Search

This corrects the article DOI: 10.1038/ejhg.2016.36.

Over 150 different proteins attach to the plasma membrane using glycosylphosphatidylinositol (GPI) anchors. Mutations in 18 genes that encode components of GPI-anchor biogenesis result in a phenotypic spectrum that includes learning disability, epilepsy, microcephaly, congenital malformations and mild dysmorphic features. To determine the incidence of GPI-anchor defects, we analysed the exome data from 4293 parent-child trios recruited to the Deciphering Developmental Disorders (DDD) study. All probands recruited had a neurodevelopmental disorder. We searched for variants in 31 genes linked to GPI-anchor biogenesis and detected rare biallelic variants in PGAP3, PIGN, PIGT (n=2), PIGO and PIGL, providing a likely diagnosis for six families. In five families, the variants were in a compound heterozygous configuration while in a consanguineous Afghani kindred, a homozygous c.709G>C; p.(E237Q) variant in PIGT was identified within 10-12 Mb of autozygosity. Validation and segregation analysis was performed using Sanger sequencing. Across the six families, five siblings were available for testing and in all cases variants co-segregated consistent with them being causative. In four families, abnormal alkaline phosphatase results were observed in the direction expected. FACS analysis of knockout HEK293 cells that had been transfected with wild-type or mutant cDNA constructs demonstrated that the variants in PIGN, PIGT and PIGO all led to reduced activity. Splicing assays, performed using leucocyte RNA, showed that a c.336-2A>G variant in PIGL resulted in exon skipping and p.D113fs*2. Our results strengthen recently reported disease associations, suggest that defective GPI-anchor biogenesis may explain ~0.15% of individuals with developmental disorders and highlight the benefits of data sharing.

The success of whole-exome sequencing to identify mutations causing single-gene disorders has been well documented. In contrast whole-exome sequencing has so far had limited success in the identification of variants causing more complex phenotypes that seem unlikely to be due to the disruption of a single gene. We describe a family where two male offspring of healthy first cousin parents present a complex phenotype consisting of peripheral neuropathy and bronchiectasis that has not been described previously in the literature. Due to the fact that both children had the same problems in the context of parental consanguinity we hypothesised illness resulted from either X-linked or autosomal recessive inheritance. Through the use of whole-exome sequencing we were able to simplify this complex phenotype and identified a causative mutation (p.R1070*) in the gene periaxin (PRX), a gene previously shown to cause peripheral neuropathy (Dejerine-Sottas syndrome) when this mutation is present. For the bronchiectasis phenotype we were unable to identify a causal single mutation or compound heterozygote, reflecting the heterogeneous nature of this phenotype. In conclusion, in this study we show that whole-exome sequencing has the power to disentangle complex phenotypes through the identification of causative genetic mutations for distinct clinical disorders that were previously masked.

Brachydactyly type A1 is an autosomal dominant disorder primarily characterized by hypoplasia/aplasia of the middle phalanges of digits 2-5. Human and mouse genetic perturbations in the BMP-SMAD signaling pathway have been associated with many brachymesophalangies, including BDA1, as causative mutations in IHH and GDF5 have been previously identified. GDF5 interacts directly as the preferred ligand for the BMP type-1 receptor BMPR1B and is important for both chondrogenesis and digit formation. We report pathogenic variants in BMPR1B that are associated with complex BDA1. A c.975A>C (p.(Lys325Asn)) was identified in the first patient displaying absent middle phalanges and shortened distal phalanges of the toes in addition to the significant shortening of middle phalanges in digits 2, 3 and 5 of the hands. The second patient displayed a combination of brachydactyly and arachnodactyly. The sequencing of BMPR1B in this individual revealed a novel c.447-1G>A at a canonical acceptor splice site of exon 8, which is predicted to create a novel acceptor site, thus leading to a translational reading frameshift. Both mutations are most likely to act in a dominant-negative manner, similar to the effects observed in BMPR1B mutations that cause BDA2. These findings demonstrate that BMPR1B is another gene involved with the pathogenesis of BDA1 and illustrates the continuum of phenotypes between BDA1 and BDA2.

The inherited prion diseases (IPD) are a group of untreatable neurodegenerative diseases that segregate as autosomal dominant traits. Mutations in the prion protein gene (PRNP) were first found to be causal of IPD in 1989, before the molecular genetic characterisation of any other neurodegenerative disease. Predictive testing for IPD has subsequently been carried out at a single UK clinical and research centre for 22 years. We have analysed the uptake, consequences and factors influencing the decision for predictive testing over this period. In all, 104 predictive tests were done on individuals at 50% risk, compared with 135 positive diagnostic tests. Using genealogies from clinical records, we estimated that 23% of those at 50% risk have completed testing. There was no gender bias, and unsurprisingly, there was a slight excess of normal results because some patients were already partly through the risk period because of their age. An unexpectedly large number of patients developed symptoms shortly after predictive testing, suggesting that undisclosed early symptoms of disease may prompt some patients to come forward for predictive testing. Fifteen per cent of predictive tests were done >10 years after molecular diagnosis in a proband. A strong determinant of the timing of testing in these patients was a second diagnosis in the family. IPD may generate infectious prions that might be transmitted by surgical procedures; however, we found no evidence that public health information influenced decisions about predictive testing.