RESUMO

Crossbreeding has been employed to address environmental challenges. One successful example is the Siboney de Cuba, developed in response to economic challenges in the 1960s. The aim of this study was to perform the first genomic characterization of the Siboney de Cuba breed, a successful hybrid breed resulting from the crossbreeding of Cuban Zebu and Holstein, using SNP array chip. For this purpose, 48 Siboney de Cuba cattle samples were collected and genotyped with the GGP Bovine 100k BeadChip, resulting in 83,314 SNPs after quality control. The genetic diversity was investigated using observed and expected heterozygosity, inbreeding coefficient, and minor allele frequency. Runs of homozygosity (ROH) analysis provided insights into molecular inbreeding. Additionally, the study investigated copy number variants (CNV), identifying CNV regions and their distribution. The genetic relationship and population structure of Siboney de Cuba were analyzed in comparison with worldwide cattle populations using ADMIXTURE, multidimensional scaling, and phylogenetic analysis. Six ROH islands containing a total of 50 genes were discovered, some of which were uncharacterized loci. Furthermore, 792 CNV with higher occurrence of genetic material loss were observed. The overall genome coverage for CNV regions was 2.16%. The Siboney de Cuba exhibited a good level of genetic variability with high heterozygosity and low inbreeding when compared with other cattle breeds worldwide. Also, the breed shared genetic similarity to hybrids from America and Bos indicus from Africa and highlighted a moderate level of genetic isolation with some overlaps with Bos taurus from America. The breed showed a complex genetic composition, influenced by historical factors. Overall, findings of the present study contribute to the understanding of genomic structure of Siboney de Cuba cattle breed.

RESUMO

Copy number variants (CNVs) remain a major etiological cause of neurodevelopmental delay and congenital malformations. Chromosomal microarray analysis (CMA) represents the gold standard for CNVs molecular characterization. We applied CMA throughout the patient's clinical diagnostic workup, as the patient's medical provider requested. We collected CMA results of 3380 patients enrolled for 5 years (2016-2021). We found 830 CNVs in 719 patients with potential clinical significance, that is, (i) pathogenic, (ii) likely pathogenic, and (iii) variants of uncertain significance (VUS), from which 10.6% (predominantly involving chromosomes 15 and 22) were most likely the final cause underpinning the patients' clinical phenotype. For those associated with neurodevelopmental phenotypes, the rate of pathogenic or likely pathogenic findings among the patients with CNVs was 60.75%. When considering epileptic phenotypes, it was 59%. Interestingly, our protocol identified two gains harbored in 17q21.31 and 9q34.3, internationally classified initially as VUS. However, because of their high frequency, we propose that these two VUS be reclassified as likely benign in this widely heterogeneous phenotypic population. These results support the diagnostic yield efficiency of CMA in characterizing CNVs to define the final molecular cause of genetic diseases in this cohort of Colombian patients, the most significant sample of patients from a Latino population, and define new benign polymorphic CNVs.

Assuntos

RESUMO

Trisomy X is the most frequent sex chromosome anomaly in women, but it is often underdiagnosed postnatally because most patients do not show any clinical manifestation. It is estimated that only 10% of patients with trisomy X are diagnosed by clinical findings. Thus, it has been proposed that the clinical spectrum is not yet fully delimited, and additional uncommon or atypical clinical manifestations could be related to this entity. The present report describes a female carrying trisomy X but presenting atypical manifestations, including severe intellectual disability, short stature, thymus hypoplasia, and congenital hypothyroidism (CH). These clinical findings were initially attributed to trisomy X. However, chromosome microarray analysis (CMA) subsequently revealed that the patient also bears a heterozygous 304-kb deletion at 16p11.2. This pathogenic copy-number variant (CNV) encompasses 13 genes, including TUFM. Some authors recommend that when a phenotype differs from that described for an identified microdeletion, the presence of pathogenic variants in the non-deleted allele should be considered to assess for an autosomal recessive disorder; thus, we used a panel of 697 genes to rule out a pathogenic variant in the non-deleted TUFM allele. We discuss the possible phenotypic modifications that might be related to an additional CNV in individuals with sex chromosome aneuploidy (SCA), as seen in our patient. The presence of karyotype-demonstrated trisomy X and CMA-identified 16p11.2 deletion highlights the importance of always correlating a patient's clinical phenotype with the results of genetic studies. When the phenotype includes unusual manifestations and/or exhibits discrepancies with that described in the literature, as exemplified by our patient, a more extensive analysis should be undertaken to enable a correct diagnosis that will support proper management, genetic counseling, and medical follow-up.

