2. Academic Validation
  3. Biallelic inactivating variants in the GTPBP2 gene cause a neurodevelopmental disorder with severe intellectual disability

Biallelic inactivating variants in the GTPBP2 gene cause a neurodevelopmental disorder with severe intellectual disability

  • Eur J Hum Genet. 2018 Apr;26(4):592-598. doi: 10.1038/s41431-018-0097-3.
Aida M Bertoli-Avella 1,  Jose M Garcia-Aznar 2,  Oliver Brandau 2,  Fahad Al-Hakami 3 4,  Zafer Yüksel 2,  Anett Marais 2,  Nana-Maria Grüning 2,  Lia Abbasi Moheb 2,  Omid Paknia 2,  Nahla Alshaikh 4 5,  Seham Alameer 4 6,  Makia J Marafi 7,  Fahd Al-Mulla 8,  Nouriya Al-Sannaa 9,  Arndt Rolfs 2 10,  Peter Bauer 2
Affiliations

Affiliations

  • 1 Centogene AG, Rostock, Germany. aida.bertoli-avella@centogene.com.
  • 2 Centogene AG, Rostock, Germany.
  • 3 Molecular Medicine Section, King Abdulaziz Medical City, Ministry of National Guard Health Affairs, Jeddah, Saudi Arabia.
  • 4 King Saud Bin Abdulaziz University For Health Sciences, Ministry of National Guard Health Affairs,, Jeddah, Saudi Arabia.
  • 5 Pediatric Neurology Section, King Abdulaziz Medical City, Ministry of National Guard Health Affairs, Jeddah, Saudi Arabia.
  • 6 Department of Pediatrics, King Abdulaziz Medical City, Ministry of National Guard Health Affairs, Jeddah, Saudi Arabia.
  • 7 Kuwait Medical Genetics Centre, Kuwait City, Kuwait.
  • 8 Genatak Center for Genomic Medicine, Kuwait City, Kuwait.
  • 9 John Hopkins Aramco Health Care, Pediatric Services, Dhahran, Saudi Arabia.
  • 10 Albrecht-Kossel-Institute for Neuroregeneration, Medical University Rostock, Rostock, Germany.
PMID: 29449720 DOI: 10.1038/s41431-018-0097-3
Abstract

Congenital neurological disorders are genetically highly heterogeneous. Rare forms of hereditary neurological disorders are still difficult to be adequately diagnosed. Pertinent studies, especially when reporting only single families, need independent confirmation. We present three unrelated families in which whole-exome Sequencing identified the homozygous non-sense variants c.430[C>T];[C>T] p.(Arg144*), c.1219[C>T];[C>T] p.(Gln407*) and c.1408[C>T];[C>T] p.(Arg470*) in GTPBP2. Their clinical presentations include early onset and apparently non-progressive motor and cognitive impairment, and thereby overlap with findings in a recently described family harbouring a homozygous GTPBP2 splice site variant. Notable differences include structural brain abnormalities (e.g., agenesis of the corpus callosum, exclusive to our patients), and evidence for brain iron accumulation (exclusive to the previously described family). This report confirms pathogenicity of biallelic GTPBP2 inactivation and broadens the phenotypic spectrum. It also underlines that a potential involvement of brain iron accumulation needs clarification. Further patients will have to be identified and characterised in order to fully define the core features of GTPBP2-associated neurological disorder, but future approaches to molecular diagnosis of neurodevelopmental disorders should implement GTPBP2.

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