Family-based Linkage Analysis Research Articles

Whole Genome Analysis in Consanguineous Families Reveals New Loci for Speech Sound Disorder (SSD).

Speech is the most common means of communication in humans. Any defect in accurate speech production ability results in the development of speech sound disorder (SSD), a condition that can significantly impair an individual's academic performance, social interactions, and relationships with peers and adults. This study investigated the genetic basis of SSD in three Pakistani families. We performed family-based genome-wide parametric linkage analysis and homozygosity mapping in three consanguineous families with SSD from the Punjab province of Pakistan. The Test for Assessment of Articulation and Phonology in Urdu (TAAPU) was used to analyze the speech articulation data and determine the Percentage Correct Consonants (PCC) score. The PCC score defined the affected and unaffected individuals in each family. Parametric linkage analysis revealed a linkage to chromosome 5 (5q21.3-5q23.1) with a significant logarithm of the odds (LOD) score of 3.13 in a Pakistani family with specific language impairment-97 (PKSLI-97) under an autosomal recessive mode of inheritance. The other two families showed a suggestive linkage at 6p22.1, 14q12, and 16q12.1 under the recessive mode of inheritance. Interestingly, homozygosity mapping showed a loss of heterozygosity in the linkage region at 5q15-5q23.1, shared among seven affected (mostly in the younger generation) and one unaffected individual of PKSLI-97. Our analysis identified the 6p22 locus previously implicated in dyslexia, childhood apraxia of speech (CAS), and language impairment, confirming the role of KIAA0319 and DCDC2 in this locus. These findings provide statistical evidence for the genomic regions associated with articulation disorder and offer future opportunities to further the role of genes in speech production.

Network-based quantitative trait linkage analysis of microbiome composition in inflammatory bowel disease families.

Introduction: Inflammatory bowel disease (IBD) is characterized by a dysbiosis of the gut microbiome that results from the interaction of the constituting taxa with one another, and with the host. At the same time, host genetic variation is associated with both IBD risk and microbiome composition. Methods: In the present study, we defined quantitative traits (QTs) from modules identified in microbial co-occurrence networks to measure the inter-individual consistency of microbial abundance and subjected these QTs to a genome-wide quantitative trait locus (QTL) linkage analysis. Results: Four microbial network modules were consistently identified in two cohorts of healthy individuals, but three of the corresponding QTs differed significantly between IBD patients and unaffected individuals. The QTL linkage analysis was performed in a sub-sample of the Kiel IBD family cohort (IBD-KC), an ongoing study of 256 German families comprising 455 IBD patients and 575 first- and second-degree, non-affected relatives. The analysis revealed five chromosomal regions linked to one of three microbial module QTs, namely on chromosomes 3 (spanning 10.79 cM) and 11 (6.69 cM) for the first module, chr9 (0.13 cM) and chr16 (1.20 cM) for the second module, and chr13 (19.98 cM) for the third module. None of these loci have been implicated in a microbial phenotype before. Discussion: Our study illustrates the benefit of combining network and family-based linkage analysis to identify novel genetic drivers of microbiome composition in a specific disease context.

The Role of Transcription Factors in Coronary Artery Disease and Myocardial Infarction.

Coronary artery disease (CAD) and its main complication, myocardial infarction (MI), is a complex disease caused by environmental and genetic factors and their interaction. Family-based linkage analysis and genome-wide association studies have indicated many of genetic variations related to CAD and MI in recent years. Some are in the coding sequence, which mediates the coding protein, while others are in the non-coding region, which affects the expression of adjacent genes and forms differential gene expression. These variants and differential expressions will have varying degrees of impact on the development of the cardiovascular system and normal heart electrical activity function, subsequently leading to CAD and MI. Among these affected genes, some Transcription Factors (TFs), as important means of transcriptional regulation, have a key role in the pathogenesis of coronary artery disease and myocardial infarction. The GATAs binding protein 2 (GATA2) enhances monocyte adhesion and promoted vessel wall permeabilization through vascular EC adhesion molecule 1 (VCAM-1) upregulation, further revealing its atherosclerosis-promoting role. Myocyte enhancer factor 2 (MEF2) has a role in fostering many functions of the atherosclerotic endothelium and is a potential therapeutic target for atherosclerosis, thrombosis, and inflammation. Nuclear factor-kappa B (NF-κB) is an important promoter of vascular endothelial growth factor (VEGF)-driven angiogenesis, and its pathway has a key role in atherosclerosis-related complications such as angiogenesis, inflammation, apoptosis, and immune effects. Activating transcription factor 3 (ATF3) may be a novel prognostic biomarker and therapeutic target for atherosclerosis. The important role of signal transducer and activator of transcription 3 (STAT3) (especially in mitochondria) in endothelial cells (EC) dysfunction, inflammation, macrophage polarization and immunity in atherosclerosis.