Assuntos

RESUMO

Purpose: To clinically and molecularly study a newly found family with North Carolina macular dystrophy (NCMD/MCDR1) from Mexico. Methods: This retrospective study comprised 6 members of a 3-generation Mexican family with NCMD. Clinical ophthalmic examinations, including fundus imaging, spectral-domain optical coherence tomography, electroretinography, and electrooculography, were performed. Genotyping with polymorphic markers in the MCDR1 region was performed to determine haplotypes. Whole-genome sequencing (WGS) was performed followed by variant filtering and copy number variant analysis. Results: Four subjects from 3 generations were found to have macular abnormalities. The proband presented with lifelong bilateral vision impairment with bilaterally symmetric vitelliform Best disease-like appearing macular lesions. Her 2 children had bilateral large macular coloboma-like malformations, consistent with autosomal dominant NCMD. The 80-year-old mother of the proband had drusen-like lesions consistent with grade 1 NCMD. WGS and subsequent Sanger sequencing found a point mutation at chr6:99593030G>C (hg38) in the noncoding region of the DNase I site thought to be a regulatory element of the retinal transcription factor gene PRDM13. This mutation is the identical site/nucleotide as in the original NCMD family (#765) but is a guanine to cytosine change rather than a guanine to thymine mutation, as found in the original NCMD family. Conclusions: We report a new noncoding mutation at the same locus (chr6:99593030G>C) involving the same DNase I site regulating the retinal transcription factor gene PRDM13. This suggests that this site, chr6:99593030, is a mutational hotspot.

RESUMO

The clinical heterogeneity in 22q11.2 deletion syndrome (22q11.2DS) underlies complex genetic mechanisms including variants in other regions of the genome, known as genetic modifiers. Congenital heart disease (CHD) is one of the most relevant phenotypes in the syndrome and copy number variants (CNVs) outside the 22q11.2 region could play a role in its variable expressivity. Since those described loci account for a small proportion of the variability, the CNV analysis in new cohorts from different ancestry-based populations constitutes a valuable resource to identify a wider range of modifiers. We performed SNP-array in 117 Brazilian patients with 22q11.2DS, with and without CHD, and leveraged genome-wide CNV analysis. After quality control, we selected 50 CNVs in 38 patients for downstream analysis. CNVs' genetic content and implicated biological pathways were compared between patients with and without CHD. CNV-affected genes in patients with CHD were enriched for several functional terms related to ubiquitination, transcription factor binding sites and miRNA targets, highlighting the complexity of the phenotype's expressivity. Cardiac-related genes were identified in both groups of patients suggesting that increasing risk and protective mechanisms could be involved. These genes and enriched pathways could indicate new modifiers to the cardiac phenotype in 22q11.2DS patients.

Assuntos

RESUMO

This study aimed to integrate GWAS and structural variants to propose possible molecular biomarkers related to gastrointestinal nematode resistance traits in Santa Inês sheep. The phenotypic records FAMACHA, haematocrit, white blood cell count, red blood cell count, haemoglobin, platelets and egg counts per gram of faeces were collected from 700 naturally infected animals, belonging to four Brazilian flocks. A total of 576 animals were genotyped using the Ovine SNP12k BeadChip and were imputed using a reference population with Ovine SNP50 BeadChip. The GWAS approaches were based on SNPs, haplotypes, CNVs and ROH. The overlapping between the significant genomic regions detected from all approaches was investigated, and the results were integrated using a network analysis. Genes related to the immune system were found, such as ABCB1, IL6, WNT5A and IRF5. Genomic regions containing candidate genes and metabolic pathways involved in immune responses, inflammatory processes and immune cells affecting parasite resistance traits were identified. The genomic regions, biological processes and candidate genes uncovered could lead to biomarkers for selecting more resilient sheep and improving herd welfare and productivity. The results obtained are the start point to identify molecular biomarkers related to indicator traits of gastrointestinal nematode resistance in Santa Inês sheep.

