MODIFIER MUTATIONS SEEM TO VARY THE NOONAN SYNDROME PHENOTYPE
Co-occurring mutations or modifying loci in the RAS-MAPK pathway may contribute to clinical variability among Noonan syndrome (NS) patients, suggest Ekvall et al (p. 1217).
They report on a young woman with cooccurring PTPN11 and SHOC2 mutations, symptoms typical of SHOC2-positive patients with NS, loose anagen hair (LAH), and several additional manifestations, some of which overlap with Costello syndrome.
Mutation analysis of the PTPN11, SOS1, RAF1, KRAS, BRAF, MEK1, MEK2, NRAS, and SHOC2 genes revealed a co-occurrence of 2 previously identified heterozygous mutations in the index patient.One was SHOC2 c.4A >G; p.Ser2Gly, a de novo mutation, while PTPN11 c.1226G > C; p.Gly409Ala was inherited from her mother and also identified in her brother. Both mother and brother present with some NS manifestations, but neither had any NS facial features, supporting the notion that the PTPN11 p.Gly409Ala mutation leads to a relatively mild phenotype.
The researchers propose that the atypical phenotype of this patient with NS may be an additive effect in which the PTPN11 mutation acts as a modifier.
AUTOSOMAL RECESSIVE SILVER–RUSSEL SYNDROME CAUSE CHALLENGED
Findings by Akawi et al (p. 1236) call into question the identity of autosomal recessive Silver–Russel syndrome (SRS), a growth disorder, and suggest that all apparently recessive SRS families should be tested for mutations in CUL7and OBSL1.
Intrauterine growth retardation (IUGR) is a nonspecific finding occurring in about 0.17% live births. However, IUGR is also a significant feature of many recognized genetic syndromes involving growth disorders. These include SRS, three M syndrome (3-M), Dubowitz syndrome, and Mulibrey nanism.
Differentiation of 3-M syndrome from autosomal recessive SRS has been difficult because of SRS's phenotypic variability. Limb length asymmetry occurs in more than half of SRS cases, while characteristic radiologic findings of 3-M syndrome do not occur in SRS.
The researchers used SNP microarrays to investigate the cause of phenotypic features of SRS that show autosomal recessive inheritance in 3 consanguineous families, 2 from United Arab Emirates (UAE), and 1 from Jordan.
The regions mapped by the researchers contained the genes CUL7 and OBSL1, which have recently been identified as the cause of 3- M syndrome. Subsequently, direct DNA sequencing of CUL7 and OBSL1 genes revealed novel mutations in both genes, including 2 mutations in OBSL1 and a nonsense mutation in CUL7. The researchers also found a sixnucleotide deletion in the UAE family, who had the typical features of 3-M.