Combined NGS Approaches Identify Mutations in the Intraflagellar Transport Gene IFT140 in Skeletal Ciliopathies with Early Progressive Kidney Disease

Ciliopathies are genetically heterogeneous disorders characterized by variable expressivity and overlaps between different disease entities. This is exemplified by the short rib‐polydactyly syndromes, Jeune, Sensenbrenner, and Mainzer‐Saldino chondrodysplasia syndromes. These three syndromes are frequently caused by mutations in intraflagellar transport (IFT) genes affecting the primary cilia, which play a crucial role in skeletal and chondral development. Here, we identified mutations in IFT140, an IFT complex A gene, in five Jeune asphyxiating thoracic dystrophy (JATD) and two Mainzer‐Saldino syndrome (MSS) families, by screening a cohort of 66 JATD/MSS patients using whole exome sequencing and targeted resequencing of a customized ciliopathy gene panel. We also found an enrichment of rare IFT140 alleles in JATD compared with nonciliopathy diseases, implying putative modifier effects for certain alleles. IFT140 patients presented with mild chest narrowing, but all had end‐stage renal failure under 13 years of age and retinal dystrophy when examined for ocular dysfunction. This is consistent with the severe cystic phenotype of Ift140 conditional knockout mice, and the higher level of Ift140 expression in kidney and retina compared with the skeleton at E15.5 in the mouse. IFT140 is therefore a major cause of cono‐renal syndromes (JATD and MSS). The present study strengthens the rationale for IFT140 screening in skeletal ciliopathy spectrum patients that have kidney disease and/or retinal dystrophy.     

The initial health-system response to the earthquake in Christchurch, New Zealand, in February, 2011

At 1251 h on Feb 22, 2011, an earthquake struck Christchurch, New Zealand, causing widespread destruction. The only regional acute hospital was compromised but was able to continue to provide care, supported by other hospitals and primary care facilities in the city. 6659 people were injured and 182 died in the initial 24 h. The massive peak ground accelerations, the time of the day, and the collapse of major buildings contributed to injuries, but the proximity of the hospital to the central business district, which was the most affected, and the provision of good medical care based on careful preparation helped reduce mortality and the burden of injury. Lessons learned from the health response to this earthquake include the need for emergency departments to prepare for: patients arriving by unusual means without prehospital care, manual registration and tracking of patients, patient reluctance to come into hospital buildings, complete loss of electrical power, management of the many willing helpers, alternative communication methods, control of the media, and teamwork with clear leadership. Additionally, atypical providers of acute injury care need to be integrated into response plans.