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Primary microcephaly, primordial dwarfism, and brachydactyly in adult cases with biallelic skipping of RTTN exon 42.

Hum Mutat. 2019 Jul;40(7):899-903. doi:10.1002/humu.23755. Epub 2019 May 24
Muhammad Zakaria 1 , Ambrin Fatima 2 , Joakim Klar 2 , Johan Wikström 3 , Uzma Abdullah 4 , Zafar Ali 4 , Talia Akram 4 , Muhammad Tariq 4 , Habib Ahmad 5 , Jens Schuster 2 , Shahid M Baig 4 , Niklas Dahl 2
Muhammad Zakaria 1 , Ambrin Fatima 2 , Joakim Klar 2 , Johan Wikström 3 , Uzma Abdullah 4 , Zafar Ali 4 , Talia Akram 4 , Muhammad Tariq 4 , Habib Ahmad 5 , Jens Schuster 2 , Shahid M Baig 4 , Niklas Dahl 2
+ et al

[No authors listed]

Author information
  • 1 Centre for Human Genetics, Hazara University, Mansehra, Pakistan.
  • 2 Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
  • 3 Department of Radiology, Uppsala University, Uppsala, Sweden.
  • 4 Human Molecular Genetics Laboratory, National Institute for Biotechnology and Genetic Engineering (NIBGE), Faisalabad, Pakistan.
  • 5 Department of Botany, Islamia College University Peshawar, Peshawar, Khyber Pakhtunkhwa, Pakistan.

摘要


Biallelic and pathogenic variants in the RTTN gene, encoding the centrosomal protein Rotatin, are associated with variable degrees of neurodevelopmental abnormalities, microcephaly, and extracranial malformations. To date, no reported case has reached their third decade. Herein, we report on a consanguineous family with three adult members, age 43, 57, and 60 years respectively, with primary microcephaly, developmental delay, primordial dwarfism, and brachydactyly segregating a homozygous splice site variant NM_173630.3:c.5648-5T>A in RTTN. The variant RTTN allele results in a nonhypomorphic skipping of exon 42 and a frameshift [(NP_775901.3:p.Ala1883Glyfs*6)]. Brain MRI of one affected individual showed markedly reduced volume of cerebral lobes and enlarged sulci but without signs of neural migration defects. Our assessment of three adult cases with a biallelic RTTN variant shows that a predicted shortened Rotatin, lacking the C-terminal end, are associated with stationary clinical features into the seventh decade. Furthermore, our report adds brachydactyly to the phenotypic spectrum in this pleiotropic entity.

KEYWORDS: RTTN gene variant, Rotatin, brachydactyly, exon skipping, microcephaly