Truncating de novo mutations in the Kruppel-type zinc-finger gene ZNF148 in patients with corpus callosum defects, developmental delay, short stature, and dysmorphisms

Background: Kruppep-type zinc finger genes (ZNF) constitute a large yet relatively poorly characterized gene family. ZNF genes encode proteins that recognize specific DNA motifs in gene promotors. They act as transcriptional co-activators or -repressors via interaction with chromatin remodeling proteins and other transcription factors. Only few ZNF genes are currently linked to human disorders and identification of ZNF gene-associated human diseases may help understand their function. Here we provide genetic, statistical, and clinical evidence to support association of ZNF148 with a new intellectual disability (ID) syndrome disorder. Methods: Routine diagnostic exome sequencing data were obtained from 2172 patients with ID and/or multiple congenital anomalies. Results: In a cohort of 2172 patient-parent trios referred for routine diagnostic whole exome sequencing for ID and/or multiple congenital anomalies (MCA) in the period 2012-2016, four patients were identified who carried de novo heterozygous nonsense or frameshift mutations in the ZNF148 gene. This was the only ZNF gene with recurrent truncating de novo mutations in this cohort. All mutations resulted in premature termination codons in the last exon of ZNF148. The number of the de novo truncating mutations in the ZNF148 gene was significantly enriched (p = 5. 42 x 10(-3)). The newly described ZNF148-associated syndrome is characterized by underdevelopment of the corpus callosum, mild to moderate developmental delay and ID, variable microcephaly or mild macrocephaly, short stature, feeding problems, facial dysmorphisms, and cardiac and renal malformations. Conclusions: We propose ZNF148 as a gene involved in a newly described ID syndrome with a recurrent phenotype and postulate that the ZNF148 is a hitherto unrecognized but crucial transcription factor in the development of the corpus callosum. Our study illustrates the advantage of whole exome sequencing in a large cohort using a parent-offspring trio approach for identifying novel genes involved in rare human diseases

Global distribution and sources of dissolved inorganic nitrogen export to the coastal zone: Results from a spatially explicit, global model

Here we describe, test, and apply a spatially explicit, global model for predicting dissolved inorganic nitrogen (DIN) export by rivers to coastal waters (NEWS‐DIN). NEWS‐DIN was developed as part of an internally consistent suite of global nutrient export models. Modeled and measured DIN export values agree well (calibration R2 = 0.79), and NEWS‐DIN is relatively free of bias. NEWS‐DIN predicts: DIN yields ranging from 0.0004 to 5217 kg N km−2 yr−1 with the highest DIN yields occurring in Europe and South East Asia; global DIN export to coastal waters of 25 Tg N yr−1, with 16 Tg N yr−1 from anthropogenic sources; biological N2 fixation is the dominant source of exported DIN; and globally, and on every continent except Africa, N fertilizer is the largest anthropogenic source of DIN export to coastal waters