Molecular Genetics of LEOPARD Syndrome

Abstract

Abstract LEOPARD syndrome (LS) is an acronym for the cardinal features lentigines, electrocardiogram conduction abnormalities, ocular hypertelorism, pulmonic stenosis, abnormal genitalia, retardation of growth and sensorineural deafness. However, other disorders, such as hypertrophic cardiomyopathy, occur frequently and represent a potentially life‐threatening problem. PTPN11 mutations, located on chromosome 12q24, are observed in up to 90% of patients with LS. Meanwhile, mutations in the RAF1 gene on chromosome 3p25.2 and mutations in the BRAF gene on chromosome 7q34 occur in 5% of the cases. Eleven different missense PTPN11 mutations, characterised by a decrease in physiological activity of the mutated protein (Tyr279Cys/Ser, Ala461Thr, Gly464Ala, Thr468Met/Pro, Arg498Trp/Leu, Gln506Pro and Gln510Glu/Pro) have been reported, two of which (Tyr279Cys and Thr468Met) occur in approximately 65% of the cases. Key Concepts: LEOPARD syndrome (LS) (OMIM #151100) and Noonan syndrome (NS) (OMIM #163950) are two disorders that are part of a newly classified family of autosomal dominant syndromes termed ‘RASopathies’, which are caused by germline mutations in components of the RAS‐MAPK (mitogen‐activated protein kinases) signal transduction pathway that is involved in the regulation of normal cell proliferation, survival and differentiation. LS is an acronym for the cardinal features lentigines, electrocardiogram conduction abnormalities, ocular hypertelorism, pulmonic stenosis, abnormal genitalia, retardation of growth and sensorineural deafness. The diagnosis of LS is made on clinical grounds by observation of key features. PTPN11, RAF1 and BRAF are the genes known to be associated with LS. Molecular genetic testing of the three genes identifies mutations in approximately 95% of affected individuals. LS may be sporadic ( de‐novo mutation) or inherited as an autosomal dominant trait. Lentigines are the most prominent manifestation of LS and are found in more than 90% of the patients. On the whole, 85% of patients with LS have heart defects. Hypertrophic cardiomyopathy is the most frequent cardiac anomaly observed, representing a potentially life‐threatening problem in these patients. To date, it is unclear whether the genotype may influence the clinical course in LS patients with hypertrophic cardiomyopathy. Although some haematologic tumours have been reported in patients with LS the association is inconclusive. Genetic counselling helps families and patients to understand and cope with the diagnosis of their genetic condition and its implications.