Clinical and genetic analysis of familial neuromyelitis optica spectrum disorder in Chinese: associated with ubiquitin-specific peptidase USP18 gene variants

BackgroundFamilial clustering of neuromyelitis optica spectrum disorder (NMOSD) was present in Chinese. This study was to investigate the clinical characteristics and genetic background of familial NMOSD.MethodsThrough questionnaires in four medical...

The Emerging Genetic Landscape of Hirschsprung Disease and Its Potential Clinical Applications.

Hirschsprung disease (HSCR) is the leading cause of neonatal functional intestinal obstruction. It is a rare congenital disease with an incidence of one in 3,500–5,000 live births. HSCR is characterized by the absence of enteric ganglia in the distal colon, plausibly due to genetic defects perturbing the normal migration, proliferation, differentiation, and/or survival of the enteric neural crest cells as well as impaired interaction with the enteric progenitor cell niche. Early linkage analyses in Mendelian and syndromic forms of HSCR uncovered variants with large effects in major HSCR genes including RET, EDNRB, and their interacting partners in the same biological pathways. With the advances in genome-wide genotyping and next-generation sequencing technologies, there has been a remarkable progress in understanding of the genetic basis of HSCR in the past few years, with common and rare variants with small to moderate effects being uncovered. The discovery of new HSCR genes such as neuregulin and BACE2 as well as the deeper understanding of the roles and mechanisms of known HSCR genes provided solid evidence that many HSCR cases are in the form of complex polygenic/oligogenic disorder where rare variants act in the sensitized background of HSCR-associated common variants. This review summarizes the roadmap of genetic discoveries of HSCR from the earlier family-based linkage analyses to the recent population-based genome-wide analyses coupled with functional genomics, and how these discoveries facilitated our understanding of the genetic architecture of this complex disease and provide the foundation of clinical translation for precision and stratified medicine.

A linkage and exome study of multiplex families with bipolar disorder implicates rare coding variants of ANK3 and additional rare alleles at 10q11-q21.

BackgroundBipolar disorder is a highly heritable psychiatric condition for which specific genetic factors remain largely unknown. In the present study, we used combined whole-exome sequencing and linkage analysis to identify risk loci and dissect the contribution of common and rare variants in families with a high density of illness.MethodsOverall, 117 participants from 15 Australian extended families with bipolar disorder (72 with affective disorder, including 50 with bipolar disorder type I or II, 13 with schizoaffective disorder–manic type and 9 with recurrent unipolar disorder) underwent whole-exome sequencing. We performed genome-wide linkage analysis using MERLIN and conditional linkage analysis using LAMP. We assessed the contribution of potentially functional rare variants using a gene-based segregation test.ResultsWe identified a significant linkage peak on chromosome 10q11-q21 (maximal single nucleotide polymorphism = rs10761725; exponential logarithm of the odds [LODexp] = 3.03; empirical p = 0.046). The linkage interval spanned 36 protein-coding genes, including a gene associated with bipolar disorder, ankyrin 3 (ANK3). Conditional linkage analysis showed that common ANK3 risk variants previously identified in genome-wide association studies — or variants in linkage disequilibrium with those variants — did not explain the linkage signal (rs10994397 LOD = 0.63; rs9804190 LOD = 0.04). A family-based segregation test with 34 rare variants from 14 genes under the linkage interval suggested rare variant contributions of 3 brain-expressed genes: NRBF2 (p = 0.005), PCDH15 (p = 0.002) and ANK3 (p = 0.014).LimitationsWe did not examine non-coding variants, but they may explain the remaining linkage signal.ConclusionCombining family-based linkage analysis with next-generation sequencing data is effective for identifying putative disease genes and specific risk variants in complex disorders. We identified rare missense variants in ANK3, PCDH15 and NRBF2 that could confer disease risk, providing valuable targets for functional characterization.

