Exome sequence analysis of siblings affected with Niemann-Pick type C disease

<p>Mutations in either the Niemann-Pick type C1 or C2 (NPC1/NPC2) gene result in a fatal lysosomal storage disorder, Niemann-Pick type C (NP-C) disease, for which there is no effective cure. The disease is characterized by systemic and neurodegenerative symptoms arising from toxic accumulation of unesterified cholesterol within the late endosome and lysosome, with a common cause of death for patients being respiratory failure or recurrent infection of pulmonary tissue. Interestingly, the disease symptoms are heterogeneous, with age of onset and severity varied, even among siblings with the same mutations in the NPC1 or NPC2 gene causing this monogenic disease. To date there is no clear explanation for disease severity in siblings with the same mutation. As siblings are raised in the same environment, the major hypothesis of this thesis is that there are genetic modifiers that explain variation in disease severity within siblings. To determine if there are genetic variants associated with disease severity, exomes were sequenced from five sibling pairs exhibiting divergent onset and progression of NPC disease. Out of 23,105 genes, 26 variants were identified that were predicted to have functional consequences in NP-C patients, of which homozygous MUC5B and MARCH8 variants segregated across siblings that exhibited increased and decreased severity of disease, respectively. A cluster of variants was discovered on chromosome 11 belonging to the matrix metalloproteinase (MMP) family. Further investigation of one of these variants, a frameshift insertion in MMP-12, confirmed that this locus regulates the accumulation of unesterified cholesterol in primary neurons derived from a murine model of NPC disease. However, this region on chromosome 11 did not have any statistically significant copy number alteration detectable through a depth of coverage analysis. Overall, these results provide groundwork into the sequence variants mediating disease severity, which with further investigations, may be novel pharmacological targets to treat NPC disease.</p>

Exome sequence analysis of siblings affected with Niemann-Pick type C disease

<p>Mutations in either the Niemann-Pick type C1 or C2 (NPC1/NPC2) gene result in a fatal lysosomal storage disorder, Niemann-Pick type C (NP-C) disease, for which there is no effective cure. The disease is characterized by systemic and neurodegenerative symptoms arising from toxic accumulation of unesterified cholesterol within the late endosome and lysosome, with a common cause of death for patients being respiratory failure or recurrent infection of pulmonary tissue. Interestingly, the disease symptoms are heterogeneous, with age of onset and severity varied, even among siblings with the same mutations in the NPC1 or NPC2 gene causing this monogenic disease. To date there is no clear explanation for disease severity in siblings with the same mutation. As siblings are raised in the same environment, the major hypothesis of this thesis is that there are genetic modifiers that explain variation in disease severity within siblings. To determine if there are genetic variants associated with disease severity, exomes were sequenced from five sibling pairs exhibiting divergent onset and progression of NPC disease. Out of 23,105 genes, 26 variants were identified that were predicted to have functional consequences in NP-C patients, of which homozygous MUC5B and MARCH8 variants segregated across siblings that exhibited increased and decreased severity of disease, respectively. A cluster of variants was discovered on chromosome 11 belonging to the matrix metalloproteinase (MMP) family. Further investigation of one of these variants, a frameshift insertion in MMP-12, confirmed that this locus regulates the accumulation of unesterified cholesterol in primary neurons derived from a murine model of NPC disease. However, this region on chromosome 11 did not have any statistically significant copy number alteration detectable through a depth of coverage analysis. Overall, these results provide groundwork into the sequence variants mediating disease severity, which with further investigations, may be novel pharmacological targets to treat NPC disease.</p>

Longitudinal study of stool-associated microbial taxa in sibling pairs with and without autism spectrum disorder

Autism Spectrum Disorder (ASD) is a complex neurodevelopmental disorder influenced by both genetic and environmental factors. Recently, gut dysbiosis has emerged as a powerful contributor to ASD symptoms. In this study, we recruited over 100 age-matched sibling pairs (between 2 and 8 years old) where one had an Autism ASD diagnosis and the other was developing typically (TD) (432 samples total). We collected stool samples over four weeks, tracked over 100 lifestyle and dietary variables, and surveyed behavior measures related to ASD symptoms. We identified 117 amplicon sequencing variants (ASVs) that were significantly different in abundance between sibling pairs across all three timepoints, 11 of which were supported by at least two contrast methods. We additionally identified dietary and lifestyle variables that differ significantly between cohorts, and further linked those variables to the ASVs they statistically relate to. Overall, dietary and lifestyle features were explanatory of ASD phenotype using logistic regression, however, global compositional microbiome features were not. Leveraging our longitudinal behavior questionnaires, we additionally identified 11 ASVs associated with changes in reported anxiety over time within and across all individuals. Lastly, we find that overall microbiome composition (beta-diversity) is associated with specific ASD-related behavioral characteristics.

