Mosaicism in ASXL3-related syndrome: Description of five patients from three families

Schirwani, Schaida; Hauser, Natalie; Platt, Anna; Punj, Sumit; Prescott, Katrina; Canham, Natalie; Study, Ddd; Mansour, Sahar; Balasubramanian, Meena

doi:10.1016/j.ejmg.2020.103925

Cited by 12 publications

(28 citation statements)

References 27 publications

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“…The prenatal diagnosis of BRPS was challenging owing to its limited ultrasonography ndings. Polyhydramonios, decreased fetal movements in late pregnancy and anthrogryposis on ultrasound were observed on separate fetus [5,11,20,29]. In our study, reduced fetal movement was found during pregnancy and bilateral varus deformity of feet was observed at birth, which were consistent with the reported fetal cases.…”

Section: Discussionsupporting

confidence: 91%

“…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%

“…In previous studies, three families had sibling recurrent variants and one family had mosaicism variant in the proband. Germline mosaicism in one of the parents seems to be a more likely explanation [20,23]. Within the families, behavioral phenotype diversity and difference in intellectual development among siblings with consistent variants have demonstrated the heterogeneity of this clinical condition [20].…”

Section: Discussionmentioning

confidence: 99%

“…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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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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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“…In previous researches, a large number of parental mosaicism studies were case reports of patients carrying parental germline mosaicism in separate genes [Satoh et al, 2017; Schirwani et al, 2020]. Although there were cohort studies on parental mosaicism, most of them were data analysis based on NGS data especially ES‐trio data.…”

Section: Resultsmentioning

confidence: 99%

Parental mosaicism in de novo neurodevelopmental diseases

Zhang

Tian

et al. 2021

American J of Med Genetics Pt A

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Neurodevelopmental diseases are increasingly recognized to be caused by “de novo” variants with the expanding use of next‐generation sequencing. The apparent de novo variants may actually be low‐level hereditary parental mosaic variants, which could increase the recurrence risk of disease by >50% and is thought to be an underappreciated cause of neurodevelopmental diseases. Our study aimed to investigate the frequency of parental mosaicism in “de novo” neurodevelopmental diseases. A total of 237 patients (and parents) with neurodevelopmental diseases carrying apparent de novo pathogenic or likely pathogenic variants were recruited consecutively. Deep next‐generation sequencing was performed on parental samples to identify parental mosaicism. Fourteen parental disease‐causing mosaicism variants (3.0%) in 11 genes were detected with alternate allele frequency (AAF) 0.22%–34%. Three parents showed milder clinical phenotypes than their offspring with relatively high AAF (23.33%, 25%, 34% separately). One recurrent variant was identified prenatally. A review of cohort study on parental mosaicism in neurodevelopmental diseases was performed. Our study highlights that identifying the parental mosaic disease‐causing variants especially the low‐level mosaicism will contribute to improving the accuracy of genetic counseling and prenatal diagnosis for reproductive risks.

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Molecular Genetics and Prenatal Diagnosis

Milunsky

2021

Genetic Disorders and the Fetus

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Mosaicism in ASXL3-related syndrome: Description of five patients from three families

Cited by 12 publications

References 27 publications

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

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

Parental mosaicism in de novo neurodevelopmental diseases

Molecular Genetics and Prenatal Diagnosis

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