Microdeletions of 5.5 Mb (4q13.2–q13.3) and 4.1 Mb (7p15.3–p21.1) associated with a saethre–chotzen‐like phenotype, severe intellectual disability, and autism

Microsatellite DNAs that form non-B structures are implicated in replication fork stalling, DNA double strand breaks (DSBs) and human disease. Fanconi anemia (FA) is an inherited disorder in which mutations in at least nineteen genes are responsible for the phenotypes of genome instability and cancer predisposition. FA pathway proteins are active in the resolution of non-B DNA structures including interstrand crosslinks, G quadruplexes and DNA triplexes. In FANCJ helicase depleted cells, we show that hydroxyurea or aphidicolin treatment leads to loss of microsatellite polymerase chain reaction signals and to chromosome recombination at an ectopic hairpin forming CTG/CAG repeat in the HeLa genome. Moreover, diverse endogenous microsatellite signals were also lost upon replication stress after FANCJ depletion, and in FANCJ null patient cells. The phenotype of microsatellite signal instability is specific for FANCJ apart from the intact FA pathway, and is consistent with DSBs at microsatellites genome-wide in FANCJ depleted cells following replication stress.

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“…6q24.1, breast cancer, neuroblastoma, melanoma (63); chr. 7p15.3, ovarian cancer (64,65); chr. 8q24.21, leukemia/lymphoma (66,67); chr.…”

Section: Discussionmentioning

confidence: 99%

FANCJ is essential to maintain microsatellite structure genome-wide during replication stress

Barthelemy

Leffak

2016

Nucleic Acids Res

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“…To the best of our knowledge, the proximal 4q chromosomal aberrations identified in patients with neurodevelopmental phenotypes are rare, non recurrent, heterogeneous in size (usually affecting several megabases of sequence) and breakpoints and, in consequence, involve different chromosome bands and a high number of genes [Zollino et al, ; Nowaczyk et al, ; Shashi et al, ; Eggermann et al, ; Bonnet et al, ; Lipska et al, ; Assawamakin et al, ; Girirajan et al, ; Matoso et al, ; Shimada et al, ; Hemati et al, 2014; Utine et al, ]. Amongst these alterations we can distinguish chromosomal aberrations restricted to 4q13 chromosome bands [Girirajan et al, ; Matoso et al, ; Shimada et al, ] (Table ), as those of our patients, from larger alterations involving additional chromosome bands [Zollino et al, ; Nowaczyk et al, ; Shashi et al, ; Eggermann et al, ; Bonnet et al, ; Lipska et al, ; Assawamakin et al, ; Hemati et al, 2014; Utine et al, ]. Figure is an schematic overview of the proximal 4q region showing the SNP array results in our patients, previously reported chromosomal alterations restricted to 4q13 chromosome bands and OMIM‐morbidity and candidate genes implicated in this interval (Fig.…”

Section: Discussionmentioning

confidence: 99%

“… RefSeq and candidate genes, genomic coordinates, size, number of genes and inheritance pattern of 4q13‐restricted chromosomal aberrations reported in the literature. [Girirajan et al, ; Matoso et al, ; Shimada et al, ]. The UCSC Genome LiftOver Tool was used for converting genome coordinates from hg18 to hg19 assemblies, where necessary.…”

Section: Discussionmentioning

confidence: 99%

“…To date, few clinical descriptions of patients with neurodevelopmental phenotypes and proximal 4q chromosomal aberrations have been reported. All of them are variable in type (both copy number losses and gains as well as complex rearrangements), size (ranging from ∼1,5 Mb to ∼25 Mb) and breakpoints and encompass different chromosome bands (restricted to 4q13 or expanding into adjacent chromosome bands) and genes [Zollino et al, ; Nowaczyk et al, ; Shashi et al, ; Eggermann et al, ; Bonnet et al, ; Lipska et al, ; Assawamakin et al, ; Girirajan et al, ; Matoso et al, ; Shimada et al, ; Hemati et al, 2014; Utine et al, ]. So that, the interpretation of their clinical implications, the discovery of candidate genes and the establishment of genotype–phenotype correlations are challenging tasks that remain to be addressed.…”

