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

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.

Fig. 1

Three families carrying homozygous GTPBP2 (NM_019096.4) non-sense variants. Stars denote individuals analysed by WES. Allelic status for the variants in question is provided below individual symbols in the pedigrees. Sequence traces confirming the primary WES data are shown to the right; the predicted consequences at protein are indicated below the traces. a Family 1 and variant c.1219C>T. b Family 2 and variant c.1408C>T. Several third and fourth-degree relatives of the index case are affected by a reportedly similar disease (grey symbols). Dotted relationship lines indicate that consanguinity is likely. c Family 3 and variant c.430C>T. d Magnet resonance imaging of the index patient III-3 from family 1 at age 6 years. On the left: sagittal T1-weighted spin-echo image discloses a thin corpus callosum (arrowhead) with absent rostrum (arrow), hypoplasia of cerebellar vermis (stippled arrow) and presence of mega cisterna magna (star). On the right: axial T2*-weighted fast field-echo image (section through upper tectum) does not reveal evidence for specific hypointensities in the globus pallidus bilaterally (arrows) or in the substantia nigra (arrow heads). e Index patient from family 3 at age 2 years. Note dysmorphic features and sparse hair