Novel mutation in the ASXL3 gene in a Chinese boy with microcephaly and speech impairment: A case report

Abstract

BACKGROUND Bainbridge-Ropers syndrome (BRPS) is a severe disorder characterized by failure to thrive, facial dysmorphism, and severe developmental delay. BRPS is caused by a heterozygous loss-of-function mutation in the ASXL3 gene. Due to limited knowledge of the disease and lack of specific features, clinical diagnosis of this syndrome is challenging. With the use of trio-based whole exome sequencing, we identified a novel ASXL3 mutation in a Chinese boy with BRPS and performed a literature review. CASE SUMMARY A 3-year-old Chinese boy was referred to our hospital due to progressive postnatal microcephaly and intellectual disability with severe speech impairment for 2 years. His other remarkable clinical features were shown as follows: Facial dysmorphism, feeding difficulties, poor growth, motor delay, and abnormal behavior. For the proband, regular laboratory tests, blood tandem mass spectrometry, urine gas chromatographic mass spectrometry, karyotype, hearing screening, and brain magnetic resonance imaging were performed, with negative results. Therefore, for the proband and his unaffected parents, trio-based whole exome sequencing and subsequent validation by Sanger sequencing were performed. A novel nonsense variant in exon 11 of the ASXL3 gene (c.1795G>T; p.E599*) was detected, present in the patient but absent from his parents. Taking into account the concordant phenotypic features of our patient with reported BRPS patients and the detected truncated variant located in the known mutational cluster region, we confirmed a diagnosis of BRPS for this proband. The rehabilitation treatment seemed to have a mild effect. CONCLUSION In this case, a novel nonsense mutation (c.1795G>T, p.E599*) in ASXL3 gene was identified in a Chinese boy with BRPS. This finding not only contributed to better genetic counseling and prenatal diagnosis for this family but also expanded the pathogenic mutation spectrum of ASXL3 gene and provided key information for clinical diagnosis of BRPS.

ASXL3‐related disorder: Molecular phenotyping and comprehensive review providing insights into disease mechanism

“…Common features included abnormal head shape (microcephaly, dolichocephaly), prominent forehead, highly arched eyebrows, synophrys, widely spaced and deep‐set eyes, down‐slanting palpebral fissures, long and tubular nose, low‐hanging columella, prominent nasal bridge, wide mouth, high arched palate, everted vermilion of the lower lip, micrognathia and crowded teeth, but these may not be recognised until after diagnosis 2 . Additional dental abnormalities have also been reported, including large teeth, missing dentition and enamel hypoplasia 42 …”

“…Myers et al 48 abnormalities have also been reported, including large teeth, missing dentition and enamel hypoplasia. 42…”

De novo nonsense variant in ASXL3 in a Chinese girl causing Bainbridge–Ropers syndrome: A case report and review of literature

“…To our knowledge, 54 cases with ASXL3 LOF variants and one splicing mutation have been reported including 12 Chinese patients (Bacrot et al, 2018 ; Bainbridge et al, 2013 ; Balasubramanian et al, 2017 ; Chinen et al, 2018 ; Dad et al, 2017 ; Dinwiddie et al, 2013 ; Duan et al, 2021 ; C. Fu et al, 2019 ; Gou et al, 2019 ; Hori et al, 2016 ; Koboldt et al, 2018 ; Kuechler et al, 2017 ; Li et al, 2020 ; Lyu et al, 2020 ; Myers et al, 2018 ; Qiao et al, 2019 ; Schirwani et al, 2020 ; Srivastava et al, 2016 ; Verhoeven et al, 2018 ; Wayhelova et al, 2019 ; Yang et al, 2020 ; Yu et al, 2021 ; Zhang et al, 2018 ; Zheng et al, 2021 ). 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 (Balasubramanian et al, 2017 ; Wayhelova et al, 2019 ; Yu et al, 2021 ).…”