Novel de novo frameshift variant in the ASXL3 gene in a child with microcephaly and global developmental delay

Wayhelova, Marketa; Oppelt, Jan; Smetana, Jan; Hladílková, Eva; Filková, Hana; Makaturova, Eva; Nikolova, Petra; Beharka, Rastislav; Gaillyová, Renata; Kuglík, Petr

doi:10.3892/mmr.2019.10303

Cited by 11 publications

(10 citation statements)

References 51 publications

(69 reference statements)

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“…Recent studies showed that WES/WGS can be applied for simultaneous detection and characterization of both CNVs and single-nucleotide variants, which could reduce the number of analyses to one complex test to reach the diagnosis [45]. In our pilot study using targeted NGS with commercially available gene panel we identified pathogenic sequence variants in some patients with negative array-CGH assay and confirm the diagnosis on the molecular level [46].…”

Section: Discussionmentioning

confidence: 84%

The clinical benefit of array-based comparative genomic hybridization for detection of copy number variants in Czech children with intellectual disability and developmental delay

et al. 2019

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Background: Chromosomal microarray analysis has been shown to be a valuable and cost effective assay for elucidating copy number variants (CNVs) in children with intellectual disability and developmental delay (ID/DD). Methods: In our study, we performed array-based comparative genomic hybridization (array-CGH) analysis using oligonucleotide-based platforms in 542 Czech patients with ID/DD, autism spectrum disorders and multiple congenital abnormalities. Prior to the array-CGH analysis, all the patients were first examined karyotypically using Gbanding. The presence of CNVs and their putative derivation was confirmed using fluorescence in situ hybridization (FISH), multiplex ligation-dependent probe amplification (MLPA) and predominantly relative quantitative polymerase chain reaction (qPCR). Results: In total, 5.9% (32/542) patients were positive for karyotypic abnormalities. Pathogenic/likely pathogenic CNVs were identified in 17.7% of them (96/542), variants of uncertain significance (VOUS) were detected in 4.8% (26/542) and likely benign CNVs in 9.2% of cases (50/542). We identified 6.6% (36/542) patients with known recurrent microdeletion (24 cases) and microduplication (12 cases) syndromes, as well as 4.8% (26/542) patients with non-recurrent rare microdeletions (21 cases) and microduplications (5 cases). In the group of patients with submicroscopic pathogenic/ likely pathogenic CNVs (13.3%; 68/510) we identified 91.2% (62/68) patients with one CNV, 5.9% (4/68) patients with two likely independent CNVs and 2.9% (2/68) patients with two CNVs resulting from cryptic unbalanced translocations. Of all detected CNVs, 21% (31/147) had a de novo origin, 51% (75/147) were inherited and 28% (41/147) of unknown origin. In our cohort pathogenic/likely pathogenic microdeletions were more frequent than microduplications (69%; 51/74 vs. 31%; 23/74) ranging in size from 0.395 Mb to 10.676 Mb (microdeletions) and 0.544 Mb to 8.156 Mb (microduplications), but their sizes were not significantly different (P = 0.83). The pathogenic/likely pathogenic CNVs (median 2.663 Mb) were significantly larger than benign CNVs (median 0.394 Mb) (P < 0.00001) and likewise the pathogenic/likely pathogenic CNVs (median 2.663 Mb) were significantly larger in size than VOUS (median 0.469 Mb) (P < 0.00001).

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Section: Discussionmentioning

confidence: 84%

The clinical benefit of array-based comparative genomic hybridization for detection of copy number variants in Czech children with intellectual disability and developmental delay

et al. 2019

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“…In addition to the spice site mutation, variant c.3106C > T (p.Arg1036*) was detected in ve patients and c.4330C > T (p.Arg1444*) was detected in three patients, which suggested they are likely mutational hotspots. The prediction that phenotype severity decreases as the variants occur further away from the 5'-end of exon 11 and towards the 3'-end needs to be further con rmed [19]. More patients should be collected to study the genotype-phenotype correlation in this severe atypical neurodevelopmental disorder.…”

Section: Discussionmentioning

confidence: 98%

“…BRPS was rst described in 2013, in four patients with ASXL3 de novo mutations. To date, 54 patients with a wide age range from 4 months to 47 years were reported [1,2,5,[11][12][13][14][15][16][17][18][19][20][22][23][24][25][26][27][28][29][30]. Mutation spectrum of ASXL3 and the number of patients were listed in Table 1.…”

Section: Discussionmentioning

confidence: 99%

“…To our knowledge, 54 cases with ASXL3 LOF variants and one splicing mutation have been reported including ten Chinese patients [12][13][14][15][16][17][18]. The studies demonstrate clinical heterogeneity exists in the affected subjects and the correlation between the position of variants and the severity of the phenotype is uncertain [5,17,19]. Nonsense variants in MCR found in phenotypically normal individuals, germline and postzygotic mosaicism were also reported [13,17,20].…”

Section: Introductionmentioning

confidence: 99%

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De Novo Nonsense Variant in ASXL3 in a Chinese Girl Causing Bainbridge–Ropers Syndrome: A Case Report and Review of Literature

