Laura E. Martínez-de-Villarreal

Identification of novel mutations in Mexican patients with Aarskog–Scott syndrome

Aarskog–Scott syndrome (AAS), also known as faciogenital dysplasia (FGD, OMIM # 305400), is an X‐linked disorder of recessive inheritance, characterized by short stature and facial, skeletal, and urogenital abnormalities. AAS is caused by mutations in the FGD1 gene (Xp11.22), with over 56 different mutations identified to date. We present the clinical and molecular analysis of four unrelated families of Mexican origin with an AAS phenotype, in whom FGD1 sequencing was performed. This analysis identified two stop mutations not previously reported in the literature: p.Gln664* and p.Glu380*. Phenotypically, every male patient met the clinical criteria of the syndrome, whereas discrepancies were found between phenotypes in female patients. Our results identify two novel mutations in FGD1, broadening the spectrum of reported mutations; and provide further delineation of the phenotypic variability previously described in AAS.

Molecular evolution and expression profile of the chemerine encoding gene RARRES2 in baboon and chimpanzee

BackgroundChemerin, encoded by the retinoic acid receptor responder 2 (RARRES2) gene is an adipocytesecreted protein with autocrine/paracrine functions in adipose tissue, metabolism and inflammation with a recently described function in vascular tone regulation, liver, steatosis, etc. This molecule is believed to represent a critical endocrine signal linking obesity to diabetes. There are no data available regarding evolution of RARRES2 in non-human primates and great apes. Expression profile and orthology in RARRES2 genes are unknown aspects in the biology of this multigene family in primates. Thus; we attempt to describe expression profile and phylogenetic relationship as complementary knowledge in the function of this gene in primates. To do that, we performed A RT-PCR from different tissues obtained during necropsies. Also we tested the hypotheses of positive evolution, purifying selection, and neutrality. And finally a phylogenetic analysis was made between primates RARRES2 protein.ResultsRARRES2 transcripts were present in liver, lung, adipose tissue, ovary, pancreas, heart, hypothalamus and pituitary tissues. Expression in kidney and leukocytes were not detectable in either species. It was determined that the studied genes are orthologous.ConclusionsRARRES2 evolution fits the hypothesis of purifying selection. Expression profiles of the RARRES2 gene are similar in baboons and chimpanzees and are also phylogenetically related.

A novel EBP c.224T>A mutation supports the existence of a male-specific disorder independent of CDPX2

Mutations in the Emopamil‐binding protein (EBP) gene cause X‐linked dominant chondrodysplasia punctata 2 (CDPX2), a disorder in which at least 95% of liveborn individuals are female and male intrauterine lethality is assumed. Several affected males with mutations in EBP have been reported. These males exhibit a phenotype similar to CDPX2 due to either somatic mosaicism or a 47, XXY karyotype in association with a null EBP allele. Alternatively, affected males may exhibit a distinct phenotype if they are hemizygous for a hypomorphic allele of EBP. Recently, we described a novel X‐linked phenotype associated with digital abnormalities, intellectual disability and short stature, and mapped it to Xp11.4–p11.21. X‐exome sequencing was performed to identify the mutated gene responsible for this phenotype. A novel missense variant, c.224T>A (p.I75N), was identified in EBP. SIFT and PolyPhen‐2 predicted this change to be deleterious. The pathogenicity of this variant was subsequently supported by increased plasma levels of 8(9)‐cholestenol in the proband and his mother. The molecular and biochemical evidence convincingly supports the pathogenicity and association of the p.I75N mutation with this newly described phenotype. This study expands the current phenotypic spectrum of males with hypomorphic EBP mutations and supports to the hypothesis that there exists an X‐linked recessive entity independent of CDPX2.

