Rett Syndrome Without MECP2: Single Gene Variant Rewrites the Diagnostic Story

A single letter change in a gene long overlooked by Rett syndrome specialists may explain why some girls who fulfill every clinical criterion for the devastating neurodevelopmental disorder carry no mutation in the gene that usually causes it. In a case report published in Molecular Genetics & Genomic Medicine, researchers in Sweden describe a 15-year-old girl diagnosed with classic Rett syndrome despite repeated normal results for MECP2, the gene responsible for 95 to 97 percent of classic cases. Whole-exome sequencing of the girl and both parents revealed the answer: a de novo variant in GABBR2, a gene that encodes a subunit of the GABA-B receptor, one of the brain’s principal inhibitory signaling molecules. The finding places GABBR2 firmly on the map of Rett-like conditions and suggests that the GABAergic pathway, long implicated in Rett biology, can be disrupted at multiple molecular points to produce strikingly similar clinical pictures.

Rett syndrome is a neurodevelopmental disorder that affects girls almost exclusively. In the typical course, infants appear healthy at birth and develop normally for the first months of life, only to stagnate and then regress, losing purposeful hand use and spoken language. Characteristic features follow: repetitive hand-to-mouth movements, teeth grinding, episodes of intense crying, constipation, sleep and feeding difficulties, and a slowing of head growth. Many children eventually enter a plateau phase in which some skills, particularly eye-mediated communication, partially recover, but dystonia, scoliosis, breathing irregularities, and epilepsy may emerge. A recent natural history study found that most skill acquisition in Rett syndrome occurs before six years of age, and that when skills are regained, that too generally happens before this age. The genetic culprit in the overwhelming majority of classic cases is MECP2, an X-linked gene encoding an epigenetic regulator that binds methylated DNA and orchestrates the activity of neuronal genes, acting as both a transcriptional repressor and activator.

The Swedish girl at the center of the new report was born in 2009 after an uneventful pregnancy, weighing 2760 grams with a normal head circumference. Yet the first months of life already hinted at trouble. By six months she was hypotonic, with poor trunk stability, delayed motor development, and feeding difficulties. Extensive early investigations, including chromosome analysis, metabolic testing, muscle biopsy, and a mitochondrial workup, all came back inconclusive. By eleven months she lacked direct eye contact, could not sit unsupported, made writhing hand movements, and screamed frequently, requiring tube feeding. At twelve months a gastrostomy was placed, and brain MRI revealed white matter loss most pronounced in the fronto-parietal regions. Sequencing of MECP2 and CDKL5, another gene associated with atypical Rett presentations, was normal, as was a chromosomal microarray that ruled out microdeletions and microduplications.

The clinical picture continued to evolve in a way that would eventually become unmistakable. At fourteen months she developed severe screaming spells, dystonia in both feet, and self-injurious hand biting. By age three she was non-ambulant, without language or eye contact, and was diagnosed with autism. At age seven, following evaluation by an Rett syndrome specialist, she was judged to fulfill the diagnostic criteria for classic Rett syndrome: partial loss of acquired purposeful hand function, loss of acquired spoken language, inability to walk, and stereotypic hand movements. She could sit unsupported, communicate with smiles and eye gaze, and return a rolling ball, but she also displayed respiratory dysfunction with intense hyperventilation and breath-holding, bruxism, and stereotypic hand-mouth movements. Now fifteen, she struggles most with behavioral problems, including cyclical screaming spells and self-injury, attending special school four to five days a week during good phases and only two days during bad ones.

To find the genetic cause, the team turned to trio-based whole-exome sequencing, analyzing the girl and both parents simultaneously. Sequencing libraries were prepared with Agilent’s SureSelect protocol and run on an Illumina HiSeq 2000, generating 12.45 gigabases of high-quality data with more than 83 percent of target regions covered at twentyfold depth. Filtering for de novo variants present in the child but absent from both parents, and prioritizing genes with relevant clinical associations, the analysis yielded a single compelling candidate: a heterozygous variant in GABBR2, designated c.1699G>A, which substitutes a threonine for an alanine at position 567 of the protein, abbreviated p.Ala567Thr. Sanger sequencing confirmed the finding. It was the only clinically relevant de novo variant in the entire exome.

