An algorithm to identify patients aged 0-3 with rare genetic disorders.

BACKGROUND: With over 7000 Mendelian disorders, identifying children with a specific rare genetic disorder diagnosis through structured electronic medical record data is challenging given incompleteness of records, inaccurate medical diagnosis coding, as well as heterogeneity in clinical symptoms and procedures for specific disorders. We sought to develop a digital phenotyping algorithm (PheIndex) using electronic medical records to identify children aged 0-3 diagnosed with genetic disorders or who present with illness with an increased risk for genetic disorders. RESULTS: Through expert opinion, we established 13 criteria for the algorithm and derived a score and a classification. The performance of each criterion and the classification were validated by chart review. PheIndex identified 1,088 children out of 93,154 live births who may be at an increased risk for genetic disorders. Chart review demonstrated that the algorithm achieved 90% sensitivity, 97% specificity, and 94% accuracy. CONCLUSIONS: The PheIndex algorithm can help identify when a rare genetic disorder may be present, alerting providers to consider ordering a diagnostic genetic test and/or referring a patient to a medical geneticist.

Deletion of ERF and CIC causes abnormal skull morphology and global developmental delay.

The ETS2 repressor factor (ERF) is a transcription factor in the RAS-MEK-ERK signal transduction cascade that regulates cell proliferation and differentiation, and pathogenic sequence variants in the ERF gene cause variable craniosynostosis inherited in an autosomal dominant pattern. The reported ERF variants are largely loss-of-function, implying haploinsufficiency as a primary disease mechanism; however, ERF gene deletions have not been reported previously. Here we describe three probands with macrocephaly, craniofacial dysmorphology, and global developmental delay. Clinical genetic testing for fragile X and other relevant sequencing panels were negative; however, chromosomal microarray identified heterozygous deletions (63.7-583.2 kb) on Chromosome 19q13.2 in each proband that together included five genes associated with Mendelian diseases (ATP1A3, ERF, CIC, MEGF8, and LIPE). Parental testing indicated that the aberrations were apparently de novo in two of the probands and were inherited in the one proband with the smallest deletion. Deletion of ERF is consistent with the reported loss-of-function ERF variants, prompting clinical copy-number-variant classifications of likely pathogenic. Moreover, the recent characterization of heterozygous loss-of-function CIC sequence variants as a cause of intellectual disability and neurodevelopmental disorders inherited in an autosomal dominant pattern is also consistent with the developmental delays and intellectual disabilities identified among the two probands with CIC deletions. Taken together, this case series adds to the previously reported patients with ERF and/or CIC sequence variants and supports haploinsufficiency of both genes as a mechanism for a variable syndromic cranial phenotype with developmental delays and intellectual disability inherited in an autosomal dominant pattern.

Genome-Wide Analysis of nsLTP Gene Family and Identification of SiLTPs Contributing to High Oil Accumulation in Sesame (Sesamum indicum L.).

The biosynthesis and storage of lipids in oil crop seeds involve many gene families, such as nonspecific lipid-transfer proteins (nsLTPs). nsLTPs are cysteine-rich small basic proteins essential for plant development and survival. However, in sesame, information related to nsLTPs was limited. Thus, the objectives of this study were to identify the Sesamum indicum nsLTPs (SiLTPs) and reveal their potential role in oil accumulation in sesame seeds. Genome-wide analysis revealed 52 SiLTPs, nonrandomly distributed on 10 chromosomes in the sesame variety Zhongzhi 13. Following recent classification methods, the SiLTPs were divided into nine types, among which types I and XI were the dominants. We found that the SiLTPs could interact with several transcription factors, including APETALA2 (AP2), DNA binding with one finger (Dof), etc. Transcriptome analysis showed a tissue-specific expression of some SiLTP genes. By integrating the SiLTPs expression profiles and the weighted gene co-expression network analysis (WGCNA) results of two contrasting oil content sesame varieties, we identified SiLTPI.23 and SiLTPI.28 as the candidate genes for high oil content in sesame seeds. The presumed functions of the candidate gene were validated through overexpression of SiLTPI.23 in Arabidopsis thaliana. These findings expand our knowledge on nsLTPs in sesame and provide resources for functional studies and genetic improvement of oil content in sesame seeds.

Development and Analytical Validation of a 29 Gene Clinical Pharmacogenetic Genotyping Panel: Multi-Ethnic Allele and Copy Number Variant Detection.

