Inspired by a patient
Bainbridge MN, Hu H, Muzny DM, et al. De novo truncating
mutations in ASXL3 are associated with a novel clinical phenotype with
similarities to Bohring-Opitz syndrome. Genome Med. 2013;5(2):11. Published
2013 Feb 5. doi:10.1186/gm415
Background: Molecular diagnostics can resolve locus heterogeneity underlying clinical phenotypes that may otherwise be co-assigned as a specific syndrome based on shared clinical features, and can associate phenotypically diverse diseases to a single locus through allelic affinity. Here we describe an apparently novel syndrome, likely caused by de novo truncating mutations in ASXL3, which shares characteristics with Bohring-Opitz syndrome, a disease associated with de novo truncating mutations in ASXL1.
Methods: We used whole-genome and whole-exome sequencing to interrogate the genomes of four subjects with an undiagnosed syndrome.
Results: Using genome-wide sequencing, we identified heterozygous, de novo truncating mutations in ASXL3, a transcriptional repressor related to ASXL1, in four unrelated probands. We found that these probands shared similar phenotypes, including severe feeding difficulties, failure to thrive, and neurologic abnormalities with significant developmental delay. Further, they showed less phenotypic overlap with patients who had de novo truncating mutations in ASXL1.
Conclusion: We have identified truncating mutations in ASXL3
as the likely cause of a novel syndrome with phenotypic overlap with
Kuechler A, Czeschik JC, Graf E, et al. Bainbridge-Ropers
syndrome caused by loss-of-function variants in ASXL3: a recognizable
condition. Eur J Hum Genet. 2017;25(2):183-191. doi:10.1038/ejhg.2016.165
Truncating ASXL3 mutations were first identified in 2013 by
Bainbridge et al. as a cause of syndromic intellectual disability in four
children with similar phenotypes using whole-exome sequencing. The clinical
features - postulated by Bainbridge et al. to be overlapping with Bohring-Opitz
syndrome - were developmental delay, severe feeding difficulties, failure to
thrive and neurological abnormalities. This condition was included in OMIM as
'Bainbridge-Ropers syndrome' (BRPS, #615485). To date, a total of nine
individuals with BRPS have been published in the literature in four reports
(Bainbridge et al., Dinwiddie et al, Srivastava et al. and Hori et al.). In
this report, we describe six unrelated patients with newly diagnosed
heterozygous de novo loss-of-function variants in ASXL3 and concordant clinical
features: severe muscular hypotonia with feeding difficulties in infancy,
significant motor delay, profound speech impairment, intellectual disability
and a characteristic craniofacial phenotype (long face, arched eyebrows with
mild synophrys, downslanting palpebral fissures, prominent columella, small
alae nasi, high, narrow palate and relatively little facial expression). The
majority of key features characteristic for Bohring-Opitz syndrome were absent
in our patients (eg, the typical posture of arms, intrauterine growth
retardation, microcephaly, trigonocephaly, typical facial gestalt with nevus
flammeus of the forehead and exophthalmos). Therefore we emphasize that BRPS
syndrome, caused by ASXL3 loss-of-function variants, is a clinically distinct
intellectual disability syndrome with a recognizable phenotype distinguishable
from that of Bohring-Opitz syndrome.
Yang L, Guo B, Zhu W, et al. Bainbridge-Ropers syndrome
caused by loss-of-function variants in ASXL3: Clinical abnormalities, medical
imaging features, and gene variation in infancy of case report. BMC Pediatr.
2020;20(1):287. Published 2020 Jun 9. doi:10.1186/s12887-020-02027-7
Background: Bainbridge-Ropers syndrome (BRPS) is a recently described developmental disorder caused by de novo truncating mutations in the Additional sex combs-like 3 (ASXL3) gene. Only four cases have been reported in China and are limited to the analysis of its clinical abnormalities, medical imaging features and gene variation. The aim of this study was to investigate the clinical phenotype, imaging manifestations and genetic characteristics of BPRS syndrome caused by ASXL3 gene mutation. Clinical data, medical imaging data and gene test results of BRPS in infant patients were retrospectively analyzed, and related literature was summarized.
Case presentation: At the age of 8 months, brain MRI showed that the subarachnoid space of the forehead was widened, part of the sulci was deepened, and the corpus callosum was thin. The development quotient (DQ) was determined using the 0~6-year-old pediatric examination table of neuropsychological development at 6 months and 8 months. The DQ of both tests was less than 69. Whole-exome sequencing revealed a heterozygous frameshift mutation c.3493_3494deTG in exon 12 of the ASXL3 gene, resulting in the amino acid change p. (Cys1165Ter). No variation was present at this site in her parents. Sanger sequencing of family members validated this analysis, suggesting a de novo mutation. The de novo ASXL3 mutations generated stop codons and were predicted, in silico, to generate a truncated ASXL3.
Conclusions: The main clinical features of the patient
included psychomotor development retardation, difficulty in feeding, hypotonia,
and special facial features. MRI features showed that brain development lagged
behind that of normal children. Genetic testing is helpful in the early
diagnosis of BRPS.