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Exome Sequencing Links De Novo Mutations to Neurodevelopmental Disorder

NEW YORK (GenomeWeb) – A Columbia University-led team of researchers has used exome sequencing to uncover a new type of neurodevelopmental syndrome.

After examining sequencing data from nearly 6,000 people with undiagnosed genetic disorders, Columbia's David Goldstein and his colleagues found 13 people with a condition marked by developmental delay who harbored an enrichment of de novo missense mutations in the GNB1 gene, as they reported in the American Journal of Human Genetics today.

The GNB1 gene encodes the guanine nucleotide-binding protein subunit beta-1, Gβ, which along with Gα and Gγ makes up G proteins, a key part of the signaling function of G-protein-coupled receptors. Most of the mutations the researchers found affect known Gβ binding sites, suggesting that they disrupt Gα-Gβγ interactions or interactions between Gβγ and downstream effectors.

"Now that we've determined that a small subset of patients with neurodevelopmental disabilities share the same mutations, we can begin to learn about the prognosis of these individuals, how these mutations lead to this syndrome, and how to develop targeted therapies," Goldstein said in a statement.

Goldstein and his colleagues sequenced the whole exomes of hundreds of patients at Columbia to find three with mutations in GNB1. As first author Slavé Petrovski described in a statement, they then reached out to other investigators to see whether they'd found similar mutations in patients they'd sequenced.

"In all, we reviewed sequencing data on 5,855 individuals and found a total of 13 individuals with GNB1 mutations," Petrovski said.

These 13 individuals, who ranged in age from 13 months to 20 years old, all exhibited global developmental delay, and most also had abnormal muscle tone, seizures, and eye problems.

Six of these individuals underwent whole-exome sequencing along with their parents. Variants from these individuals were compared to those of their parents and to databases of control individuals to uncover de novo GNB1 mutations.

While the other seven individuals initially underwent proband-only exome sequencing, once GNB1 de novo mutations were found in the others, these probands and their parents underwent Sanger sequencing for GNB1 mutations.

All 13 individuals, the researchers reported, had a de novo missense GNB1 mutation that was confirmed through Sanger sequencing.

These mutations, though, affected different parts of the GNB1 gene. The Combined Annotation Dependent Depletion score indicated that all these missense mutations in GNB1 were among the 1 percent most deleterious in the human genome, the researchers reported.

Some of the mutations roughly corresponded with differences in observed symptoms. For instance, four of the five patients with a p.Ile substitution had growth delay, while the two patients with a p.Met101 substitution were the only ones also diagnosed with autism spectrum disorder. The researchers cautioned, though, that a larger cohort of individuals with GNB1 mutations is needed to determine whether these are significant associations.

Still, nine of the mutations the researchers uncovered could be traced to a residue that's encoded by exon 6 of the GNB1 gene. This region is known, they noted, to be important for the interactions between Gα and Gβγ in the G protein complex.

In particular, the mutations found in five individuals affect a Gβ residue that is important for inhibiting calcium channels, activating potassium channels, activating phospholipase C-β2, and Gα binding. At the same time, a GNB1 mutation found in two individuals affects a residue that's involved in activating adenylyl cyclase 2, inhibiting calcium channels, activating phospholipase C-β2, and G-protein-coupled receptors.

In the general population, the researchers noted that GNB1 doesn't harbor much functional variation, indicating that it might be under strong purifying selection. This presumption, the researchers noted, is supported by genic intolerance metrics and other analyses.

The researchers also noted that somatic GNB1 mutations have recently been uncovered in some cancers, and that five of the 13 variants they uncovered overlapped with five recurrent oncogenic amino acid residues recently described by another team. Goldstein and his colleagues noted that though none of their cohort reported any malignancies, it would be something to watch out for as the individuals are followed.

"Moving forward, we hope to determine exactly how these mutations cause disease and then use that information to identify druggable targets — completing the entire precision medicine circle for this condition, from gene discovery to functional biology to the development of targeted therapeutics," Goldstein added.