YY1AP1 – Grange Syndrome

Evidence from multiple independent studies indicates a robust association between loss‐of‐function variants in YY1AP1 and Grange syndrome, an autosomal recessive disorder characterized primarily by arterial occlusions, hypertension, syndactyly, and bone fragility. Several case reports and multi‐patient studies have identified various disruptive mutations—including nonsense, frameshift, and splice site variants—in unrelated families. For instance, one study reported compound heterozygous variants in three affected siblings and subsequently identified additional unrelated probands carrying homozygous nonsense or frameshift alleles (PMID:27939641); similar evidence was provided by other reports describing splice variants and homozygous intragenic deletions (PMID:30556293, PMID:37698238, PMID:37323195). The recurrent identification of deleterious variants—such as c.1976T>A (p.Leu659Ter)—across studies, along with segregation of these alleles in affected relatives, strongly supports the genetic link.

Genetic analyses reveal an autosomal recessive pattern of inheritance with segregation seen in multiple affected siblings in individual families. The reported variants consistently result in premature truncation or loss of protein function, underscoring a mechanism of haploinsufficiency that disrupts the normal regulation of vascular smooth muscle cell proliferation and differentiation. Functional assessments further confirm that YY1AP1 deficiency leads to abnormal cell cycle arrest and impaired TGF-β mediated smooth muscle cell differentiation, which aligns with the clinical features of Grange syndrome (PMID:27939641, PMID:30556293).

Collectively, these findings provide strong genetic and functional evidence for the role of YY1AP1 in the pathogenesis of Grange syndrome. The convergence of multiple lines of evidence—from comprehensive genetic screening to in vitro functional studies—confirms that alterations in YY1AP1 are causative for the phenotypic manifestations of this ultra-rare disorder. Additional studies have further expanded the allelic spectrum, although the cumulative evidence decisively favors a causative role.

Key Take‑home: The integration of robust genetic data with concordant functional assays confirms that YY1AP1 loss‑of‑function is central to Grange syndrome, supporting its use in diagnostic decision‑making and targeted therapeutic strategies.

References

• American journal of human genetics • 2017 • Loss-of-Function Mutations in YY1AP1 Lead to Grange Syndrome and a Fibromuscular Dysplasia-Like Vascular Disease PMID:27939641
• American journal of medical genetics. Part A • 2019 • Identification of pathogenic YY1AP1 splice variants in siblings with Grange syndrome by whole exome sequencing PMID:30556293
• American journal of medical genetics. Part A • 2023 • Identification of the first homozygous intragenic deletion in the YY1AP1 gene in a consanguineous family: New insights into the phenotypic variability associated with Grange syndrome PMID:37698238
• Molecular syndromology • 2023 • The New Youngest Case of Grange Syndrome with a Novel Biallelic Pathogenic Variant in YY1AP1 PMID:37323195

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