CIROZ is dispensable in ancestral vertebrates but essential for left-right patterning in humans.

Four genes-DAND5, PKD1L1, MMP21, and CIROP-form a genetic module that has specifically evolved in vertebrate species that harbor motile cilia in their left-right organizer (LRO). We find here that CIROZ (previously known as C1orf127) is also specifically expressed in the LRO of mice, frogs, and fish, where it encodes a protein with a signal peptide followed by 3 zona pellucida N domains, consistent with extracellular localization. We report 16 individuals from 10 families with bi-allelic CIROZ inactivation variants, which cause heterotaxy with congenital heart defects.

Pathogenic PDE12 variants impair mitochondrial RNA processing causing neonatal mitochondrial disease.

Pathogenic variants in either the mitochondrial or nuclear genomes are associated with a diverse group of human disorders characterized by impaired mitochondrial function. Within this group, an increasing number of families have been identified, where Mendelian genetic disorders implicate defective mitochondrial RNA biology. The PDE12 gene encodes the poly(A)-specific exoribonuclease, involved in the quality control of mitochondrial non-coding RNAs.

Randomized Phase II Study of Durvalumab with or without Tremelimumab in Patients with Metastatic Castration-Resistant Prostate Cancer.

Purpose: PD-L1 is overexpressed by dendritic cells in patients with metastatic castration-resistant prostate cancer (mCRPC) progressing on androgen receptor pathway inhibitors. We tested whether checkpoint blockade could enhance antitumor activity in mCRPC.

Patients And Methods: In a multicenter open-label noncomparative randomized phase II study, patients with mCRPC treated with ≤1 prior cytotoxic chemotherapy, with measurable disease and progression on abiraterone and/or enzalutamide, were randomized to durvalumab 1,500 mg intravenously every 4 weeks ±4 doses of tremelimumab 75 mg intravenously.

Final analysis of the ALTTO trial: adjuvant trastuzumab in sequence or in combination with lapatinib in patients with HER2-positive early breast cancer [BIG 2-06/NCCTG N063D (Alliance)].

Background: Dual anti-human epidermal growth factor receptor 2 (HER2) blockade has improved the outcomes of patients with early and metastatic HER2-positive breast cancer. Here we present the final 10-year analysis of the ALTTO trial.

Patients And Methods: The ALTTO trial (NCT00490139) is a prospective randomized, phase III, open-label, multicenter study that investigated the role of adjuvant chemotherapy and trastuzumab alone, in combination or sequentially with lapatinib.

Rare disease genomic testing in the UK and Ireland: promoting timely and equitable access.

Purpose And Scope: The aim of this position statement is to provide recommendations regarding the delivery of genomic testing to patients with rare disease in the UK and Ireland. The statement has been developed to facilitate timely and equitable access to genomic testing with reporting of results within commissioned turnaround times.

Methods Of Statement Development: A 1-day workshop was convened by the UK Association for Clinical Genomic Science and attended by key stakeholders within the NHS Genomic Medicine Service, including clinical scientists, clinical geneticists and patient support group representatives.