RAF1 – LEOPARD syndrome 2

LEOPARD syndrome 2 (LS-2) is a rare autosomal dominant RASopathy characterized by lentigines, ECG conduction abnormalities, ocular hypertelorism, pulmonary stenosis, genital anomalies, growth retardation, sensorineural deafness, and hypertrophic cardiomyopathy. Causation is linked to activating missense variants in the RAF1 gene disrupting regulatory phosphorylation and 14-3-3 binding RAF1 – LEOPARD syndrome 2.

Two unrelated female patients fitting the LS-2 phenotype were identified with novel RAF1 missense substitutions: Ser257Leu (c.770C>T (p.Ser257Leu)) (PMID:22389993) in a 10-year-old PTPN11-negative patient and Ser259Leu (p.Ser259Leu) in a 2-year-old infant. Both presented with biventricular obstructive hypertrophic cardiomyopathy, supraventricular extrasystoles or paroxysmal supraventricular tachycardia.

Inheritance is autosomal dominant. Genetic evidence comprises two unrelated probands with pathogenic RAF1 missense variants; no segregation data are reported. Variant spectrum in LS-2 is dominated by CR2 domain missense alterations altering key phosphorylation sites.

The c.770C>T (p.Ser257Leu) and p.Ser259Leu substitutions occur at conserved serine residues critical for 14-3-3 docking. Functional assays of Raf-1 phosphorylation demonstrate that Ser259 mutant proteins exhibit a twofold increase in kinase activity compared with wild-type, consistent with a gain-of-function mechanism driving LS-2 pathology (PMID:8349614).

No studies have yet disputed the RAF1–LS-2 association. The combined case-level and functional data support a moderate level of clinical validity.

Key Take-home: RAF1 should be included in genetic testing panels for LEOPARD syndrome 2 to enable early diagnosis and management of hypertrophic cardiomyopathy in affected individuals.

References

• The Turkish journal of pediatrics • 2011 • Two cases of LEOPARD syndrome--RAF1 mutations firstly described in children. PMID:22389993
• The Journal of biological chemistry • 1993 • Identification of the major phosphorylation sites of the Raf-1 kinase. PMID:8349614

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