Ataxia with Ocular Apraxia Type 1 (AOA1) (APTX, W279* Mutation): Neurological, Neuropsychological, and Molecular Outlining of a Heterogenous Phenotype in Four Colombian Siblings

Hereditary ataxias are a group of devastating neurological disorders that affect coordination of gait and are often associated with poor coordination of hands, speech, and eye movements. Ataxia with Ocular Apraxia type 1 (AOA1) (OMIM: 606350.0006) is characterized by slowly progressive symptoms of childhood-onset and pathogenic mutations in APTX; the only known cause underpinning AOA1. APTX encodes the protein Aprataxin, composed of three domains sharing homology with proteins involved in DNA damage, signaling, and repair. We present four siblings from an endogamic family in a rural, isolated town of Colombia with ataxia and ocular apraxia of childhood-onset and confirmed molecular diagnosis of AOA1, homozygous for the W279* p.Trp279Ter mutation. We predicted the mutated APTX with Alpha Fold to demonstrate the effects of this stop-gain mutation that deletes three beta helices encoded by amino acid 270 to 339 rescinding the C2H2-type zinc fingers (Znf) (C2H2 Znf) DNA-binding and DNA-repair domain and the whole tridimensional structure of the APTX. All siblings exhibited different ages of onset (4, 6, 8, and 11 y/o) and heterogeneous patterns of dysarthria (ranging from absence to mild-moderate dysarthria). Neuropsychological evaluation showed no neurocognitive impairment in three siblings, but one sibling showed temporospatial disorientation, semantic and phonologic fluency impairment, episodic memory affection, constructional apraxia, moderate anomia, low executive function, and symptoms of depression. This heterogeneous phenotype suggests genetic interactions can shape the natural history of AOA1. To our knowledge, this report represents the most extensive series of siblings affected with AOA1 in Latin America, and the genetic analysis completed adds important knowledge to outline this family’s disease and general complex phenotype of hereditary ataxias.

Evaluation of Frequency of PGC1-α and CKMM Genes Polymorphisms Among Iranian Elite Hockey Athletes

Background: Physical activity is a complex phenotype influenced by millions of genes and environmental factors. It is well known that physical performance and sports ability are linked to genes variations. Objectives: The aim of this study was to evaluate the frequency of PGC1-α and CKMM gene polymorphisms in elite hockey athletes. Methods: Fifty Iranian elite national hockey athletes and 100 non-athletes participated in this study. To determine the genotypes of PGC1-α and CKMM gene polymorphisms, 2 ml of saliva was sampled and used for DNA extraction. To determine the genotypes, the PCR-RFLP method was employed. After examining the variants, the allele and genotype frequencies of subjects were measured. Results: The results showed no significant differences for the PPARGC1A gene in the percentage of AA, GG, and AG genotypes. Similarly, the percentage of these genotypes of the CKMM gene did not differ significantly between athletes and non-athletes. Conclusions: The results suggest that the gene polymorphisms of PGC1-α and CKMM are the same between the Iranian elite hockey athletes and non-athletes, which may be due to the overlapping effect of other genes and/or the small sample size of the study.

Genetics of diaphragmatic hernia

Congenital diaphragmatic hernia (CDH) is a life-threatening malformation characterised by failure of diaphragmatic development with lung hypoplasia and persistent pulmonary hypertension of the newborn (PPHN). The incidence is 1:2000 corresponding to 8% of all major congenital malformations. Morbidity and mortality in affected newborns are very high and at present, there is no precise prenatal or early postnatal prognostication parameter to predict clinical outcome in CDH patients. Most cases occur sporadically, however, genetic causes have long been discussed to explain a proportion of cases. These range from aneuploidy to complex chromosomal aberrations and specific mutations often causing a complex phenotype exhibiting multiple malformations along with CDH. This review summarises the genetic variations which have been observed in syndromic and isolated cases of congenital diaphragmatic hernia.