Genetics of Asthma and Allergic Diseases.

Asthma genes have been identified through a range of approaches, from candidate gene association studies and family-based genome-wide linkage analyses to genome-wide association studies (GWAS). The first GWAS of asthma, reported in 2007, identified multiple markers on chromosome 17q21 as associates of the childhood-onset asthma. This remains the best replicated asthma locus to date. However, notwithstanding undeniable successes, genetic studies have produced relatively heterogeneous results with limited replication, and despite considerable promise, genetics of asthma and allergy has, so far, had limited impact on patient care, our understanding of disease mechanisms, and development of novel therapeutic targets. The paucity of precise replication in genetic studies of asthma is partly explained by the existence of numerous gene-environment interactions. Another important issue which is often overlooked is that of time of the assessment of the primary outcome(s) and the relevant environmental exposures. Most large GWASs use the broadest possible definition of asthma to increase the sample size, but the unwanted consequence of this is increased phenotypic heterogeneity, which dilutes effect sizes. One way of addressing this is to precisely define disease subtypes (e.g. by applying novel mathematical approaches to rich phenotypic data) and use these latent subtypes in genetic studies.

Genome-wide linkage analysis of carotid artery traits in exceptionally long-lived families

Background and aimsAtherosclerosis develops with age and is partially controlled by genetics. Research to date has identified common variants with small effects on atherosclerosis related traits. We aimed to use family-based genome-wide linkage analysis to identify chromosomal regions potentially harboring rare variants with larger effects for atherosclerosis related traits. MethodsParticipants included 2205 individuals from the Long Life Family Study (LLFS), which recruited families with exceptional longevity from Boston, New York, Pittsburgh, and Denmark. Participants underwent B-mode ultrasonography of the carotid arteries to measure intima-media thickness (IMT), inter-adventitial diameter (IAD), and plaque presence and severity. We conducted residual heritability and genome-wide linkage analyses adjusted for age, age2, sex, and field center using pedigree-based maximum-likelihood methods in SOLAR. ResultsAll carotid traits were significantly heritable with a range of 0.68 for IAD to 0.38 for IMT. We identified three chromosomal regions with linkage to IAD (3q13; max LOD 5.3), plaque severity (17q22-q23, max LOD 3.2), and plaque presence (17q24, max LOD 3.1). No common allelic variants within these linkage peaks were associated with the carotid artery traits. ConclusionsWe identified three chromosomal regions with evidence of linkage to carotid artery diameter and atherosclerotic plaque in exceptionally long-lived families. Since common allelic variants within our linkage peaks did not account for our findings, future follow-up resequencing of these regions in LLFS families should help advance our understanding of atherosclerosis, CVD, and healthy vascular aging.

Genetic Aspects of Keratoconus: A Literature Review Exploring Potential Genetic Contributions and Possible Genetic Relationships with Comorbidities.