Wang

Zhang

Jiang

et al. 2021

Preprint

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Background: Bainbridge-Ropers syndrome (BRPS, OMIM #615485) was first identified in 2013 by Bainbridge et al. and is a neurodevelopment disorder characterized by failure to thrive, facial dysmorphism, and severe developmental delay. BRPS is caused by heterozygous loss-of function (LOF) variants in the additional sex combs-like 3 (ASXL3) gene which are mostly located in two mutational cluster regions (MCR). Due to the limited specific recognizable features and overlapping symptoms with Bohring–Opitz syndrome, clinical diagnosis of BRPS is challenging. Case presentation: In this study, a 2-year-8-month-old Chinese girl was referred for genetic evaluation of severe developmental delay. Reduced fetal movement was found during antenatal period and bilateral varus deformity of feet was observed at birth. Whole exome sequencing and Sanger sequencing were used to detect and confirm the variant. A novel nonsense variant c.1063G>T (p.E355X) in the ASXL3 gene (NM_030632.3) was identified in the proband and the clinical symptoms were compatible with BRPS. The parents were physical and genetic normal and prenatal diagnosis was requested for her pregnant mother with a negative Sanger sequencing result. Conclusion: The study revealed a de novo LOF variant in the ASXL3 gene and expanded the mutation spectrum for this clinical condition. By performing a literature review, we analyzed the clinical phenotype with limited fetal features and summarized genetic results of all BPRSs reported so far. More cases study may help to elucidate the function of ASXL3 gene that may be critical to understand the genetic etiology of this syndrome and assist in accurate genetic counselling, informed decision making and prenatal diagnosis.

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“…We have previously made several contributions to the literature with publication of three papers delineating the phenotype of ASXL3 ‐related syndrome (Balasubramanian et al, 2017; Myers et al, 2018; Schirwani et al, 2020). So far, clinical details from a total of 45 patients with ASXL3 ‐related syndrome have been reported in literature (Bainbridge et al, 2013; Balasubramanian et al, 2017; Contreras‐Capetillo et al, 2018; Dad et al, 2017; Dinwiddie et al, 2013; Hori et al, 2016; Koboldt et al, 2018; Kuechler et al, 2017; Myers et al, 2018; Neeta Lakhani et al, 2017; Qiao et al, 2019; Schirwani et al, 2020; Srivastava et al, 2016; Verhoeven et al, 2018; Wayhelova et al, 2019). Clinically, ASXL3 ‐related syndrome, also known as Bainbridge–Ropers syndrome (MIM# 615485), is characterized by a variable degree of intellectual disability (ID), developmental delay (DD) with absent or very limited speech development, hypotonia, feeding difficulties, behavioral problems, and characteristic craniofacial features.…”

Section: Introductionmentioning

confidence: 99%

Expanding the phenotype of ASXL3‐related syndrome: A comprehensive description of 45 unpublished individuals with inherited and de novo pathogenic variants in ASXL3

Schirwani

Albaba

Carere³

et al. 2021

American J of Med Genetics Pt A

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The study aimed at widening the clinical and genetic spectrum of ASXL3‐related syndrome, a neurodevelopmental disorder, caused by truncating variants in the ASXL3 gene. In this international collaborative study, we have undertaken a detailed clinical and molecular analysis of 45 previously unpublished individuals with ASXL3‐related syndrome, as well as a review of all previously published individuals. We have reviewed the rather limited functional characterization of pathogenic variants in ASXL3 and discuss current understanding of the consequences of the different ASXL3 variants. In this comprehensive analysis of ASXL3‐related syndrome, we define its natural history and clinical evolution occurring with age. We report familial ASXL3 pathogenic variants, characterize the phenotype in mildly affected individuals and discuss nonpenetrance. We also discuss the role of missense variants in ASXL3. We delineate a variable but consistent phenotype. The most characteristic features are neurodevelopmental delay with consistently limited speech, significant neuro‐behavioral issues, hypotonia, and feeding difficulties. Distinctive features include downslanting palpebral fissures, hypertelorism, tubular nose with a prominent nasal bridge, and low‐hanging columella. The presented data will inform clinical management of individuals with ASXL3‐related syndrome and improve interpretation of new ASXL3 sequence variants.

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Novel de novo frameshift variant in the ASXL3 gene in a child with microcephaly and global developmental delay

Cited by 11 publications

References 51 publications

The clinical benefit of array-based comparative genomic hybridization for detection of copy number variants in Czech children with intellectual disability and developmental delay

The clinical benefit of array-based comparative genomic hybridization for detection of copy number variants in Czech children with intellectual disability and developmental delay

De Novo Nonsense Variant in ASXL3 in a Chinese Girl Causing Bainbridge–Ropers Syndrome: A Case Report and Review of Literature

Expanding the phenotype of ASXL3‐related syndrome: A comprehensive description of 45 unpublished individuals with inherited and de novo pathogenic variants in ASXL3

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