First Mosaic Case Rewrites the Genetic Story of a Rare Overgrowth Syndrome

In the world of rare disease genetics, a single patient can redraw the boundaries of what medicine believes is possible. That is precisely what has happened with the publication of a case report describing a 12-year-old girl whose overgrowth and neurodevelopmental delay were traced to a mosaic variant in the EED gene, the first time mosaicism has ever been documented for Cohen–Gibson syndrome. Until now, every one of the 21 individuals described in the medical literature with this ultra-rare condition carried the disease-causing variant in every cell of their body, a so-called germline change, usually arising de novo in the egg or sperm from which they developed. The new finding, published in Molecular Genetics & Genomic Medicine, demonstrates that a mutation occurring after fertilization, during early embryonic development, can produce a clinically recognizable form of the same syndrome, opening a fresh diagnostic pathway for patients whose genetic tests have repeatedly come back negative.

To appreciate why this matters, it helps to understand what EED actually does. The gene encodes a core subunit of the Polycomb Repressive Complex 2, or PRC2, one of the most important epigenetic machines in human cells. Alongside its partners EZH2, SUZ12, and the retinoblastoma binding proteins RBBP4 and RBBP7, EED helps silence genes by recognizing and propagating a chemical mark on histones, the protein spools around which DNA is wound. Specifically, the complex deposits and maintains tri-methylation of histone H3 at lysine 27, a modification that compacts chromatin and shuts down transcription. EED plays the crucial role of reading this mark and extending it along the chromosome, a mechanism essential for regulating developmental genes and preserving cellular identity. When one copy of EED is disabled, the fine-tuning of gene expression during growth and brain development goes awry, producing the overgrowth syndromes that have fascinated geneticists for the past decade.

The clinical family of PRC2-related overgrowth disorders is small but distinctive. Heterozygous germline variants in EZH2 cause Weaver syndrome, marked by tall stature, macrocephaly, advanced bone age, and characteristic facial features. Variants in EED produce Cohen–Gibson syndrome, while alterations in SUZ12 underlie Imagawa–Matsumoto syndrome. All three overlap substantially with one another and with Sotos syndrome, featuring prenatal and postnatal overgrowth, hypotonia, and intellectual disability of variable severity. The facial gestalt of EED-related cases can usually be distinguished from Weaver syndrome, particularly in older children, by features such as telecanthus, narrow palpebral fissures, ptosis, downslanted upper eyelids, and eversion of the lower lateral eyelid margins. Some individuals also present with congenital heart defects, genitourinary anomalies, structural brain abnormalities, and epilepsy, reflecting the variable expressivity of these epigenetic disorders.

The girl at the center of the new report was born at 36 weeks and three days of gestation by cesarean section, prompted by maternal edema and hypertension. From the very first moments of life, the signs of overgrowth were unmistakable: she weighed 4500 grams, more than three and three-quarter standard deviations above the mean, measured 55 centimeters in length, and had a head circumference of 38 centimeters. Postnatal hypotonia was noted immediately. Developmental milestones arrived late, with unsupported walking at around 24 months and first words at about 30 months. Today she attends a school for children with intellectual disabilities and receives a broad program of physiotherapy, occupational therapy, and speech therapy. At age 12, her height measured 173.5 centimeters, nearly three standard deviations above average, and facial examination revealed hypertelorism, narrow palpebral fissures, periorbital fullness, and large, posteriorly rotated ears, alongside genu valgum, thin calves, and slender fingers with short first and fifth metacarpals.

Notably, her bone age at 10 years and 4 months matched her chronological age, but projected adult height, calculated by the Bayley and Pinneau method, reached an estimated 192 centimeters, dramatically exceeding the mid-parental target height of 163 centimeters. Endocrinological workup was unremarkable, chromosomal analysis showed a normal 46,XX karyotype, and the family history across three generations was entirely uneventful, with no other affected individuals. Intriguingly, two artificial intelligence tools designed to recognize rare disease from facial photographs, GestaltMatcher and Face2Gene, both flagged Cohen–Gibson syndrome among their top suggestions, with Face2Gene assigning it to the ultra-rare category at 76 percent gestalt similarity. That computational nudge helped steer the diagnostic team toward the right corner of the genome.

Whole-exome sequencing of blood-derived DNA then delivered the decisive clue: a missense variant in exon 10 of EED, designated c.1091G>T, which substitutes leucine for the conserved tryptophan at position 364 of the protein. Crucially, the variant was present at a variant allele fraction of only about 28 percent, far below the 50 percent expected for a heterozygous germline change. Targeted deep sequencing confirmed a fraction of 31 percent in blood, 30 percent in saliva, and between 11 and 17 percent in two independently collected buccal mucosa samples. Neither parent carried the variant above the assay’s validated detection threshold of roughly 1 percent, and the trace reads observed in their samples were consistent with sequencing artifacts. The tissue distribution, spanning both mesoderm-derived blood and ectoderm-derived buccal mucosa, pointed to a postzygotic mutation arising early in embryogenesis, after fertilization but before the embryo’s cells had fully committed to their developmental fates.