IntroductionKeratoconus (KC) is a complex, genetically heterogeneous, multifactorial degenerative disorder that is accompanied by corneal ectasia which usually progresses asymmetrically. With an incidence of approximately 1 per 2000 and 2 cases per 100,000 population presenting annually, KC follows an autosomal recessive or dominant pattern of inheritance and is, apparently, associated with genes that interact with environmental, genetic, and/or other factors. This is an important consideration in refractive surgery in the case of familial KC, given the association of KC with other genetic disorders and the imbalance between dizygotic twins. The present review attempts to identify the genetic loci contributing to the different KC clinical presentations and relate them to the common genetically determined comorbidities associated with KC.MethodsThe PubMed, MEDLINE, Google Scholar, and GeneCards databases were screened for KC-related articles published in English between January 2006 and November 2017. Keyword combinations of “keratoconus,” “risk factor(s),” “genetics,” “genes,” “genetic association(s),” and “cornea” were used. In total, 217 articles were retrieved and analyzed, with greater weight placed on the more recent literature. Further bibliographic research based on the 217 articles revealed another 124 relevant articles that were included in this review. Using the reviewed literature, an attempt was made to correlate genes and genetic risk factors with KC characteristics and genetically related comorbidities associated with KC based on genome-wide association studies, family-based linkage analysis, and candidate-gene approaches.ResultsAn association matrix between known KC-related genes and KC symptoms and/or clinical signs together with an association matrix between identified KC genes and genetically related KC comorbidities/syndromes were constructed.ConclusionTwenty-four genes were identified as potential contributors to KC and 49 KC-related comorbidities/syndromes were found. More than 85% of the known KC-related genes are involved in glaucoma, Down syndrome, connective tissue disorders, endothelial dystrophy, posterior polymorphous corneal dystrophy, and cataract.

Aristaless-Like Homeobox protein 1 (ALX1) variant associated with craniofacial structure and frontonasal dysplasia in Burmese cats

Frontonasal dysplasia (FND) can have severe presentations that are medically and socially debilitating. Several genes are implicated in FND conditions, including Aristaless-Like Homeobox 1 (ALX1), which is associated with FND3. Breeds of cats are selected and bred for extremes in craniofacial morphologies. In particular, a lineage of Burmese cats with severe brachycephyla is extremely popular and is termed Contemporary Burmese. Genetic studies demonstrated that the brachycephyla of the Contemporary Burmese is a simple co-dominant trait, however, the homozygous cats have a severe craniofacial defect that is incompatible with life. The craniofacial defect of the Burmese was genetically analyzed over a 20 year period, using various genetic analysis techniques. Family-based linkage analysis localized the trait to cat chromosome B4. Genome-wide association studies and other genetic analyses of SNP data refined a critical region. Sequence analysis identified a 12bp in frame deletion in ALX1, c.496delCTCTCAGGACTG, which is 100% concordant with the craniofacial defect and not found in cats not related to the Contemporary Burmese.

Genome-wide association analysis reveals genetic loci and candidate genes for meat quality traits in Chinese Laiwu pigs

Meat quality traits have economically significant impacts on the pig industry, and can be improved using molecular approaches in pig breeding. Since 1994 when the first genome-wide scan for quantitative trait loci (QTLs) in pig was reported, over the past two decades, numerous QTLs have been identified for meat quality traits by family based linkage analyses. However, little is known about the genetic variants for meat quality traits in Chinese purebred or outbred populations. To unveil it, we performed a genome-wide association study for 10 meat quality traits in Chinese purebred Laiwu pigs. In total, 75 significant SNPs (P<1.01×10(-6)) and 33 suggestive SNPs (P<2.03×10(-5)) were identified. On SSC12, a region between 56.22 and 61.49Mb harbored a cluster of SNPs that were associated with meat color parameters (L*, lightness; a*, redness; b*, yellowness) and moisture content of longissimus muscle (LM) and semimembranosus muscle at the genome-wide significance level. A region on SSC4 also has pleiotropic effects on moisture content and drip loss of LM. In addition, this study revealed at least five novel QTLs and several candidate genes including 4-linked MYH genes (MYH1, MYH2, MYH3, and MYH13), MAL2, LPAR1, and PRKAG3 at four significant loci. Except for the SSC12 QTL, other QTLs are likely tissue-specific. These results provide new insights into the genetic basis of meat quality traits in Chinese Laiwu pigs and some significant SNPs reported here could be incorporated into the selection programs involving this breed.

The role of transcription factors in atrial fibrillation.

