An update on clinical presentation and responses to therapy of patients with hereditary hypophosphatemic rickets with hypercalciuria (HHRH).

Pathogenic variants in solute carrier family 34, member 3 (SLC34A3), the gene encoding the sodium-dependent phosphate cotransporter 2c (NPT2c), cause hereditary hypophosphatemic rickets with hypercalciuria (HHRH). Here, we report a pooled analysis of clinical and laboratory records of 304 individuals from 145 kindreds, including 20 previously unreported HHRH kindreds, in which two novel SLC34A3 pathogenic variants were identified. Compound heterozygous/homozygous carriers show above 90% penetrance for kidney and bone phenotypes. The biochemical phenotype for heterozygous carriers is intermediate with decreased serum phosphate, tubular reabsorption of phosphate (TRP (%)), fibroblast growth factor 23, and intact parathyroid hormone, but increased serum 1,25-dihydroxy vitamin D, and urine calcium excretion causing idiopathic hypercalciuria in 38%, with bone phenotypes still observed in 23% of patients. Oral phosphate supplementation is the current standard of care, which typically normalizes serum phosphate. However, although in more than half of individuals this therapy achieves correction of hypophosphatemia it fails to resolve the other outcomes. The American College of Medical Genetics and Genomics score correlated with functional analysis of frequent SLC34A3 pathogenic variants in vitro and baseline disease severity. The number of mutant alleles and baseline TRP (%) were identified as predictors for kidney and bone phenotypes, baseline TRP (%) furthermore predicted response to therapy. Certain SLC34A3/NPT2c pathogenic variants can be identified with partial responses to therapy, whereas with some overlap, others present only with kidney phenotypes and a third group present only with bone phenotypes. Thus, our report highlights important novel clinical aspects of HHRH and heterozygous carriers, raises awareness to this rare group of disorders and can be a foundation for future studies urgently needed to guide therapy of HHRH.

3q29 duplications: A cohort of 46 patients and a literature review.

Duplications of the 3q29 cytoband are rare chromosomal copy number variations (CNVs) (overlapping or recurrent ~1.6 Mb 3q29 duplications). They have been associated with highly variable neurodevelopmental disorders (NDDs) with various associated features or reported as a susceptibility factor to the development of learning disabilities and neuropsychiatric disorders. The smallest region of overlap and the phenotype of 3q29 duplications remain uncertain. We here report a French cohort of 31 families with a 3q29 duplication identified by chromosomal microarray analysis (CMA), including 14 recurrent 1.6 Mb duplications, eight overlapping duplications (>1 Mb), and nine small duplications (<1 Mb). Additional genetic findings that may be involved in the phenotype were identified in 11 patients. Focusing on apparently isolated 3q29 duplications, patients present mainly mild NDD as suggested by a high rate of learning disabilities in contrast to a low proportion of patients with intellectual disabilities. Although some are de novo, most of the 3q29 duplications are inherited from a parent with a similar mild phenotype. Besides, the study of small 3q29 duplications does not provide evidence for any critical region. Our data suggest that the overlapping and recurrent 3q29 duplications seem to lead to mild NDD and that a severe or syndromic clinical presentation should warrant further genetic analyses.

Deliver Smart, Not More! Building Economically Sustainable Competitiveness on the Ground of High Agri-Food Trade Specialization in the EU.

Competitiveness has always been a multifaceted illusive concept, which has made it a real challenge for scholars and practitioners to find the most suitable measurement tools to completely encapsulate all the complex nuances of competitiveness. This becomes even more of a challenge when approached in relation to particular economic sectors. The agri-food sector is no exception, especially when considering all its interconnections with the other sectors: water, energy, transport, waste. All of them impact the achievement of the Sustainable Development Goals (SDGs). Similarly, scholars have been debating the meaning of sustainability for decades, some even arguing that it is a political, subjective, and, in some cases, self-contradictory concept. As far as the sustainability of agricultural competitiveness is concerned, the literature is still developing. It is much more focused on fostering environmental competitiveness, and less attention was paid to the strategies designed to capitalize on sustainable economic competitiveness-a concept that has attracted divergent opinions in the literature, mainly due to ambiguity. Thus, instead of falling into the pitfall of vagueness, this paper was aimed at bringing its contribution to this field by undertaking the research objective of exploring a single facet of sustainable agricultural competitiveness: the economic facet. Hence, this paper proposes the construction of the sustainable economic competitiveness index (SECI) with direct application for agri-food value chains. It consists of three attributes: (a) factor endowments, resource independence; (b) agricultural chain performance; and (c) national agricultural chain strategies and policies. In this study, SECI was tested against the cereal chain for a selection of EU countries, based on the data taken over from FAOSTAT and INTRACEN Trade Map, in the case of the 2011-2020 period. Various statistical and econometric methods were used to test the robustness of SECI. Results stand as proof that building sustainable agricultural economic competitiveness relies on a mix of strategic actions. The key vector in this mix is that trade flow patterns and policies must be calibrated in accordance with national factor endowments in order to achieve high levels of SECI. To add more managerial implications, this paper argues for the smart delivery of agri-food products with high added value instead of focusing on exporting big volumes of raw agricultural materials with little added value.

A novel synonymous variant in exon 1 of GNAS gene results in a cryptic splice site and causes pseudohypoparathyroidism type 1A and pseudo-pseudohypoparathyroidism in a French family.

INTRODUCTION: Pseudohypoparathyroidism type 1A (PHP1A) and pseudopseudohypoparathyroidism (PPHP) (Inactivating PTH/PTHrP Signaling Disorders type 2, IPPSD2) are two rare autosomal disorders caused by loss-of-function mutations on either maternal or paternal allele, respectively, in the imprinted GNAS gene, which encodes the α subunit of the ubiquitously-expressed stimulatory G protein (Gαs). CASE PRESENTATION: We investigated a synonymous GNAS variant NM_001077488.2: c.108C>A / p.(Val36=) identified in a family presenting with IPPSD2 phenotype. In silico splicing prediction algorithms were in favor of a deleterious effect of this variant, by creating a new donor splicing site. The GNAS expression studies in blood suggested haploinsufficiency and showed an alternate splice product demonstrating the unmasking of a cryptic site, leading to a 34 base pairs deletion and the creation of a probable unstable RNA.We present the first familial case of IPPSD2 caused by a pathogenic synonymous variant in GNAS gene.