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  • UBTF haploinsufficiency associated with UBTF-related global developmental delay and distinctive facial features without neuroregression

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Developmental defects
Original research
UBTF haploinsufficiency associated with UBTF-related global developmental delay and distinctive facial features without neuroregression
  1. Xueqian Wang1,2,
  2. Bingyu Yang1,3,
  3. Shengnan Wu4,
  4. Qisang Fan1,3,
  5. Qing Wang1,3,
  6. Dandan Zhang1,3,
  7. Hongying Wang1,
  8. Tao Feng1,
  9. Haitao Lv1,5,
  10. Ting Chen1,3,6
  1. 1 Suzhou Clinical Center for Rare Diseases in Children, Children's Hospital of Soochow University, Suzhou, Jiangsu, China
  2. 2 Department of Medical Genetics and Prenatal Diagnosis, Affiliated Maternity and Child Health Care Hospital of Nantong University, Nantong, Jiangsu, China
  3. 3 Department of Endocrinology, Genetics and Metabolism, Children's Hospital of Soochow University, Suzhou, Jiangsu, China
  4. 4 Shanghai Children’s Hospital, Shanghai Jiao Tong University, Shanghai, Shanghai, China
  5. 5 Department of Cardiology, Children's Hospital of Soochow University, Suzhou, Jiangsu, China
  6. 6 Department of Pediatrics, Kunshan Sixth People's Hospital, Suzhou, Jiangsu, China
  1. Correspondence to Dr Ting Chen; chenting888{at}suda.edu.cn

Abstract

Background The Upstream Binding Transcription Factor (UBTF) gene encodes two nucleolar proteins, UBTF1 and UBTF2. UBTF1 regulates rRNA transcription by RNA polymerase I, while UBTF2 regulates mRNA transcription by RNA polymerase II. A recurrent de novo dominant mutation c.628G>A (p.Glu210Lys) has been identified as a gain-of-function mutation associated with childhood onset neurodegeneration with brain atrophy (CONDBA). Evidence from large-scale population databases and Ubtf+/− mouse models indicates that UBTF haploinsufficiency is not tolerated.

Methods Three unrelated patients with global developmental delay and distinctive facial features were recruited for the study. Whole exome sequencing (WES) was performed to identify potential genetic abnormalities. Additionally, copy number variation analysis was conducted based on the WES data.

Results All three patients exhibited intellectual disabilities, social challenges and developmental delays in language and gross motor skills. Distinctive facial features included a wide forehead, sparse eyebrows, hypertelorism, narrow palpebral fissures, single-fold eyelids, a flat nasal bridge, anteverted nares, a long philtrum and a thin upper lip. Additionally, patient C presented with more severe language delay, recurrent hepatic dysfunction and an atrial septal defect. Patient A was found to have a nonsense variant, c.1327C>T (p.R443Ter), in the exon 13 of UBTF. Patients B and C both carried a heterozygous deletion encompassing the UBTF gene.

Conclusion In this study, we analysed the detailed phenotypes associated with UBTF haploinsufficiency, which, to our knowledge, have not been previously reported. We propose that UBTF haploinsufficiency-related global developmental delay and distinctive facial features, without neuroregression, constitute a new syndrome distinct from CONDBA.

  • Genetic Diseases, Inborn
  • Pediatrics
  • Neurology

Data availability statement

Data are available in a public, open access repository. Data are available on reasonable request. All data relevant to the study are included in the article or uploaded as online supplemental information.

https://doi.org/10.1136/jmg-2024-110061

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    Data availability statement

    Data are available in a public, open access repository. Data are available on reasonable request. All data relevant to the study are included in the article or uploaded as online supplemental information.

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    Footnotes

    • XW, BY and SW contributed equally.

    • Contributors TC and XW supervised this work and TC is the guarantor. XW, BY, SW and TC designed the research. XW, BY and QF analysed the data. QF, QW, DZ, HW and TF conducted the lab work. QF, QW, DZ, HW, TF and HL conducted all clinical works. XW, BY, QF and TC drafted the manuscript and all authors took part in revising and improving the manuscript.

    • Funding This study was supported by a Suzhou Personnel Planning Project (project codes GSWS2020046), a Suzhou Science and Technology Development Project (SKY2023007), a Research Project of Jiangsu Commission of Health (M2021082) and a Summit Project of Clinical Medicine (ML13100523) awarded to TC. It is supported by the Jiangsu Health Innovation Team Program awarded to XW, and the Natural Science Foundation of Jiangsu Province (BK20220253) awarded to BY. It is also supported by a Jiangsu Provincial Maternal and Child Health Care Program (F202119) awarded to HW and the Suzhou Clinical Center for Rare Disease (Szlcyxzxj202105).

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.