On the cover: The cover image, by Patrick Revy et al., represents an anaphase bridge, which is a hallmark of the genomic instability that occurs in RTEL1-deficient cells. It is based on the Brief Report Mutations of the RTEL1 Helicase in a Hoyeraal-Hreidarsson Syndrome Patient Highlight the Importance of the ARCH Domain, Pages 469–472, DOI: 10.1002/humu.22966.

This mutation update collates all known patients (192, in 171 families) and mutations (109) associated with severe MTHFR deficiency. The majority of mutations are of the missense type, predominantly found in the N-terminal catalytic domain. In severe MTHFR deficiency, lower enzymatic activity correlates with early onset (<1 year) disease, suggesting residual enzymatic function is an important determinant of disease.

UMD-Predictor is a new bionformatics system to predict the pathogenicity of human genes mutations. It is today the most efficient system and it can be integrated in any NGS analysis pipeline. It will benefit to a wide range of users and applications varying from gene discovery to clinical diagnosis.

mutation3D is a new algorithm and Web server designed to find clusters of somatic cancer mutations in three-dimensional protein structures. Users may input their mutation data in a variety of popular formats for small or large-scale discovery of mutation hotspots across the structural proteome. Further, we demonstrate the ability of mutation3D to indicate many well-validated driver genes as well as several new and underexplored target candidates.

We have developed a tool for detecting single exon copy number variations (CNVs) in targeted next-generation sequencing data: CoNVaDING (Copy Number Variation Detection In Next-generation sequencing Gene panels). CoNVaDING includes a stringent quality control metric, that excludes or flags low quality exons. Since this quality control shows exactly which exons can be reliably analysed and which exons are in need of an alternative analysis method, CoNVaDING is also useful for CNV detection in clinical diagnostics.

We report evidence for UPD as a cause of Fanconi anemia(FA), a rare, mostly recessive disorder. We discovered patients with homozygous pathogenic variants in FANCA and FANCP/SLX4, where only one of their parents was a carrier. Using high density SNP arrays, and short tandem repeat markers (inverted triangles), we identified these patients lack a contribution of the entire chromosome 16 from one of their parents, and present homozygosity of the inherited mutant region from the other parent.

Ribbon representation of a model of the 3D structure of the RTEL1 catalytic domain, highlighting the position of the ARCH domain. This model was constructed on the basis of the alignment of the RTEL1 sequences with the 3D structures of archaeal XPD.

A DGAT2 mutation (p.Y223H) was found in an autosomal dominant axonal CMT family. In the zebrafish larvae, the over-expressed mutant DGAT2 showed an abrogated formation of the bundle of neuronal axons (fascicles) in the trunk at 3 dpf and significantly decreased number of branched axons per fascicle (BPF) in the peripheral nervous system at 15 dpf.

We identified a novel mutation in the motor-head of MYO3A causing dominant non-syndromic deafness. The mutation severely alters the ATPase activity and motility of the protein. The mutant protein fails to accumulate in filopodia tips in COS7 cells, but was able to reach explant hair cell stereocilia tips. We also found that MYO3A interacts with integral tip-link protein protocadherin 15 (PCDH15), which led us to speculate about a local dominant effect of mutant MYO3A on MET complex positioning.

We show that the rate of mutation varies substantially both with and between three genes associated with Mendelian disease: RB1, NF1 and MECP2. We find that the rate of CpG transition can be several hundred-fold higher than the rate of non-CpGtransversion mutation, much higher than the genomic average. We also find that the rate of all mutations, except CpG transitions, varies by at least 30-fold within our three genes genes.