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Dual diagnosis in a patient with mosaic Trisomy 22 and a de novo frameshift variant in ASXL3  

Clinical Genetics and Therapeutics
  • Primary Categories:
    • Clinical Genetics
  • Secondary Categories:
    • Clinical Genetics
Introduction
Bainbridge-Ropers Syndrome (BRS) is a rare genetic disease first described in 2013 and is part of the family of chromatinopathies. De novo truncating variants in the ASXL3 gene have been implicated in BRS, with less than 100 individuals reported to date, meaning, the phenotypic spectrum remains to be fully established.

Case Presentation
Herein, we describe a 19-year-old male with intellectual disability, autism, dysmorphic and coarse facial features, metopic craniosynostosis, a partial anomalous pulmonary venous return, scoliosis, leg length discrepancy, amblyopia, astigmatism, obesity, tall stature, supernumerary teeth, fatty liver, elevated liver enzymes, low vitamin D level, constipation, and chronic fatigue. The patient presented to clinic with a known diagnosis of 20% mosaic Trisomy 22 on skin biopsy, identified at age 9 years from a different institution. They returned to Genetics to seek a second opinion for his calvarial defect that had failed to close after corrective surgery of the metopic synostosis at 9 months of age and multiple consecutive scar surgical revisions, resulting in chronic headaches. Upon assessment, his medical concerns were only partially explained by the mosaic trisomy 22 which prompted further testing with the aim of finding a second genetic condition that would lead to therapeutic information for his skull closure failure and improve his headaches.

 

Diagnostic Workup
We performed trio exome sequencing which revealed a de novo heterozygous frameshift deletion in ASXL3, namely c.50100_5011del, predicted to result in an abnormal protein length.

Treatment and Management
The new molecular diagnosis was shared with plastic surgery and his other clinical providers.

 

Outcome and Follow-Up
Our patient was referred to the Chromatinopathies clinic within our institution to establish medical care.

Discussion
BRS is mainly characterized by neurodevelopmental disorders with or without absent speech. While the result did not achieve an explanation for the calvarial defect, it provided further information on his severe intellectual disability and autism spectrum disorder, as well as some of his dysmorphic features including down-slanting palpebral fissures and a broad nasal tip. However, our patient did not present with failure to thrive, microcephaly, and feeding issues which are seen in some patients with BRS-harboring ASXL3 variants. Our patient presented with additional symptoms not commonly reported in the BRS spectrum, such as coarse facial features, tall stature, obesity, amblyopia, astigmatism, and metopic craniosynostosis. While craniosynostosis has been reported in the ASXL1-related disorder population, there is only one other individual in the literature with BRS that has presented with metopic craniosynostosis. A dual diagnosis should be considered as a driver for some of the phenotype in our patient that are not characteristic of BRS or mosaic Trisomy 22.

Conclusion
We provide additional evidence that metopic craniosynostosis may be an associated phenotype of BRS driven by ASXL3. This highlights the need for continued research in the chromatinopathies space to more accurately delineate the phenotypic spectrum of BRS, and to understand whether ASXL3 overexpression in bone is a mechanism of disease given the phenotype observed in our patient. The association of a dual diagnosis contributing to our patient’s unique phenotype should also be considered, underscoring the importance of clinicians to consider dual diagnoses in complex, unresolved cases.

Agenda

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