YY1 – Gabriele-de Vries Syndrome

Gabriele-de Vries syndrome (GADEVS) is a rare autosomal dominant neurodevelopmental disorder caused by haploinsufficient de novo pathogenic variants in the YY1 transcription factor (PMID:34729769). Patients typically present with global developmental delay, intellectual disability, distinctive facial dysmorphism, and a spectrum of neurologic features. Movement disorders, including cerebellar ataxia and dystonia, are frequent but variably reported. GADEVS is clinically and molecularly defined by heterozygous variants in YY1, with no evidence for inherited transmission.

To date, at least five distinct heterozygous YY1 variants have been reported in unrelated individuals: c.907T>C (p.Cys303Arg) (PMID:32627382), c.690delA (p.Asp231IlefsTer25) (PMID:34729769), c.1106A>G (p.Asn369Ser) (PMID:35829845), c.458_476del (p.Val153AlafsTer?) (PMID:37658636), and c.385del (p.Asp129IlefsTer127) (PMID:40655401). These include two missense and three frameshift alleles, all classified as pathogenic according to ACMG guidelines. Thus far, a total of 28 unrelated de novo YY1 variant carriers have been documented in the literature, each presenting with consistent GADEVS features (PMID:37658636).

The phenotypic spectrum encompasses moderate to severe intellectual disability (ID) (HP:0001249), characteristic facial dysmorphism (HP:0000271), ataxia (HP:0001251), gait disturbance (HP:0001288), autistic behavior (HP:0000729), brain atrophy (HP:0012444), ocular anomalies including chorioretinitis (HP:0012424) and strabismus (HP:0000486), hearing impairment (HP:0000365), and endocrine features such as hypothyroidism (HP:0000821) and Hashimoto thyroiditis (HP:0000872).

Mechanistic studies support YY1 haploinsufficiency as the underlying cause. Heterozygous disruption of Yy1 in mice leads to developmental delay and neurulation defects, demonstrating dosage sensitivity (PMID:10490658). In humans, a consistent DNA methylation episignature was identified in 13 individuals with GADEVS (PMID:35027293), and X-chromosome inactivation skewing was observed in a female with a de novo missense variant, further supporting dosage effects (PMID:35829845).

No studies to date have provided conflicting evidence or alternative genetic explanations for GADEVS. The concordance of de novo genetic findings, consistent clinical presentation, animal modeling, and epigenetic biomarkers establish a robust gene-disease relationship.

References

• American journal of medical genetics. Part A • 2020 • Complex movement disorder in a patient with heterozygous YY1 mutation (Gabriele-de Vries syndrome). PMID:32627382
• Annals of human genetics • 2022 • Clinical features of patients with Yin Yang 1 deficiency causing Gabriele-de Vries syndrome: A new case and review of the literature. PMID:34729769
• Metabolic brain disease • 2022 • A de novo YY1 missense variant expanding the Gabriele-de Vries syndrome phenotype and affecting X-chromosome inactivation. PMID:35829845
• Molecular genetics & genomic medicine • 2024 • Clinical analysis of Gabriele-de Vries caused by YY1 mutations and literature review. PMID:37658636
• Frontiers in endocrinology • 2025 • Hashimoto's thyroiditis and nanophthalmos in Gabriele-de Vries syndrome: a case report. PMID:40655401
• Genetics in medicine • 2022 • DNA methylation episignature in Gabriele-de Vries syndrome PMID:35027293
• Molecular and cellular biology • 1999 • Targeted disruption of mouse Yin Yang 1 transcription factor results in peri-implantation lethality. PMID:10490658

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