The molecular properties of the variant strengthen the case for its pathogenicity. The altered tryptophan sits within the WD40 repeat domain of EED and forms part of the aromatic cage that binds trimethylated H3K27, the very interaction that allosterically activates PRC2 and allows the complex to propagate its repressive marks. A single nucleotide change at this residue is extraordinarily rare: population databases record it exactly once among nearly 1.6 million alleles, and it appears in neither ClinVar nor the Human Gene Mutation Database. A battery of computational predictors, including AlphaMissense, CADD, PolyPhen, REVEL, PhyloP, PrimateAI-3D, and SIFT, uniformly predicted a deleterious effect. Under American College of Medical Genetics and Genomics guidelines, the variant was classified as likely pathogenic on the strength of its confirmed de novo status, its extreme rarity, the computational evidence, and the highly specific match between the patient’s phenotype and known EED-related disease.

Perhaps the most elegant piece of evidence came not from DNA sequencing at all but from the epigenome. Genome-wide DNA methylation profiling on the Illumina EPIC BeadChip platform, analyzed with the EpiSign METRIC software, revealed a methylation pattern that matched the established episignature of PRC2 complex disorders, which encompasses both EED-associated syndrome and EZH2-associated Weaver syndrome. In hierarchical clustering heatmaps, multidimensional scaling plots, and t-distributed stochastic neighbor embedding visualizations, the patient’s sample clustered tightly with the PRC2 reference cohort and separated cleanly from controls. In other words, the mutation is not merely present; it is functionally active, leaving a measurable genome-wide fingerprint of dysregulated gene silencing. This convergence of sequencing, structural biology, and epigenetic profiling illustrates how modern molecular diagnostics can triangulate a diagnosis from multiple independent lines of evidence.

The discovery also reshapes thinking about mosaicism in overgrowth syndromes more broadly. Postzygotic mosaicism is a well-established mechanism in disorders driven by somatic activating variants in genes such as PIK3CA and AKT1, which cause conditions like CLOVES syndrome and Proteus syndrome. But for PRC2-related overgrowth, mosaicism had never been observed, and variant databases list only germline alterations. The new case shows that intermediate-level mosaicism, with variant allele fractions between 11 and 31 percent across tissues, is sufficient to produce a multisystemic phenotype of moderate severity, including cardiac valvular insufficiency, musculoskeletal anomalies, and increased patellar reflexes. It also carries a practical lesson: had the diagnostic workup relied on blood alone, or on a single tissue, the variant might have been missed or its significance underestimated. Multi-tissue sequencing, the authors argue, should be considered whenever clinical suspicion remains high despite negative or ambiguous initial testing.

Limitations remain, as the researchers themselves acknowledge. This is a single-case observation, and no functional assays were performed to directly demonstrate how the variant perturbs PRC2 activity in cells. Whether the degree of mosaicism correlates with phenotypic severity is still an open question, and systematic studies in larger cohorts will be needed to establish standardized approaches for assessing the clinical relevance of mosaic PRC2 variants. Nevertheless, the message for clinicians is clear: mosaicism deserves a routine place in the differential diagnosis of PRC2-related syndromes, particularly in patients with unexplained or atypical overgrowth and developmental delay. For the families of children who have endured years of inconclusive genetic testing, the recognition that a postzygotic mutation can masquerade as, or produce, Cohen–Gibson syndrome offers a new and potentially decisive avenue toward the answer they have been searching for.

Subject of Research: Mosaic EED variant causing Cohen–Gibson syndrome, a PRC2-related overgrowth and neurodevelopmental disorder

Article Title: Mosaicism for Cohen–Gibson Syndrome in a Female Individual With Overgrowth and Neurodevelopmental Delay

Article References: Song, F., Michels, M., Betz, B., Vorhoff, W., Neuhann, T., Senninger, L., & Wieczorek, D. (2026). Mosaicism for Cohen–Gibson Syndrome in a Female Individual With Overgrowth and Neurodevelopmental Delay. Molecular Genetics & Genomic Medicine, 14(10), Article e70286. https://doi.org/10.1002/mgg3.70286

Image Credits: AI Generated

DOI: 10.1002/mgg3.70286

Keywords: Cohen-Gibson syndrome, EED, PRC2, mosaicism, overgrowth syndrome, Weaver syndrome, epigenetics, DNA methylation, episignature, whole-exome sequencing, neurodevelopmental delay, rare disease