnosis: a fetus conceived using preimplantation genetic testing due to a t(12;14)(q22;q13) balanced paternal reciprocal translocation.

Project description:IntroductionDe novo balanced reciprocal translocations mosaicism in fetus conceived using preimplantation genetic testing from a different balanced translocation carrier parent has been rarely reported.MethodsChromosomal microarray analysis, karyotype analysis and fluorescent in situ hybridization were performed to verify the type and heredity of the rearrangement. STR analysis was conducted to identify potential contamination and verify kinship. In addition, a local BLAST engine was performed to locate potentially homologous segments which might contribute to the translocation in breakpoints of chromosome.ResultsA rare de novo balanced reciprocal translocations mosaicism mos 46,XY,t(1;3)(q42;q25)[40]/46,XY[39] was diagnosed in a fetus conceived using preimplantation genetic testing due to a 46,XY,t(12;14)(q22;q13) balanced translocation carrier father through multiplatform genetic techniques. Two of the largest continuous high homology segments were identified in chromosomal band 1q42.12 and 3q25.2. At the 21-months follow up, infant has achieved all psychomotor development milestones as well as growth within the normal reference range.ConclusionWe present a prenatal diagnosis of a rare de novo balanced reciprocal translocations mosaicism in a fetus who conceived by preimplantation genetic testing. The most reasonable driving mechanism was that a de novo mitotic error caused by nonallelic homologous recombination between 1q42.12 and 3q25.2 in a zygote within the first or early cell divisions, which results in a mosaic embryo with the variant present in a half proportion of cells.

| S-EPMC8645079 | biostudies-literature

FISH mapping of de novo apparently balanced chromosome rearrangements identifies characteristics associated with phenotypic abnormality.

Project description:We report fluorescence in situ hybridization (FISH) mapping of 152, mostly de novo, apparently balanced chromosomal rearrangement (ABCR) breakpoints in 76 individuals, 30 of whom had no obvious phenotypic abnormality (control group) and 46 of whom had an associated disease (case group). The aim of this study was to identify breakpoint characteristics that could discriminate between these groups and which might be of predictive value in de novo ABCR (DN-ABCR) cases detected antenatally. We found no difference in the proportion of breakpoints that interrupted a gene, although in three cases, direct interruption or deletion of known autosomal-dominant or X-linked recessive Mendelian disease genes was diagnostic. The only significant predictor of phenotypic abnormality in the group as a whole was the localization of one or both breakpoints to an R-positive (G-negative) band with estimated predictive values of 0.69 (95% CL 0.54-0.81) and 0.90 (95% CL 0.60-0.98), respectively. R-positive bands are known to contain more genes and have a higher guanine-cytosine (GC) content than do G-positive (R-negative) bands; however, whether a gene was interrupted by the breakpoint or the GC content in the 200 kB around the breakpoint had no discriminant ability. Our results suggest that the large-scale genomic context of the breakpoint has prognostic utility and that the pathological mechanism of mapping to an R-band cannot be accounted for by direct gene inactivation.

| S-EPMC2491339 | biostudies-literature

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