Atrial fibrillation (AF) is a complex disease that results from genetic and environmental factors and their interactions. In recent years, genome-wide association studies (GWAS) and family-based linkage analysis have found amounts of genetic variants associated with AF. Some of them lie in coding sequences and thus mediate the encoded proteins, some in non-coding regions and influence the expression of adjacent genes. These variants exert influence on the development of cardiovascular system and normal cardiac electrical activity in different levels, and eventually contribute to the occurrence of AF. Among these affected genes, as a crucial means of transcriptional regulation, several transcription factors play important roles in the pathogenesis of AF. In this review, we will focus on the potential role of PITX2, PRRX1, ZHFX3, TBX5, and NKX2.5 in AF.

The genetic and environmental factors for keratoconus.

Keratoconus (KC) is the most common cornea ectatic disorder. It is characterized by a cone-shaped thin cornea leading to myopia, irregular astigmatism, and vision impairment. It affects all ethnic groups and both genders. Both environmental and genetic factors may contribute to its pathogenesis. This review is to summarize the current research development in KC epidemiology and genetic etiology. Environmental factors include but are not limited to eye rubbing, atopy, sun exposure, and geography. Genetic discoveries have been reviewed with evidence from family-based linkage analysis and fine mapping in linkage region, genome-wide association studies, and candidate genes analyses. A number of genes have been discovered at a relatively rapid pace. The detailed molecular mechanism underlying KC pathogenesis will significantly advance our understanding of KC and promote the development of potential therapies.

Molecular Genetic Evidence for Shared Etiology of Autism and Prodigy

Child prodigies are rare individuals with an exceptional working memory and unique attentional skills that may facilitate the attainment of professional skill levels at an age well before what is observed in the general population. Some characteristics of prodigy have been observed to be quantitatively similar to those observed in autism spectrum disorder (ASD), suggesting possible shared etiology, though objectively validated prodigies are so rare that evidence has been sparse. We performed a family-based genome-wide linkage analysis on 5 nuclear and extended families to search for genetic loci that influence the presence of both prodigy and ASD, assuming that the two traits have the same genetic etiology in the analysis model in order to find shared loci. A shared locus on chromosome 1p31-q21 reached genome-wide significance with two extended family-based linkage methods consisting of the Bayesian PPL method and the LOD score maximized over the trait parameters (i.e., MOD), yielding a simulation-based empirical significance of p = 0.000742 and p = 0.000133, respectively. Within linkage regions, we performed association analysis and assessed if copy number variants could account for the linkage signal. No evidence of specificity for either the prodigy or the ASD trait was observed. This finding suggests that a locus on chromosome 1 increases the likelihood of both prodigy and autism in these families.

Homozygous loss of DIAPH1 is a novel cause of microcephaly in humans.

The combination of family-based linkage analysis with high-throughput sequencing is a powerful approach to identifying rare genetic variants that contribute to genetically heterogeneous syndromes. Using parametric multipoint linkage analysis and whole exome sequencing, we have identified a gene responsible for microcephaly (MCP), severe visual impairment, intellectual disability, and short stature through the mapping of a homozygous nonsense alteration in a multiply-affected consanguineous family. This gene, DIAPH1, encodes the mammalian Diaphanous-related formin (mDia1), a member of the diaphanous-related formin family of Rho effector proteins. Upon the activation of GTP-bound Rho, mDia1 generates linear actin filaments in the maintenance of polarity during adhesion, migration, and division in immune cells and neuroepithelial cells, and in driving tangential migration of cortical interneurons in the rodent. Here, we show that patients with a homozygous nonsense DIAPH1 alteration (p.Gln778*) have MCP as well as reduced height and weight. diap1 (mDia1 knockout (KO))-deficient mice have grossly normal body and brain size. However, our histological analysis of diap1 KO mouse coronal brain sections at early and postnatal stages shows unilateral ventricular enlargement, indicating that this mutant mouse shows both important similarities as well as differences with human pathology. We also found that mDia1 protein is expressed in human neuronal precursor cells during mitotic cell division and has a major impact in the regulation of spindle formation and cell division.