GABBR2 sits on chromosome 9 at band 9q22.33 and encodes a 941-amino-acid membrane protein belonging to the G protein-coupled receptor family, with seven transmembrane domains. The protein forms a subunit of the GABA-B receptor, the metabotropic receptor for gamma-aminobutyric acid, the central nervous system’s main inhibitory neurotransmitter. Unlike the ion-channel GABA-A and GABA-C receptors, GABA-B receptors modulate neuronal activity by regulating neurotransmitter release, and the receptor is highly expressed across many brain regions. Crucially, prior work has already tied GABAergic dysfunction to Rett biology: mice lacking MeCP2 specifically in GABAergic neurons initially appear normal but then develop forepaw stereotypies, compulsive grooming, impaired motor coordination, abnormal EEG hyperexcitability, severe respiratory dysrhythmias, and premature death. Because MeCP2 is essential for normal GABAergic neuron function, a pathogenic variant in a GABA-B receptor subunit could plausibly converge on the same inhibitory signaling pathways that MeCP2 disruption impairs.

Remarkably, the p.Ala567Thr variant is not a one-off. It affects a highly conserved residue within the third transmembrane domain, and a literature review identified seventeen heterozygous de novo GABBR2 variants in patients with intellectual disability, autism spectrum disorder, and drug-resistant epilepsy, seven of which were this exact variant. With the new case, ten patients with p.Ala567Thr have now been reported, making the Swedish girl the eleventh. The first, described in 2016, was a girl with developmental stagnation at seven months followed by regression, absent language, hand stereotypies, hyperventilation, bruxism, abnormal sleep, crying spells, autistic features, and small feet, though she never had seizures. The same variant appeared in another patient meeting Rett criteria that same year, and in 2017 researchers screening 34 MECP2-negative patients with Rett-like presentations found it in two more, providing functional evidence of reduced receptor activity in both in vitro and in vivo models.

Across these eleven patients, seven fulfill clinical Rett criteria, though most were classified as atypical rather than classic. The most common features are intellectual disability, autism spectrum disorder, and an Rett-like phenotype, while only about half have epilepsy, despite GABBR2’s established links to epileptic encephalopathy. The Swedish girl stands out as one of the most Rett-like cases reported to date, meeting criteria for classic rather than atypical Rett syndrome. OMIM currently lists two phenotype entries for GABBR2, neither formally linked to Rett syndrome, though one, neurodevelopmental disorder with poor language and loss of hand skills, is described as reminiscent of Rett. The overlap across these diagnostic categories suggests that GABBR2-related disease is best understood as a phenotypic spectrum rather than a single discrete syndrome, with the specific variant location and transmembrane domain involved shaping the resulting clinical picture.

The case also carries therapeutic implications. The girl’s self-injurious behavior and sleep problems have been treated with clonidine, benzodiazepines, aripiprazole, sertraline, melatonin, promethazine, and risperidone, with risperidone offering the best but only short-lived effect. Notably, benzodiazepines had no effect on her self-injury, a finding the authors attribute to mechanism: benzodiazepines enhance inhibition through the GABA-A receptor, whereas the variant disrupts the GABA-B receptor. Baclofen, a GABA-B agonist, is the only drug acting on this receptor, but its low blood-brain barrier penetration, short duration, and rapid tolerance limit its usefulness. More promising avenues include positive and negative allosteric modulators of GABA-B receptors and transcranial magnetic stimulation, which is partly mediated through GABA-B-dependent inhibition. The p.Ala567Thr variant reduces receptor activity to roughly 30 percent of wild-type levels, so restoring receptor function could meaningfully benefit affected patients.

The authors conclude that patients with an Rett phenotype may carry pathogenic variants in genes other than MECP2, and that as diagnostic strategies shift toward broader sequencing, the recurrent p.Ala567Thr variant may prove more common than currently recognized. They argue that GABBR2 should be included in testing panels when comprehensive approaches such as whole-genome sequencing are unavailable, and that phenotype-driven variant prioritization can reduce the risk of missing cases. Given the severe, lifelong neurodevelopmental burden of Rett spectrum conditions, and the possibility that future therapies will target GABAergic dysfunction directly, an early molecular diagnosis may become increasingly consequential for families and clinicians alike.

Subject of Research: A de novo GABBR2 GABA-B receptor variant identified as the cause of classic Rett syndrome in an MECP2-negative girl

Article Title: A Heterozygous Variant in the GABBR2 Gene in a Girl With Clinical Classic Rett Syndrome

Article References: Klintenstedt, J., Baeck, P., Engerström, I. W., & Gunnarsson, C. (2026). A Heterozygous Variant in the GABBR2 Gene in a Girl With Clinical Classic Rett Syndrome. Molecular Genetics & Genomic Medicine, 14(10), Article e70303. https://doi.org/10.1002/mgg3.70303

Image Credits: AI Generated

DOI: 10.1002/mgg3.70303

Keywords: Rett syndrome, GABBR2, GABA-B receptor, MECP2, whole-exome sequencing, neurodevelopmental disorder, GABAergic signaling, de novo variant, autism spectrum disorder, intellectual disability, genotype-phenotype correlation, epileptic encephalopathy