Evaluation of familial factors in a Mexican population-based setting with gastroschisis: Further evidence for an underlying genetic susceptibility

PURPOSE To evaluate the occurrence of gastroschisis attributable to familial factors in a Mexican population-based setting. METHODS A descriptive study was performed among gastroschisis cases born from 2010 through 2016 at Tijuana General Hospital (Baja California, Mexico) to generate multigenerational pedigrees. RESULTS There were 87 gastroschisis cases from 57,217 live births. Six probands (6.9%) had another affected family member. Two half-siblings, a set of monozygotic twins, a mother-and-daughter occurrence, a distant paternal cousin and a distant maternal uncle were identified. Sibling recurrence was 5.5%. From 174 males and 153 females studied (n=327, involving 180 nuclear families), sex-dependent influence analysis evidenced an increased susceptibility to gastroschisis in males (3.2%) compared to females (1.8%) with an overall of 2.5% adjusted for proband. CONCLUSIONS Our results provide a greater liability attributable to familial factors on gastroschisis. In spite of the predominant sporadic occurrence, underlying genetic susceptibility and environmental influences point to a complex interplay between genes and environmental factors in gastroschisis. LEVEL OF EVIDENCE Level IV.

GJB2 and GJB6 mutations are an infrequent cause of autosomal-recessive nonsyndromic hearing loss in residents of Mexico.

OBJECTIVES Mutations in the DFNB1 locus are the most common cause of autosomal-recessive nonsyndromic hearing loss (ARNSHL) worldwide. The aim of this study was to identify the most frequent mutations in patients with ARNSHL who reside in Northeastern Mexico. METHODS We determined the nucleotide sequence the coding region of GJB2 of 78 patients with ARNSHL. Polymerase chain reaction assays were used to detect the GJB2 IVS1+1G>A mutation and deletions within GJB6. RESULTS GJB2 mutations were detected in 9.6% of the alleles, and c.35delG was the most frequent. Six other less-frequent mutations were detected, including an extremely rare variant (c.645_648delTAGA), a novel mutation (c.35G>A), and one of possible Mexican origin (c.34G>T). GJB6 deletions and GJB2 IVS1+1G>A were not detected. CONCLUSIONS These data suggest that mutations in the DFNB1 locus are a rare cause of ARNSHL among the population of Northeastern Mexico. This confirms the genetic heterogeneity of this condition and indicates that further research is required to determine the other mechanisms of pathogenesis of ARNSHL in Mexicans.

Familial occurrence of gastroschisis: a population-based overview on recurrence risk, sex-dependent influence, and geographical distribution

PurposeThere is uncertainty over whether familial recurrences in gastroschisis might be higher. Moreover, scant information is available regarding its sociodemographic features. We aim to explore the recurrence risk, sex-dependent influence, and geographical distribution of familial gastroschisis.MethodsA systematic review of the literature and data extraction from population-based studies published 1970–2017 (PubMed/MEDLINE) was independently performed by two reviewers. Familial ocurrence of gastroschisis, whereas sociodemographic features from 11 studies were pooled including 862 probands as a base. A descriptive analysis and Chi-square test were performed.ResultsTwenty-four probands had a positive family history of gastroschisis including 49 affected family members, for a recurrence risk of 5.7 and 3% adjusted for proband. Siblings’ recurrence was 4.3%. Sex-dependent influence analysis (n = 879, from three studies) evidenced an increased susceptibility to gastroschisis in males (2.5%) compared to females (1.3%) adjusted for proband. Heterogeneity was identified by Fisher’s exact test (P = 0.023).ConclusionOur findings support a greater liability attributable to familial factors on gastroschisis along with significant information for family and prenatal counseling. We suggest that future studies should include for a more accurate account for both familial and environmental confounding factors to uncover relatives and environmental exposures that more limited family histories may have missed.

Reference values for amino acids and acylcarnitines in peripheral blood in Quarter horses and American Miniature horses

AbstractBackgroundFree amino acids and acylcarnitines circulating in the blood can be used for diagnosis for metabolic illness and imbalances. To date, the normal reference ranges of amino acids and acylcarnitines in horse peripheral blood have not been established. In this study, the concentrations of 12 amino acids and 26 acylcarnitines were determined by tandem mass spectrometry in complete blood from 100 healthy horses (50 Quarter horses (QH) [23 males and 27 females] and 50 American Miniature horses (AMH) [15 males and 35 females]) with no signs of metabolic disease. The means and standard deviations were determined and data statistically analyzed.FindingsConcentrations of short, medium, and long chain acylcarnitines were significantly higher in male AMH than in male QH. The concentrations of the amino acids alanine, arginine, glycine, proline (glycogenic), and leucine (ketogenic) were higher in the QH than in the AMH. Female AMH had higher concentrations of propionylcarnitine, leucine, proline, arginine, and ornithine than female QH.ConclusionsNormal reference ranges of amino acids and acylcarnitines were established for AMH and QH. Significant differences were found in concentration of these compounds between breeds and gender.