Disentangling environmental drivers of circadian metabolism in desert-adapted mice

ABSTRACT Metabolism is a complex phenotype shaped by natural environmental rhythms, as well as behavioral, morphological and physiological adaptations. Metabolism has been historically studied under constant environmental conditions, but new methods of continuous metabolic phenotyping now offer a window into organismal responses to dynamic environments, and enable identification of abiotic controls and the timing of physiological responses relative to environmental change. We used indirect calorimetry to characterize metabolic phenotypes of the desert-adapted cactus mouse (Peromyscus eremicus) in response to variable environmental conditions that mimic their native environment versus those recorded under constant warm and constant cool conditions, with a constant photoperiod and full access to resources. We found significant sexual dimorphism, with males being more prone to dehydration than females. Under circadian environmental variation, most metabolic shifts occurred prior to physical environmental change and the timing was disrupted under both constant treatments. The ratio of CO2 produced to O2 consumed (the respiratory quotient) reached greater than 1.0 only during the light phase under diurnally variable conditions, a pattern that strongly suggests that lipogenesis contributes to the production of energy and endogenous water. Our results are consistent with historical descriptions of circadian torpor in this species (torpid by day, active by night), but reject the hypothesis that torpor is initiated by food restriction or negative water balance.

A Rare Case of Brachyolmia with Amelogenesis Imperfecta Caused by a New Pathogenic Splicing Variant in LTBP3

In recent years, a rare form of autosomal recessive brachyolmia associated with amelogenesis imperfecta (AI) has been described as a novel nosologic entity. This disorder is characterized by skeletal dysplasia (e.g., platyspondyly, short trunk, scoliosis, broad ilia, elongated femoral necks with coxa valga) and severe enamel and dental anomalies. Pathogenic variants in the latent transforming growth factor-β binding protein 3 (LTBP3) gene have been found implicated in the pathogenesis of this disorder. So far, biallelic pathogenic LTBP3 variants have been identified in less than 10 families. We here report a young boy born from consanguineous parents with a complex phenotype including skeletal dysplasia associated with aortic stenosis, hypertrophic cardiomyopathy, hypodontia and amelogenesis imperfecta caused by a previously unreported homozygous LTBP3 splice site variant. We also compare the genotypes and phenotypes of patients reported to date. This work provides further evidence that brachyolmia with amelogenesis imperfecta is a distinct nosologic entity and that variations in LTBP3 are involved in its pathogenesis.

Rational design of complex phenotype via network models

We demonstrate a modeling and computational framework that allows for rapid screening of thousands of potential network designs for particular dynamic behavior. To illustrate this capability we consider the problem of hysteresis, a prerequisite for construction of robust bistable switches and hence a cornerstone for construction of more complex synthetic circuits. We evaluate and rank most three node networks according to their ability to robustly exhibit hysteresis where robustness is measured with respect to parameters over multiple dynamic phenotypes. Focusing on the highest ranked networks, we demonstrate how additional robustness and design constraints can be applied. We compare our results to more traditional methods based on specific parameterization of ordinary differential equation models and demonstrate a strong qualitative match at a small fraction of the computational cost.

Whole Exome Sequencing Is the Minimal Technological Approach in Probands Born to Consanguineous Couples

We report on two siblings suffering from different pathogenic conditions, born to consanguineous parents. A multigene panel for brain malformations and microcephaly identified the homozygous splicing variant NM_005886.3:c.1416+1del in the KATNB1 gene in the older sister. On the other hand, exome sequencing revealed the homozygous frameshift variant NM_005245.4:c.9729del in the FAT1 gene in the younger sister, who had a more complex phenotype: in addition to bilateral anophthalmia and heart defects, she showed a right split foot with 4 toes, 5 metacarpals, second toe duplication and preaxial polydactyly on the right hand. These features have been never reported before in patients with pathogenic FAT1 variants and support the role of this gene in the development of limb buds. Notably, each parent was heterozygous for both of these variants, which were ultra-rare and rare, respectively. This study raises awareness about the value of using whole exome/genome sequencing rather than targeted gene panels when testing affected offspring born to consanguineous couples. In this way, exomic data from the parents are also made available for carrier screening, to identify heterozygous pathogenetic and likely pathogenetic variants in genes responsible for other recessive conditions, which may pose a risk for subsequent pregnancies.