The spectrum of pathogenic mutations in SPINK5 in 19 families with Netherton syndrome: Implications for mutation detection and first case of prenataldiagnosis

The Comel-Netherton syndrome is an autosomal recessive multisystemic disord er characterized by localized or generalized congenital ichthyosis, hair sh aft abnormalities, immune deficiency, and markedly elevated IgE levels. Lif e-threatening complications during infancy include temperature and electrol yte imbalance, recurrent infections, and failure to thrive. To study the cl inical presentations of the Comel-Netherton syndrome and its molecular caus e, we ascertained 19 unrelated families of various ethnic backgrounds. Resu lts of initial linkage studies mapped the Comel-Netherton syndrome in 12 mu ltiplex families to a 12 cM interval on 5q32, thus confirming genetic homog eneity of Comel-Netherton syndrome across families of different origins. Th e Comel-Netherton syndrome region harbors the SPINK5 gene, which encodes a multidomain serine protease inhibitor (LEKTI) predominantly expressed in ep ithelial and lymphoid tissues. Recently, recessive mutations in SPINK5 were identified in several Comel-Netherton syndrome patients from consanguineou s families. We used heteroduplex analysis followed by direct DNA sequencing to screen all 33 exons and flanking intronic. sequences of SPINK5 in the a ffected individuals of our cohort. Mutation analysis revealed 17 distinct m utations, 15 of which were novel, segregating in 14 Comel-Netherton syndrom e families. The nucleotide changes included four non-sense mutations, eight small deletions or insertions leading to frameshift, and five splice site defects, all of which are expected to result in premature terminated or alt ered translation of SPINK5. Almost half of the mutations clustered between exons 2 and 8, including two recurrent mutations. Genotype-phenotype correl ations suggested that homozygous nucleotide changes resulting in early trun cation of LEKT1 are associated with a severe phenotype. For the first time, we used molecular data to perform prenatal testing, thus demonstrating the feasibility of molecular diagnosis in the Comel-Netherton syndrome.