GNB5 mutation causes a novel neuropsychiatric disorder featuring attention deficit hyperactivity disorder, severely impaired language development and normal cognition

Abstract

BackgroundNeuropsychiatric disorders are common forms of disability in humans. Despite recent progress in deciphering the genetics of these disorders, their phenotypic complexity continues to be a major challenge. Mendelian neuropsychiatric disorders are rare but their study has the potential to unravel novel mechanisms that are relevant to their complex counterparts.ResultsIn an extended consanguineous family, we identified a novel neuropsychiatric phenotype characterized by severe speech impairment, variable expressivity of attention deficit hyperactivity disorder (ADHD), and motor delay. We identified the disease locus through linkage analysis on 15q21.2, and exome sequencing revealed a novel missense variant in GNB5. GNB5 encodes an atypical β subunit of the heterotrimeric GTP-binding proteins (Gβ5). Gβ5 is enriched in the central nervous system where it forms constitutive complexes with members of the regulator of G protein signaling family of proteins to modulate neurotransmitter signaling that affects a number of neurobehavioral outcomes. Here, we show that the S81L mutant form of Gβ5 has significantly impaired activity in terminating responses that are elicited by dopamine.ConclusionsWe demonstrate that these deficits originate from the impaired expression of the mutant Gβ5 protein, resulting in the decreased ability to stabilize regulator of G protein signaling complexes. Our data suggest that this novel neuropsychiatric phenotype is the human equivalent of Gnb5 deficiency in mice, which manifest motor deficits and hyperactivity, and highlight a critical role of Gβ5 in normal behavior as well as language and motor development in humans.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-016-1061-6) contains supplementary material, which is available to authorized users.

The epileptology of GNB5 encephalopathy

“…1 All nine of our children had biallelic variants predicted to result in protein truncation and a profound DEE. 1,4 Two siblings without seizures were homozygous for a variant that was predicted to affect splicing, but this was not proven in vitro. Homozygosity for the same missense variant has been seen in three families with nonepileptic, milder phenotypes, with either speech delay or mild intellectual disability.…”

“…Homozygosity for the same missense variant has been seen in three families with nonepileptic, milder phenotypes, with either speech delay or mild intellectual disability. 1,4 Two siblings without seizures were homozygous for a variant that was predicted to affect splicing, but this was not proven in vitro. 1 Of interest, two recently reported children who were compound heterozygous for frameshift and missense variants had an intermediate phenotype.…”

“…1 Twenty-two affected individuals from 10 families were reported in 2016-2018. [1][2][3][4][5] Homozygous and compound heterozygous truncating variants are found in a severe phenotype with hypotonia, visual loss, early onset sinus node dysfunction, epilepsy and profound impairment. A milder cognitive phenotype without seizures is seen in individuals with nontruncating mutations.…”

“…These receptors regulate numerous cellular functions including neurotransmission. 4 GNB5 knockout mice have impaired neurologic, cardiac, and retinal function. 1 Here we delineate the epileptology of GNB5 developmental and epileptic encephalopathy in five new and four previously reported patients, 1 enabling earlier recognition of GNB5 developmental and epileptic encephalopathy (DEE).…”

Intellectual developmental disorder with cardiac arrhythmia syndrome in a child with compound heterozygous GNB5 variants

“…3 Individuals at the milder and severe end of the GNB5-associated pathologies carry homozygous S81L and biallelic loss-of-function variants, respectively. [1][2][3] We describe a 2-year-old male proband compound heterozygote for GNB5 (NM_006578.…”