ERF – Chitayat syndrome

Chitayat syndrome is an ultrarare autosomal dominant disorder characterized by facial dysmorphism, hyperphalangism, respiratory compromise and variable skeletal anomalies. It is caused by heterozygous variants in ERF, a transcriptional repressor in the RAS/MAPK pathway, and defines a distinct clinical entity from ERF-related craniosynostosis and Noonan-like RASopathy.

A total of 13 unrelated individuals have been reported with the recurrent ERF c.266A>G (p.Tyr89Cys) variant: five patients in the initial cohort (3 de novo, 2 familial) ([PMID:27738187]), one case report ([PMID:30728880]), one patient ([PMID:30569521]) and six additional individuals ([PMID:32592542]). Paternal transmission in two families provides segregation evidence with two affected relatives.

The variant spectrum in Chitayat syndrome is dominated by the single missense change c.266A>G (p.Tyr89Cys) within the ETS DNA-binding domain; no other variant classes have been repeatedly associated with this phenotype.

Functional data specific to p.Tyr89Cys are not yet available, but its location in a highly conserved ETS domain predicts disrupted DNA binding and impaired repressor activity. No rescue or biochemical assays have been reported for this allele.

There is no conflicting evidence for p.Tyr89Cys in Chitayat syndrome; ERF loss-of-function variants cause overlapping but distinct RASopathy and craniosynostosis phenotypes.

In aggregate, the recurrent de novo and familial occurrences of c.266A>G (p.Tyr89Cys), consistent phenotype across 13 probands, and segregation in multiple families support a strong gene–disease association. Molecular testing for ERF c.266A>G enables definitive diagnosis and informed genetic counselling.

References

• Journal of medical genetics • 2017 • Chitayat syndrome: hyperphalangism, characteristic facies, hallux valgus and bronchomalacia results from a recurrent c.266A>G p.(Tyr89Cys) variant in the ERF gene. PMID:27738187
• Radiology case reports • 2019 • Radiography of Chitayat syndrome in an infant male. PMID:30728880
• American journal of medical genetics. Part A • 2019 • Molecular analysis provides further evidence that Chitayat syndrome is caused by the recurrent p.(Tyr89Cys) pathogenic variant in the ERF gene. PMID:30569521
• American journal of medical genetics. Part A • 2020 • Variable pulmonary manifestations in Chitayat syndrome: Six additional affected individuals. PMID:32592542

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