Assuntos

RESUMO

OBJECTIVE: To investigate the frequency of genetic diagnoses among infants with critical congenital heart disease (CHD) using a comprehensive cardiovascular genetics approach and to identify genotype-phenotype correlations. STUDY DESIGN: A retrospective chart review of patients evaluated by cardiovascular genetics in a pediatric cardiac intensive care unit from 2010 to 2015 was performed. Infants with CHD who were <1 month of age were included. CHD was classified using structured phenotype definitions. Cardiac and noncardiac phenotypes were tested for associations with abnormal genetic testing using χ1 and Fisher exact tests. RESULTS: Genetic evaluation was completed in 293 infants with CHD, of whom 213 had isolated congenital heart disease (iCHD) and 80 had multiple congenital anomalies. Overall, the yield of abnormal genetic testing was 26%. The multiple congenital anomalies cohort had a greater yield of genetic testing (39%) than the iCHD cohort (20%) (OR 2.7). Using a non-hierarchical CHD classification and excluding 22q11.2 deletion and common aneuploidies, right ventricular obstructive defects were associated with abnormal genetic testing (P = .0005). Extracardiac features associated with abnormal genetic testing included ear, nose, and throat (P = .003) and brain (P = .0001) abnormalities. A diagnosis of small for gestational age or intrauterine growth retardation also was associated with abnormal genetic testing (P = .0061), as was presence of dysmorphic features (P = .0033, OR 3.5). Infants without dysmorphia with iCHD or multiple congenital anomalies had similar frequencies of abnormal genetic testing. CONCLUSIONS: The present study provides evidence to support a comprehensive cardiovascular genetics approach in evaluating infants with critical CHD while also identifying important genotype-phenotype considerations.

Assuntos

RESUMO

BACKGROUND: Copy number variations are genome polymorphism that influence phenotypic variation and are an important source of genetic variation in populations. The aim of this study was to investigate genetic variability in the Mexican Creole chicken population using CNVs. RESULTS: The Hidden Markov Model of the PennCNV software detected a total of 1924 CNVs in the genome of the 256 samples processed with Axiom® Genome-Wide Chicken Genotyping Array (Affymetrix). The mapped CNVs comprised 1538 gains and 386 losses, resulting at population level in 1216 CNV regions (CNVRs), of which 959 gains, 226 losses and 31 complex (i.e. containing both losses and gains). The CNVRs covered a total of 47 Mb of the whole genome sequence length, corresponding to 5.12% of the chicken galGal4 autosome assembly. CONCLUSIONS: This study allowed a deep insight into the structural variation in the genome of unselected Mexican chicken population, which up to now has not been genetically characterized. The genomic study disclosed that the population, even if presenting extreme morphological variation, cannot be organized in differentiated genetic subpopulations. Finally this study provides a chicken CNV map based on the 600 K SNP chip array jointly with a genome-wide gene copy number estimates in a native unselected for more than 500 years chicken population.

Assuntos

RESUMO

OBJECTIVE: To determine whether children with attention deficit hyperactivity disorder (ADHD) and mild intellectual disability (ID) are a clinically distinct ADHD subgroup. STUDY DESIGN: This was a cross-sectional study comparing clinical characteristics (ADHD subtypes, total number of symptoms, and rates of common comorbidities) between children with ADHD and mild ID and those with ADHD and IQ test scores >70, and also between children with ADHD and ID and a general population sample of children with ID alone. The sample comprised a clinical sample of children with ADHD with ID (n = 97) and without ID (n = 874) and a general population sample of children with ID and without ADHD (n = 58). RESULTS: After correcting for multiple statistical tests, no differences were found between the 2 ADHD groups on any measure except the presence of conduct disorder (CD) symptoms and diagnoses. Children with ADHD and ID had higher rates of both (OR, 2.38; 95% CI, 1.71-3.32 and OR, 2.69; 95% CI, 1.69-4.28, respectively). Furthermore, children with ADHD and ID had significantly higher rates of oppositional defiant disorder (OR, 5.54; 95% CI, 2.86-10.75) and CD (OR, 13.66; 95% CI, 3.25-57.42) symptoms and a higher incidence of oppositional defiant disorder diagnoses (OR, 30.99; 95% CI, 6.38-150.39) compared with children with ID without ADHD. CONCLUSION: Children with ADHD and mild ID appear to be clinically typical of children with ADHD except for more conduct problems. This finding has implications for clinicians treating these children in terms of acknowledging the presence and impact of ADHD symptoms above and beyond ID and dealing with a comorbid CD.

Assuntos