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.

Clinical delineation of GTPBP2‐associated neuro‐ectodermal syndrome: Report of two new families and review of the literature

“…The individuals described in this report are the first non‐Middle Eastern patients; we also describe the first compound heterozygous individual. Our patients are strikingly similar to those reported in Bertoli‐Avella et al with cerebellar hypoplasia, corpus callosum malformation, severe microcephaly, epilepsy, ectodermal manifestations, vision impairment, and dysmorphic features (Figures and , Appendix S1 and Table ). Interestingly, these patients all have nonsense mutations, while the three adult siblings reported in Jaberi et al have a milder neurological phenotype and splice site variants which may result in some functional protein.…”

“…The first clinical report described three adult siblings with evidence of brain iron accumulation, while the three children (all under the age of 10 years) in the second report did not . However, the optimal technique for detecting brain iron is susceptibility‐weighted imaging (SWI), which was used in the first study but not in the second.…”

“…Interestingly, these patients all have nonsense mutations, while the three adult siblings The first clinical report described three adult siblings with evidence of brain iron accumulation, 1 while the three children (all under the age of 10 years) in the second report did not. 2 However, the optimal technique for detecting brain iron is susceptibility-weighted imaging (SWI), 4 which was used in the first study but not in the second. We also did not see evidence of brain iron accumulation in our patients at ages 12 months and 10 years with SWI, but when per- The GTPBP2 gene encodes a guanosine triphosphate (GTP)binding protein whose function is unknown.…”

“…The affected individuals also had sparse, brittle hair. Two years later, Bertoli‐Avella et al described an additional three unrelated children with homozygous nonsense variants in GTPBP2. Similar to the family reported by Jaberi et al ectodermal findings were present, but the children had profound developmental disability with cerebellar atrophy and hypogenesis of the corpus callosum and no evidence of brain iron accumulation.…”

NEMF mutations that impair ribosome-associated quality control are associated with neuromuscular disease

“…This conclusion is supported by a genome-wide association analysis which included NEMF variants among several genes potentially implicated in cognitive phenotypes 21 . Similarly, mutation of GTPBP2 , a GTPase that mediates the splitting of stalled ribosomes upstream of RQC 22 , causes Jaberi–Elahi syndrome 23 – 25 , an early onset neurodegenerative disease characterized by dystonia, motor and sensory neuropathy, ataxia, and cognitive dysfunction. Future experiments will address the potential for cognitive dysfunction in Nemf mutant mice, although we anticipate that the interpretation of such analyses may be confounded by the presence of motor and sensory deficits.…”