Prenatal genetic diagnosis of oculocutaneous albinism type II through mutation detection combined with SNPs linkage analysis

To provide prenatal diagnosis for two families affected with oculocutaneous albinism (OCA), in both of which only 1 pathogenic allele has been identified. To determine the clinical classification of OCA through DNA sequencing for TYR, P, TYRP1 and SLC45A2 genes in combination with phenotype analysis. Prenatal diagnosis was carried out by direct sequencing and intragenic SNPs family-based linkage analysis. In the first family, only 1 heterozygous mutation c.1255C>T was found in the proband, which was inherited from her mother. Together with its clinical phenotype, the proband was suspected to have OCA2 Screening of amniotic fluid, however, has found no mutation. With family-based linkage analysis, the fetus was deemed to be an OCA2 carrier. In the second family, again only one heterozygous mutation c.1920_1949 del30bp and ins AACA was found in the proband, which was inherited from her father. Together with its clinical phenotype, the proband was suspected to have OCA2. Screening of amniotic fluid has revealed a heterozygous mutation c.1920_1949 del30bp and ins AACA. By family-based linkage analysis, the fetus was deemed to be an OCA2 carrier. Both fetuses had a normal phenotype at birth. Prenatal genetic diagnosis has been provided for the first time for two families affected with OCA, in which only 1 pathogenic mutant allele was detected. The combined mutation detection and SNPs linkage analysis has turned out to be successful.

Genetic and Epigenetic Factors in Etiology of Diabetes Mellitus Type 1

Diabetes mellitus type 1 (T1D) is a complex disease resulting from the interplay of genetic, epigenetic, and environmental factors. Recent progress in understanding the genetic basis of T1D has resulted in an increased recognition of childhood diabetes heterogeneity. After the initial success of family-based linkage analyses, which uncovered the strong linkage and association between HLA gene variants and T1D, genome-wide association studies performed with high-density single-nucleotide polymorphism genotyping platforms provided evidence for a number of novel loci, although fine mapping and characterization of these new regions remains to be performed. T1D is one of the most heritable common diseases, and among autoimmune diseases it has the largest range of concordance rates in monozygotic twins. This fact, coupled with evidence of various epigenetic modifications of gene expression, provides convincing proof of the complex interplay between genetic and environmental factors. In T1D, epigenetic phenomena, such as DNA methylation, histone modifications, and microRNA dysregulation, have been associated with altered gene expression. Increasing epidemiologic and experimental evidence supports the role of genetic and epigenetic alterations in the etiopathology of diabetes. We discuss recent results related to the role of genetic and epigenetic factors involved in development of T1D.

Identification Of The Disease-Causing Mutation In Autosomal Dominant Familial Immune Thrombocytopenia By Genome-Wide Linkage Analysis and Whole Genome Sequencing