Spatial Similarity of MRI-Visible Perivascular Spaces in Healthy Young Adult Twins

Purpose This study aims to determine whether genetic factors affect the location of dilated perivascular spaces (dPVS) by comparing healthy young twins and non-twin (NT) siblings. Methods A total of 700 healthy young adult twins and NT siblings (138 monozygotic (MZ) twin pairs, 79 dizygotic (DZ) twin pairs, and 133 NT sibling pairs) were collected from the Human Connectome Project dataset. dPVS was automatically segmented and normalized to standard space. Then, spatial similarity indices (mean squared error [MSE], structural similarity [SSIM], and dice similarity [DS]) were calculated for dPVS in the basal ganglia (BGdPVS) and white matter (WMdPVS) between paired subjects before and after propensity score matching of dPVS volumes between groups. Within-pair correlations for the regional volumes of dVPS were also assessed using the intraclass correlation coefficient (ICC). Results The spatial similarity of dPVS was significantly higher in MZ twins (higher DS [median, 0.382 and 0.310] and SSIM [0.963 and 0.887] and lower MSE [0.005 and 0.005] for BGdPVS and WMdPVS, respectively) than DZ twins (DS [0.121 and 0.119], SSIM [0.941 and 0.868], and MSE [0.010 and 0.011]) and NT siblings (DS [0.106 and 0.097], SSIM [0.924 and 0.848], and MSE [0.016 and 0.017]). No significant difference was found between DZ twins and NT siblings. Similar results were found even after subjects were matched according to dPVS volume. Regional dPVS volumes were also more correlated within pairs in MZ twins than DZ twins and NT siblings. Conclusion Our results suggest that genetic factors affect the location of dPVS.

Cohort Profile: Genetic data in the German Socio-Economic Panel Innovation Sample (Gene-SOEP)

The German Socio-Economic Panel (SOEP) serves a global research community by providing representative annual longitudinal data of private households in Germany. The sample provides a detailed life course perspective based on a rich collection of information about living conditions, socio-economic status, family relationships, personality, values, preferences, and health. We collected genetic data from 2,598 individuals in the SOEP Innovation Sample, yielding the first genotyped sample that is representative of the entire German population (Gene-SOEP). The Gene-SOEP sample is a longitudinal study that includes 107 full-sibling pairs, 501 parent-offspring pairs, and 152 parent-offspring trios that are overlapping with the parent-offspring pairs. We constructed a repository of 66 polygenic indices in the Gene-SOEP sample based on results from well-powered genome-wide association studies. The Gene-SOEP data provides a valuable resource to study individual differences, inequalities, life-course development, health, and interactions between genetic predispositions and environment.

Assessment of Dental Arch Parameters in Turkish Twins

Background: The aim of this study is to investigate the relative contributions of genetic and environmental factors to variations in dental dimensions in a sample of Turkish twins, and to estimate heritability using dental casts. Study design: The study samples were selected from the twin children between 3–15 years old who referred for their first dental examination. Fifty nine monozygotic and one hundred and forty three dizygotic twin pairs were examined in the study. The alginate impression material used to create the plaster model of maxilla and mandible. Anterior arch width, posterior arch width, arch length and arch circumference were measured on models prepared from measurements taken for both maxilla and mandible with digital caliper. The similarities and differences of the measurements were compared between pairs of twins and zygocytes. Morever, the effects of bad oral habits, bruxism, a result of psychosocial factors on measurements were examined. Statistical analysis was performed using Paired T Test, Wilcoxon Test and Mann Whitney U test. Results: A total of 404 dental models of 118 (29.2%) monozygotic and 286 (70.8%) dizygotic twins were evaluated. There was no statistical difference between sibling pairs in both monozygotic and dizygotic twins. The measurement similarity between twin siblings differed according to zygosity in all measurements (p&lt;0.05). It has been observed that the finger sucking and mouth breathing affect the dental arch measurements (p&lt;0.05). Conclusion: These results indicate that the differences in dental arch dimensions between monozygotic twin pairs are less than the difference between dizygotic twin pairs.

