DLG2 mutations in the etiology of pubertal delay and Idiopathic Hypogonadotropic Hypogonadism

Introduction: Idiopathic Hypogonadotropic hypogonadism (IHH) is caused by dysfunction of the hypothalamic-pituitary-gonadal axis. DLG2 was recently implicated as a gene associated with delayed puberty and which may also contribute to IHH. The confirmation of the candidate puberty genes in independent IHH cohorts has become crucial due to the lack proper genotype phenotype segregations in reported pedigrees. Therefore, we aimed to screen DLG2 in patients variants in a large cohort of IHH patients. Methods: The present study included a total of 336 IHH patients from 290 independent families. The coding and flanking regions of the DLG2 were screened for potentially important variants in the WES data. Candidate variants were evaluated in the gnomAD and GME databases according to their allele frequencies, and only those with a frequency <0.0001 were considered rare. Detected variants were classified according to the ACMG/AMP criteria. Results: We found one homozygous and two heterozygous missense variants in three independent pedigrees. Identified variants were found extremely rare or not reported in gnomAD. Two variants were categorized as “uncertain significance” the other one was “likely pathogenic” according to the ACMG criteria. All patients were normosmic, and in two of the three families there were no causal variants in other IHH-related genes. Conclusion: We detected three rare sequencing variants in DLG2 in five patients with IHH or delayed puberty in a large IHH cohort. Our results support the contention that the DLG2 mutations are associated with IHH in human puberty.

Biallelic loss-of-function variants in WDR11 are associated with microcephaly and intellectual disability

Heterozygous missense variants in the WD repeat domain 11 (WDR11) gene are associated with hypogonadotropic hypogonadism in humans. In contrast, knockout of both alleles of Wdr11 in mice results in a more severe phenotype with growth and developmental delay, features of holoprosencephaly, heart defects and reproductive disorders. Similar developmental defects known to be associated with aberrant hedgehog signaling and ciliogenesis have been found in zebrafish after Wdr11 knockdown. We here report biallelic loss-of-function variants in the WDR11 gene in six patients from three independent families with intellectual disability, microcephaly and short stature. The findings suggest that biallelic WDR11 variants in humans result in an overlapping but milder phenotype compared to Wdr11-deficient animals. However, the observed human phenotype differs significantly from dominantly inherited variants leading to hypogonadotropic hypogonadism, suggesting that recessive WDR11 variants result in a clinically distinct entity.

Mathematically and biologically consistent framework for presence-absence pairwise indices of diversity

Aim A large number of indices that compare two or more assemblages have been proposed or reinvented. The interpretation of the indices varies across the literature, despite efforts for clarification and unification. Most of the effort has focused on interdependence between the indices and the mathematics behind them. At the same time, following issues have been underestimated: (i) the difference between statistical independence of indices and the independence based on their informational value, and (ii) the inferences from the indices about diversity patterns and phenomena. Here we offer an alternative framework for diversity indices. Methods We distinguish different classes of dependence, and show that three indices which are mutually independent in terms of their information content are sufficient for appropriate inferences. This applies regardless of whether the indices are statistically correlated or not. We classify 20 existing indices into three main and four minor mutually independent families, and demonstrate how similarity between assemblages violates the stability of the families, confusing conceptually different patterns. We show what can be inferred about spatial diversity phenomena from different indices, demonstrate problems with most of the indices of nestedness, and show which combinations of indices may be used for meaningful ecological inference. Results and Main conclusions We demonstrate that no single index can properly filter out a single effect of a phenomena because the phenomena inevitably bound each other (e.g. species richness gradient bounds possible values of Jaccard index of community similarity). Consequently, inventing indices which seemingly purify these effect (e.g. pure turnover or pure nestedness) leads to misleading inference. In contrast, a proper inference is obtained by using a combination of classical indices from different, mutually independent families. Our framework provides a practical clue how to compare different indices across the literature.

A nonseparable invariant extension of Lebesgue measure – A generalized and abstract approach

In this paper, we use some methods of combinatorial set theory, in particular, the ones related to the construction of independent families of sets and also some modified version of the notion of small sets originally introduced by Riečan and Neubrunn, to give an abstract and generalized formulation of a remarkable theorem of Kakutani and Oxtoby related to a nonseparable invariant extension of the Lebesgue measure in spaces with transformation groups.

First Complete Mitochondrial Genome of Melyridae(Coleoptera, Cleroidea): Genome Description and Phylogenetic Implications

To explore the characteristics of the mitogenome of Melyridae and reveal phylogenetic relationships, the mitogenome of Cordylepherus sp. was sequenced and annotated. This is the first time a complete mitochondrial genome has been generated in this family. Consistent with previous observations of Cleroidea species, the mitogenome of Cordylepherus sp. is highly conserved in gene size, organization and codon usage, and secondary structures of tRNAs. All protein-coding genes (PCGs) initiate with the standard start codon ATN, except ND1, which starts with TTG, and terminate with the complete stop codons of TAA and TAG, or incomplete forms, TA- and T-. Most tRNAs have the typical clover-leaf structure, except trnS1 (Ser, AGN), whose dihydrouridine (DHU) arm is reduced. In the A+T-rich region, three types of tandem repeat sequence units are found, including a 115 bp sequence tandemly repeated twice, a 16 bp sequence tandemly repeated three times with a partial third repeat and a 10 bp sequence tandemly repeated seven times. Phylogenetic analyses based on 13 protein-coding genes by both Bayesian inference (BI) and maximum likelihood (ML) methods suggest that Melyridae sensu lato is polyphyletic, and Dasytinae and Malchiinae are supported as independent families.

PAX6 missense variants in two families with isolated foveal hypoplasia and nystagmus: evidence of paternal postzygotic mosaicism

PAX6 is considered the master regulator of eye development, the majority of variants affecting this gene cause the pan-ocular developmental eye disorder aniridia. Although no genotype-phenotype correlations are clearly established, missense variants affecting the DNA-binding paired domain of PAX6 are usually associated with non-aniridia phenotypes like microphthalmia, coloboma or isolated foveal hypoplasia. In this study, we report two missense heterozygous variants in the paired domain of PAX6 resulting in isolated foveal hypoplasia with nystagmus in two independent families: c.112 C > G; p.(Arg38Gly) and c.214 G > C; p.(Gly72Arg) in exons 5 and 6, respectively. Furthermore, we provide evidence that paternal postzygotic mosaicism is the cause of inheritance, with clinically unaffected fathers and reduced affected allele fraction. This work contributes to increase the phenotypic spectrum caused by PAX6 variants, and to our knowledge, is the first report to describe the presence of postzygotic parental mosaicism causing isolated foveal hypoplasia with nystagmus. These results support the growing evidence that suggest an overestimation of sporadic cases with PAX6 variants, which has strong implications for both genetic counselling and family planning.