BackgroundImmune thrombocytopenia (ITP) is an autoimmune-mediated bleeding disorder characterized by low blood platelet count. The etiology of ITP remains an area of active research, and the predisposing risk factors are unclear. Genetic studies on the hereditary form of ITP, which is very rare, may help to decipher the underlying cause of disease predisposition. Herein we report a four-generation family from Michigan with multiple members affected with ITP during childhood (Figure 1). The pedigree is consistent with an autosomal dominant inheritance pattern. We performed the first family-based genetic study of ITP using genome-wide linkage analysis in combination with whole genome sequencing (WGS) in order to identify the disease-causing mutation. [Display omitted] MethodsPeripheral blood specimens were collected from eight family members for DNA extraction and clinical information of the four affected individuals was obtained. Genome-wide genotyping was performed with high density Illumina HumanOmni1-Quad BeadChips, followed by linkage analysis with MERLIN. Two affected family members (II2 and IV1) were chosen for WGS on Illumina HiSeq with 30X coverage. Sequence alignment and variant calling were done with DNAnexus. The variants, which are common (minor allele frequency >=1%), outside of the linkage region, not shared by the two members, or silent mutations, were removed. Copy number variation (CNV) data obtained from the arrays were analyzed to identify co-segregation with the phenotype. Conservation of sequence, predicted impact on protein function and biological plausibility were considered to further filter the variants. The final disease-causing candidate variant NOS3 (nitric oxide synthase 3) c.1267G>A was validated by Sanger sequencing. The potential impact of this variant on the NOS3 protein function was evaluated by protein structure modeling. Furthermore, the wild-type and mutant NOS3 expression constructs were generated and transfected into COS-7 cells for transient protein expression. The total NOx production (nitrite and nitrate), measured with a HPLC assay, was normalized to expressed NOS3 and phospho-NOS3 protein, quantitated with western blot. ResultsMutations within the 5'UTR of ANKRD26 gene were reported to account for the autosomal dominant thrombocytopenia in some cases; however, no mutation was detected within the 5'UTR of ANKRD26 in this family and the linkage analysis also confirmed ANKRD26 gene being outside of the linkage region. The disease locus is mapped to a total of 215MB chromosomal region (6.92% of genome) by parametric linkage analysis with a LOD score of 1.1953. Within the linkage region, no CNV co-segregates with the phenotype. After removing common variants from those shared by II2 and IV1, no indel variants and 12 non-synonymous SNP variants were identified within the coding sequence. Following further removal of the SNP variants with low conservation scores or predicted by Polyphen to be a benign change on protein function, 5 variants from 5 genes remained, of which NOS3 is most biologically plausible based on the well-known role of NO in autoimmunity and oxidative stress. The co-segregation of the NOS3 variant with the phenotype of ITP in this family was validated via Sanger sequencing. Finally, an in vitro study demonstrated reduced NO production by mutant NOS3 protein compared to wild type NOS3 protein. ConclusionIn this first genetic study of familial ITP, we identified the disease-causing mutation by using family-based linkage analysis and WGS. This finding will not only uncover the underlying genetic cause for the predisposition to childhood ITP in this Michigan kindred, but may also provide useful insights on the understanding of the pathogenesis of ITP in general. Disclosures:No relevant conflicts of interest to declare.

Association between Interferon Regulatory Factor 6 Gene Polymorphisms and Nonsyndromic Cleft Lip with or without Cleft Palate in a Chinese Population

Objective : To further confirm the association between two IRF6 single nucleotide polymorphisms and nonsyndromic cleft lip with or without cleft palate in a Chinese population. Participants : A total of 106 nonsyndromic cleft lip with or without cleft palate case trios and 129 control trios. Intervention : Two IRF6 single nucleotide polymorphisms, rs2235371 and rs642961, were genotyped for all case and control families. Case-control analysis and family-based linkage analysis were both performed for the two single nucleotide polymorphisms. Results : The genotype and allele frequencies of rs2235371 (odds ratioAG+AA vs. GG, 0.581; 95% confidence interval, 0.345 to 0.976; P = .039) and rs642961 (odds ratioAG+AA vs. GG, 5.389; 95% confidence interval, 2.936 to 9.893; P = 5e-08) were significantly higher in nonsyndromic cleft lip with or without cleft palate patients compared with controls. There was an obvious dosage effect of allele A at rs642961. The transmission of a major allele (G) of rs2235371 and a minor allele (A) of rs642961 was in disequilibrium (P < .05) in complete case-parent trios. The association between the two single nucleotide polymorphisms and nonsyndromic cleft lip with or without cleft palate was confirmed by the Family-Based Association Test for rs642961 (P = .008), but there was no significance for rs2235371 (P = 0.057). Haplotype analysis found that rs2235371 G/rs642961 A haplotype increased the risk of nonsyndromic cleft lip with or without cleft palate (P = 2.42e-07); whereas, rs2235371 A/rs642961 G haplotype reduced the risk of nonsyndromic cleft lip with or without cleft palate (P = 4.37e-05). No evidence of linkage disequilibrium was found between the two single nucleotide polymorphisms (D' = 0.303, r(2) = 0.017). Conclusion : Our results confirmed the involvement of the IRF6 variants rs642961 and rs2235371 in the etiology of nonsyndromic cleft lip with or without cleft palate in a Chinese population.

Comprehensive genomic analyses associate UGT8 variants with musical ability in a Mongolian population

BackgroundMusical abilities such as recognising music and singing performance serve as means for communication and are instruments in sexual selection. Specific regions of the brain have been found to be...