A novel microdeletion in LOR causing autosomal dominant loricrin keratoderma

DEAR EDITOR, The dramatic presentation of a collodion baby is most commonly associated with a diagnosis of autosomal recessive ichthyosis (ARCI). We investigated a family wherein the father and all four children were collodion at birth, implying an autosomal dominant inheritance pattern. Postnatally, the affected individuals presented with variable degrees of generalized ichthyosis and palmoplantar keratoderma (PPK) (Fig. 1). These clinical features were more pronounced in the father than in the children, and were reported to have become more prominent with age. The phenotype was of generalized nonerythematous xerosis and fine scaling, with adherent larger scale on the lower legs, and mild PPK that exhibited honeycomb patterning. The mother was unaffected and the parents were nonconsanguineous. One of the children also had moderate neurodevelopmental delay and microcephaly, and the father had asthma. With research ethics committee approval, blood was taken from one child and both parents, and DNA was extracted using standard methods. Skin scrapings were obtained from the father and the child, with a 4-mm punch skin biopsy taken from the father. Next-generation sequencing of leucocyte DNA was performed using a Nextera Custom Enrichment Kit (Illumina, San Diego, CA, U.S.A.) targeting exonic regions of clinically relevant published dermatology genes, including known ichthyosis and PPK genes (Table S1; see Supporting Information). A 50-ng DNA sample was simultaneously fragmented using Illumina Enrichment Sample Prep and tagged with adaptors. Polymerase chain reaction (PCR) introduced sample-specific indexes to the library, and following quantification this was hybridized to the customcapture probes. Streptavidin beads captured the probes containing the targeted regions of interest and a series of washes removed nonspecific binding from the beads. This enrichment and capture was repeated once to enrich the target regions further. The enriched library was amplified by limited rounds of PCR, quantified, diluted and sequenced on the Illumina MiSeq. Analysis was using an in-house pipeline, where FASTQ files were aligned using Burrows– Wheeler Aligner and indexed with SAMtools (http://samtools.sourceforge.net/). Variant calling was performed with VarScan (http://varscan.sourceforge.net/), and VCF files were annotated with Variant Effect Predictor (http://www. ensembl.org). Annotated variants were then filtered in Microsoft Excel, BAM files reviewed manually and mutations confirmed using Sanger sequencing. A novel heterozygous deletion inducing a frameshift was found in the loricrin gene Chr1 (GRCh37): g.153234085_ 153234086del, LOR c.660_661delGC, p.Gln222Alafs*113, Ref