Section: Introductionmentioning

confidence: 99%

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Interstitial microdeletions including the chromosome band 4q13.2 and the UBA6 gene as possible causes of intellectual disability and behavior disorder

Quintela

Barros

Prieto

et al. 2015

American J of Med Genetics Pt A

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The few proximal 4q chromosomal aberrations identified in patients with neurodevelopmental phenotypes that have been published to date are variable in type, size and breakpoints and, therefore, encompass different chromosome bands and genes, making the establishment of genotype-phenotype correlations a challenging task. Here, microarray-based copy number analysis allowed us the detection of two novel and partially overlapping deletions in two unrelated families. In Family 1, a 4q13.1-q13.2 deletion of 3.84 Mb was identified in a mother with mild intellectual disability and in her two children, both with mild intellectual disability and attention deficit hyperactivity disorder. In Family 2, a de novo 4q13.2-q13.3 deletion of 6.81 Mb was detected in a female patient, born to unaffected parents, with a diagnosis of mild intellectual disability, behavioral disorder and facial dysmorphism. The shortest region of overlap between these two aberrations is located at chromosome 4q13.2 and includes 17 genes amongst of which we suggest UBA6 (ubiquitin-like modifier-activating enzyme 6) as a strong candidate gene for these phenotypes.

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“…Most of the previously reported deletions involving the 4q13.3 region are large chromosomal alterations with a common loss of band 4q21, resulting in marked growth restriction, severe intellectual disability, and absent or severely delayed speech [5][6][7][8][9]14]. The deletion detected in our patients is unique.…”

Section: Discussionmentioning

confidence: 76%

A case report of familial 4q13.3 microdeletion in three individuals with syndromic intellectual disability

et al. 2020

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Background: Interstitial 4q deletions are rare chromosomal alterations. Most of the previously reported deletions involving the 4q13.3 region are large chromosomal alterations with a common loss of band 4q21 resulting in marked growth restriction, severe intellectual disability, and absent or severely delayed speech. A microdeletion of 4q13.3 hasn't been previously reported. We discuss the involvement of genes and the observed phenotype, comparing it with that of previously reported patients.Case presentation: We report on a 4q13.3 microdeletion detected in three affected individuals of a Lithuanian family. The clinical features of two affected children and their affected mother are very similar and include short stature, congenital heart defect, skeletal anomalies, minor facial anomalies, delayed puberty, and intellectual disability. Whole genome SNP microarray analysis of one child revealed an interstitial 4q13.3 microdeletion, 1.56 Mb in size. FISH analysis confirmed the deletion in the proband and identified the same deletion in her affected sib and mother, while it was not detected in a healthy sib. Deletion includes ADAMTS3, ANKRD17, COX18, GC, and NPFFR2 protein-coding genes. Conclusions: Our findings suggest that 4q13.3 microdeletion is a cause of a recognizable phenotype of three affected individuals. The detected microdeletion is the smallest interstitial deletion in 4q13. We highlight ADAMTS3, ANKRD17 and RNU4ATAC9P as candidate genes for intellectual disability, growth retardation and congenital heart defect.

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Microdeletions of 5.5 Mb (4q13.2–q13.3) and 4.1 Mb (7p15.3–p21.1) associated with a saethre–chotzen‐like phenotype, severe intellectual disability, and autism

Cited by 12 publications

References 16 publications

FANCJ is essential to maintain microsatellite structure genome-wide during replication stress

FANCJ is essential to maintain microsatellite structure genome-wide during replication stress

Interstitial microdeletions including the chromosome band 4q13.2 and the UBA6 gene as possible causes of intellectual disability and behavior disorder

A case report of familial 4q13.3 microdeletion in three individuals with syndromic intellectual disability

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