Alagille Syndrome: A New Missense Mutation Detected by Whole-Exome Sequencing in a Case Previously Found to Be Negative by DHPLC and MLPA.

Alagille syndrome (ALGS, MIM 118450) is an autosomal dominant, multisystem disorder with high variability. Two genes have been described: JAG1 and NOTCH2. The population prevalence is 1:70,000 based on the presence of neonatal liver disease. The majority of cases (∼97%) are caused by haploinsufficiency of the JAG1 gene on 20p11.2p12, either due to mutations or deletions at the locus. Less than 1% of cases are caused by mutations in NOTCH2. The most widely used methods for mutational screening include denaturing high-performance liquid chromatography (DHPLC) and multiplex ligation-dependent probe amplification (MLPA). Very recently, whole-exome sequencing (WES) has become technically feasible due to the recent advances in next-generation sequencing technologies, therefore offering new opportunities for mutations/genes identification. A proband and its family, negative for the presence of mutations in JAG1 and NOTCH2 genes by neither DHPLC nor MLPA, were analyzed by WES. A missense mutation, not previously described, in JAG1 gene was identified. This result shows an improvement in the mutation detection rate due to novel sequencing technology suggesting the strong need to reanalyze all negative cases.

Two Novel COH1 Mutations in an Italian Patient with Cohen Syndrome.

Cohen syndrome (CS) is an autosomal recessive disease caused by mutations in the COH1 gene. It is characterized by intellectual disability, hypotonia, joint hyperlaxity, severe myopia, characteristic facial dysmorphisms and, in some cases, intermittent isolated neutropenia. We investigated an Italian patient with CS together with his family. Genetic analysis disclosed 2 novel mutations: the first is an intronic mutation (c.8697-9A>G) creating a new splice site 8 nucleotides upstream, and the second is a duplication of 1 base (c.10156dupA) generating a premature stop codon. The compound heterozygous mutations explain the proband's phenotype and improved the knowledge of genotype-phenotype correlation.