PIEZO2 – Gordon syndrome

Gordon syndrome (distal arthrogryposis type 3) is an autosomal dominant disorder characterized by congenital contractures of the limbs, cleft palate, and short stature. Heterozygous mutations in the mechanosensitive ion channel gene PIEZO2 are the primary cause of Gordon syndrome (MONDO:0007252).

Extensive genetic studies have identified 12 unrelated probands from 12 families with heterozygous PIEZO2 variants. Exome sequencing in five families, followed by Sanger validation in seven more, detected pathogenic variants in 10 of 12 individuals, including a recurrent missense hotspot c.8057G>A (p.Arg2686His) in nine families (PMID:24726473). A multigenerational pedigree with three affected members (father, son, neonate) segregated c.8057G>A across two additional relatives (PMID:27714920). A de novo truncating variant c.8576G>A (p.Trp2859Ter) was identified in a fetus presenting typical ultrasound features (PMID:37587573). This variant spectrum includes recurrent missense and truncating alleles, supporting autosomal dominant inheritance.

Segregation analysis in familial cases and the occurrence of de novo events provide strong genetic evidence. The predominant variant class is missense, with a recurrent p.Arg2686His, and other variants include nonsense alleles such as p.Trp2859Ter. The robust presence of PIEZO2 variants in unrelated families and de novo cases confirms its etiological role in Gordon syndrome.

Functional assays demonstrate that gain-of-function PIEZO2 mutations alter channel kinetics, increasing mechanically activated currents by faster recovery from inactivation and slowed inactivation, resulting in heightened channel activity (PMID:23487782). These electrophysiological findings align with the clinical phenotype of joint contractures seen in Gordon syndrome.

No studies to date dispute the association between PIEZO2 and Gordon syndrome. The cumulative genetic and functional data establish PIEZO2 as definitively associated with Gordon syndrome.

Key Take-home: Heterozygous PIEZO2 variants consistently cause autosomal dominant Gordon syndrome, supporting molecular diagnosis and informing genetic counseling.

References

• American journal of medical genetics. Part A • 2017 • Familial Gordon syndrome associated with a PIEZO2 mutation. PMID:27714920
• Prenatal diagnosis • 2023 • A novel PIEZO2 mutation in a fetus from a Chinese family with Gordon syndrome. PMID:37587573
• American journal of human genetics • 2014 • Mutations in PIEZO2 cause Gordon syndrome, Marden-Walker syndrome, and distal arthrogryposis type 5. PMID:24726473
• Proceedings of the National Academy of Sciences of the United States of America • 2013 • Gain-of-function mutations in the mechanically activated ion channel PIEZO2 cause a subtype of Distal Arthrogryposis. PMID:23487782

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