Compound heterozygous variants in SHQ1 are associated with a spectrum of neurological features, including early-onset dystonia

SHQ1 is essential for biogenesis of H/ACA ribonucleoproteins, a class of molecules important for processing ribosomal RNAs, modifying spliceosomal small nuclear RNAs and stabilizing telomerase. Components of the H/ACA ribonucleoprotein complex have been linked to neurological developmental defects. Here, we report two sibling pairs from unrelated families with compound heterozygous variants in SHQ1. Exome sequencing was used to detect disease causing variants, which were submitted to ‘matching’ platforms linked to MatchMaker Exchange. Phenotype comparisons supported these matches. The affected individuals present with early-onset dystonia, with individuals from one family displaying additional neurological phenotypes, including neurodegeneration. As a result of cerebrospinal fluid studies suggesting possible abnormal dopamine metabolism, a trial of levodopa replacement therapy was started but no clear response was noted. We show that fibroblasts from affected individuals have dramatic loss of SHQ1 protein. Variants from both families were expressed in Saccharomyces cerevisiae, resulting in a strong reduction in H/ACA snoRNA production and remarkable defects in rRNA processing and ribosome formation. Our study identifies SHQ1 as associated with neurological disease, including early-onset dystonia, and begins to delineate the molecular etiology of this novel condition.

Characteristics of 1270 Chinese sibling pairs with cancer

Background Previous research found that the cancer history of an individual’s sibling may be a better indicator than that of the parents. We aim to provide recommendations for opportunistic screening for individuals whose sibling had been diagnosed with cancer. Methods During the physical examination in Cancer Hospital, Chinese Academy of Medical Sciences, 43,300 people were asked if they have at least two siblings who developed cancer. Results A total of 1270 sibling-pairs from 766 families developed cancer, including 367 pairs of brothers (Bro-pairs), 368 pairs of sisters (Sis-pairs), and 535 pairs of brother-and-sister (BroSis-pairs). The mean ages at diagnosis of cancer for the three groups were from 58 to 62 years. More than half of Bro-pairs (55.3%) or Sis-pairs (51.1%) had cancer from the same systemic origin, and more than a quarter of Bro-pairs (28.1%) and Sis-pairs (37.2%) developed the same type of cancer. However, only 36.0% of BroSis-pairs developed cancers from the same systemic origin, and 18.9% developed the same type of cancer. In Bro-pairs and BroSis-pairs, lung cancer and digestive system cancer were the most common cancers, while in Sis-pairs, breast cancer, lung cancer, cervical cancer, liver cancer and thyroid cancer were the most common ones. Conclusions If an individual’s sibling is diagnosed with cancer, the individual should consider participating in opportunistic screening annually, especially for lung cancer and digestive system cancers for both sexes. For sisters, breast cancer, cervical cancer and thyroid cancer should be screened early. Additionally, genetic services are essential for individuals who have siblings with cancer.

Genome-Wide Linkage and Association Study of Childhood Gender Nonconformity in Males

Male sexual orientation is influenced by environmental and complex genetic factors. Childhood gender nonconformity (CGN) is one of the strongest correlates of homosexuality with substantial familiality. We studied brothers in families with two or more homosexual brothers (409 concordant sibling pairs in 384 families, as well as their heterosexual brothers), who self-recalled their CGN. To map loci for CGN, we conducted a genome-wide linkage scan (GWLS) using SNP genotypes. The strongest linkage peaks, each with significant or suggestive two-point LOD scores and multipoint LOD score support, were on chromosomes 5q31 (maximum two-point LOD = 4.45), 6q12 (maximum two-point LOD = 3.64), 7q33 (maximum two-point LOD = 3.09), and 8q24 (maximum two-point LOD = 3.67), with the latter not overlapping with previously reported strongest linkage region for male sexual orientation on pericentromeric chromosome 8. Family-based association analyses were used to identify associated variants in the linkage regions, with a cluster of SNPs (minimum association p = 1.3 × 10–8) found at the 5q31 linkage peak. Genome-wide, clusters of multiple SNPs in the 10–6 to 10–8p-value range were found at chromosomes 5p13, 5q31, 7q32, 8p22, and 10q23, highlighting glutamate-related genes. This is the first reported GWLS and genome-wide association study on CGN. Further increasing genetic knowledge about CGN and its relationships to male sexual orientation should help advance our understanding of the biology of these associated traits.