GWAS meta-analysis of intrahepatic cholestasis of pregnancy implicates multiple hepatic genes and regulatory elements

Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disorder affecting 0.5–2% of pregnancies. The majority of cases present in the third trimester with pruritus, elevated serum bile acids and abnormal serum liver tests. ICP is associated with an increased risk of adverse outcomes, including spontaneous preterm birth and stillbirth. Whilst rare mutations affecting hepatobiliary transporters contribute to the aetiology of ICP, the role of common genetic variation in ICP has not been systematically characterised to date. Here, we perform genome-wide association studies (GWAS) and meta-analyses for ICP across three studies including 1138 cases and 153,642 controls. Eleven loci achieve genome-wide significance and have been further investigated and fine-mapped using functional genomics approaches. Our results pinpoint common sequence variation in liver-enriched genes and liver-specific cis-regulatory elements as contributing mechanisms to ICP susceptibility

Two patients with Hermansky Pudlak syndrome type 2 and novel mutations in AP3B1

Hermansky Pudlak syndrome type 2 (HPS2) is a rare disorder associated with mutations in the Adaptor Protein 3 (AP-3) complex, which is involved in sorting transmembrane proteins to lysosomes and related organelles. We now report 2 unrelated subjects with HPS2 who show a characteristic clinical phenotype of oculocutaneous albinism, platelet and T-lymphocyte dysfunction and neutropenia. The subjects were homozygous for different deletions within AP3B1 (g.del180242-180866, c.del153-156), which encodes the AP-3β3A subunit, resulting in frame shifts and introduction of nonsense substitutions (p.E693fsX13, p.E52fsX11). In the subject with p.E693fsX13, this resulted in expression of a truncated variant β3A protein. Cytotoxic T-lymphocyte (CTL) clones from both study subjects showed increased cell-surface expression of CD63 and reduced cytotoxicity. Platelets showed impaired aggregation and reduced uptake of 3H-serotonin. These findings are consistent with CTL granule and platelet dense granule defects, respectively. This report extends the clinical and laboratory description of HPS2

Acquisition of genome-wide copy number alterations in monozygotic twins with acute lymphoblastic leukemia

Chimaeric fusion genes are highly prevalent in childhood acute lymphoblastic leukaemia (ALL) and are mostly pre-natal, early genetic events in the evolutionary trajectory of this cancer. ETV6-RUNX1-positive ALL also has multiple (~six per case) copy number alterations (CNA) as revealed by genome-wide SNP arrays. Recurrent CNA are probably 'driver' events contributing critically to clonal diversification and selection but, at diagnosis, their developmental timing is 'buried' in the leukaemia's covert natural history. This conundrum can be resolved with twin pairs. We identified and compared CNA in five pairs of monozygotic twins with concordant ETV6-RUNX1-positive ALL and one pair discordant for ETV6-RUNX1 positive ALL. We compared, within each pair, CNA classified as potential 'driver' or 'passenger' mutations based upon recurrency and, where known, gene function. An average of 5.1 (range 3-11) CNAs (excluding immunoglobulin/T-cell receptor alterations) were identified per case. All 'driver' CNA (total 32) were distinct within each of the five twin pairs with concordant ALL. 'Driver' CNA in another twin with ALL were all absent in the shared ETV6-RUNX1-positive pre-leukaemic clone of her healthy co-twin. These data place all 'driver' CNA secondary to the pre-natal gene fusion event and most probably post-natal in the sequential, molecular pathogenesis of ALL

Myelodysplasia and liver disease extend the spectrum of RTEL1 related telomeropathies.

Regulator of telomere elongation helicase 1 (RTEL1) is a DNA helicase involved in telomere maintenance.1,2 Germline biallelic RTEL1 variants have been previously reported in a subset of patients with dyskeratosis congenita (DC) and its severe variant Hoyeraal-Hreidarsson syndrome (HH).3–6 Furthermore, germline heterozygous RTEL1 variants have been linked to a subset of patients with pulmonary fibrosis.2,7,8 We have undertaken sequencing analysis (whole exome and targeted9) of RTEL1, using genomic DNA extracted from peripheral blood of 429 patients from our international bone marrow failure registry which includes DC, HH, aplastic anemia (AA), and familial myelodysplasia/leukemia (MDS/AML). This has revealed that 35 out of the 429 patients have RTEL1 variants (Table 1). Based on the minor allele frequency in the population reported on the Exome Aggregation Consortium database (ExAC – http://exac.broadinstitute.org/), the type of variant (missense, nonsense and indels), telomere length, the Combined Annotation Depletion (CADD) score,10 and segregation as well as information found in literature, we classified these variants into four different groups: (1) biallelic variants, (2) heterozygous loss of function (LOF) variants, (3) heterozygous missense variants of unknown significance (VUS) and (4) heterozygous missense bystander variants

Characteristics of patients aged younger than 10, or 10 and older with CNS relapses.

<p>Characteristics of patients aged younger than 10, or 10 and older with CNS relapses.</p

Temporal pattern of relapses.

<p>Isolated (iCNS) and combined (c-CNS) relapses occur significantly earlier than those with isolated bone marrow (iBM) relapses (Log rank p = <0.001). Figures in parenthesis show mean duration of remission in months for each group with ± standard deviation.</p

Differences in outcome in patients with CNS relapse, allocated either transplantation or chemoradiotherapy according to whether they received Idarubicin or Mitoxantrone.

<p>c-CNS = combined CNS relapse; i-CNS = isolated CNS relapse; TRM = Therapy related mortality; SCT = allogeneic transplantation; CR2 = second remission; Ida = Idarubicin; Mito = Mitoxantrone. *Patients allocated SCT were, all those with very early relapse; early i-CNS relapses and early and late c-CNS relapses with MRD ≥10⁻⁴ at the end of induction. Where MRD was not evaluable, decision to transplant was based on duration of CR1. All other patients were allocated chemoradiotherapy.</p><p>Differences in outcome in patients with CNS relapse, allocated either transplantation or chemoradiotherapy according to whether they received Idarubicin or Mitoxantrone.</p

Endpoint of PFS and OS in patients with CNS relapse grouped by treatment allocation, and according to drug received Idarubicin vs Mitoxantrone.

<p>Endpoint of PFS and OS in patients with CNS relapse grouped by treatment allocation, and according to drug received Idarubicin vs Mitoxantrone.</p