Association of the polymorphism 12109g>A from the REN gene as a risk factor for preterm birth

Introduction: Preterm birth is the most important cause of neonatal mortality and morbidity. It is a multifactorial disease with different etiologies, including genetic factors. Genetic variability is represented by single nucleotide polymorphisms (SNPs) in genes of proteins involved in the contractile activity. We determine the association between SNP 12109G> A in REN associated with preterm birth and premature rupture of membrane. Materials and methods: A study of cases (N=112, 22–36 weeks of gestation; mean: 31, 95% confidence interval 30.7–32.2) and controls (N=66; 38–40 weeks of gestation from the last menstrual period; mean: 39.8, 95% confidence interval 38.9–39.4) was performed. Genomic DNA was isolated in all patients from peripheral blood. The SNP 12109G> A (Mbo I) in REN was typified by PCR-restriction fragment length polymorphism. Results: A significant difference in the case group for the SNP 12109G>A was observed. The A allele was increased in women with preterm birth (81% cases vs. 15% control, p<0.0000004). There was also a significant difference between genotypes, mainly an excess of G/A heterozygotes in women with preterm birth (60% cases vs. 23% controls). The phenotype 12109G> A has odds ratio 6.62 (95% confidence interval 3.14–14.15), which means a high risk of preterm birth/premature rupture of membrane in presence of allele A, both in homozygotes and in heterozygotes. Conclusion: Allelic frequency of A of SNP 12109G>A was higher in women with preterm birth than in women with normal vaginal delivery and could be considered a risk factor.

Detection of Turner Syndrome by Quantitative PCR of SHOX and VAMP7 Genes

Turner Syndrome (TS) is an unfavorable genetic condition with a prevalence of 1:2500 in newborn girls. Prompt and effective diagnosis is very important to appropriately monitor the comorbidities. The aim of the present study was to propose a feasible and practical molecular diagnostic tool for newborn screening by quantifying the gene dosage of the SHOX, VAMP7, XIST, UBA1, and SRY genes by quantitative polymerase chain reaction (qPCR) in individuals with a diagnosis of complete X monosomy, as well as those with TS variants, and then compare the results to controls without chromosomal abnormalities. According to our results, the most useful markers for these chromosomal variants were the genes found in the pseudoautosomic regions 1 and 2 (PAR1 and PAR2), because differences in gene dosage (relative quantification) between groups were more evident in SHOX and VAMP7 gene expression. Therefore, we conclude that these markers are useful for early detection in aneuploidies involving sex chromosomes.

Genetic variants conferring susceptibility to gastroschisis: a phenomenon restricted to the interaction with the environment?

BackgroundGenes involved in gastroschisis have shown a strong interaction with environmental factors. However, less is known about its influence. We aimed to systematically review the genetic associations of gastroschisis, to summarize whether its genetic susceptibility has been restricted to the interaction with the environment, and to identify significant gaps that remain for consideration in future studies.MethodsGenetic association studies of gastroschisis published 1980–2017 (PubMed/MEDLINE) were independently searched by two reviewers. Significant SNP–gastroschisis associations were grouped into crude and stratified risks, whereas SNPs were assessed from two or more independent studies. Frequencies, odds ratios, and 95% confidence intervals were pooled using descriptive analysis and Chi-square test accounting for heterogeneity.ResultsSeven eligible articles capturing associations of 14 SNPs from 10 genes for crude risk (including 10 and 4 SNPs with increased and decreased risk, respectively) and 30 SNPs from 14 genes for stratified risk in gastroschisis (including 37 and 14 SNPs with increased and decreased risk, respectively) were identified (Fisher’s exact test, P = 0.438). The rs4961 (ADD1), rs5443 (GNB3), rs1042713, and rs1042714 (ADRB2) were significantly associated with gastroschisis.ConclusionsGenetic susceptibility in gastroschisis is not restricted to the interaction with the environment and should not be too narrowly focused on environmental factors. We found significant associations with four SNPs from three genes related to blood pressure regulation, which supports a significant role of vascular disruption in the pathogenesis of gastroschisis. Future studies considering gene–gene or gene–environmental interactions are warranted for better understanding the etiology of gastroschisis.