To develop a novel pharmacogenetic genotyping panel, a multidisciplinary team evaluated available evidence and selected 29 genes implicated in interindividual drug response variability, including 130 sequence variants and additional copy number variants (CNVs). Of the 29 genes, 11 had guidelines published by the Clinical Pharmacogenetics Implementation Consortium. Targeted genotyping and CNV interrogation were accomplished by multiplex single-base extension using the MassARRAY platform (Agena Biosciences) and multiplex ligation-dependent probe amplification (MRC Holland), respectively. Analytical validation of the panel was accomplished by a strategic combination of > 500 independent tests performed on 170 unique reference material DNA samples, which included sequence variant and CNV accuracy, reproducibility, and specimen (blood, saliva, and buccal swab) controls. Among the accuracy controls were 32 samples from the 1000 Genomes Project that were selected based on their enrichment of sequence variants included in the pharmacogenetic panel (VarCover.org). Coupled with publicly available samples from the Genetic Testing Reference Materials Coordination Program (GeT-RM), accuracy validation material was available for the majority (77%) of interrogated sequence variants (100% with average allele frequencies > 0.1%), as well as additional structural alleles with unique copy number signatures (e.g., CYP2D6*5, *13, *36, *68; CYP2B6*29; and CYP2C19*36). Accuracy and reproducibility for both genotyping and copy number were > 99.9%, indicating that the optimized panel platforms were precise and robust. Importantly, multi-ethnic allele frequencies of the interrogated variants indicate that the vast majority of the general population carries at least one of these clinically relevant pharmacogenetic variants, supporting the implementation of this panel for pharmacogenetic research and/or clinical implementation programs.

Lessons learned from expanded reproductive carrier screening in self-reported Ashkenazi, Sephardi, and Mizrahi Jewish patients.

BACKGROUND: Next-generation sequencing (NGS)-based panels have gained traction as a strategy for reproductive carrier screening. Their value for screening Ashkenazi Jewish (AJ) individuals, who have benefited greatly from population-wide targeted testing, as well as Sephardi/Mizrahi Jewish (SMJ) individuals (an underserved population), has not been fully explored. METHODS: The clinical utilization by 6,805 self-reported Jewish individuals of an expanded NGS panel, along with several ancillary assays, was assessed retrospectively. Data were extracted for a subset of 96 diseases that, during the panel design phase, were classified as being AJ-, SMJ-, or pan-Jewish/pan-ethnic-relevant. RESULTS: 64.6% of individuals were identified as carriers of one or more of these 96 diseases. Over 80% of the reported variants would have been missed by following recommended AJ screening guidelines. 10.7% of variants reported for AJs were in "SMJ-relevant genes," and 31.2% reported for SMJs were in "AJ-relevant genes." Roughly 2.5% of individuals carried a novel, likely pathogenic variant. One in 16 linked cohort couples was identified as a carrier couple for at least one of these 96 diseases. CONCLUSION: For maximal carrier identification, this study supports using expanded NGS panels for individuals of all Jewish backgrounds. This approach can better empower at-risk couples for reproductive decision making.

Root diversity in sesame (Sesamum indicum L.): insights into the morphological, anatomical and gene expression profiles.

MAIN CONCLUSION: Sesame harbors a large diversity in root morphological and anatomical traits and a high root biomass improves the plant aboveground biomass as well as the seed yield. Sesame provides one of the most nutritious and healthy vegetable oils, sparking an increasing demand of its seeds. However, with the low yield and productivity of sesame, there is still a huge gap between the seed demand and supply. Improving the root system has a high potential to increase crop productivity, but information on the diversity of the sesame root systems is still lacking. In this study, 40 diverse sesame varieties were grown in soil and hydroponics systems and the diversity of the root system was investigated. The results showed that sesame holds a large root morphological and anatomical diversity, which can be harnessed in breeding programmes. Based on the clustering of the genotypes in hydroponics and soil culture systems, we found that similar genotypes were commonly clustered either in the small-root or in the big-root group, indicating that the hydroponics system can be employed for a large-scale root phenotyping. Our results further revealed that the root biomass positively contributes to increased seed yield in sesame, based on multi-environmental trials. By comparing the root transcriptome of two contrasting genotypes, 2897 differentially expressed genes were detected and they were enriched in phenylpropanoid biosynthesis, starch and sucrose metabolism, stilbenoid, diarylheptanoid and gingerol biosynthesis, flavonoid biosynthesis, suggesting that these pathways are crucial for sesame root growth and development. Overall, this study sheds light on the diversity of sesame root system and offers the basis for improving root traits and increasing sesame seed yield.

Prenatal cytogenomic identification and molecular refinement of compound heterozygous STRC deletion breakpoints.

Here, we report the prenatal detection of a compound heterozygous deletion at chromosome 15q15.3 by clinical chromosomal microarray (CMA) testing that included the CATSPER2 male infertility gene. However, given the low resolution of CMA at this homologous locus, it was unclear if the neighboring STRC hearing loss gene was also affected. Therefore, we developed a novel allele-specific PCR strategy, which narrowed the proximal breakpoint of the maternally inherited deletion to a 310 bp interval that was 440 bp upstream from the STRC transcription start site.

Integrated CYP2D6 interrogation for multiethnic copy number and tandem allele detection.

AIM: To comprehensively interrogate CYP2D6 by integrating genotyping, copy number analysis and novel strategies to identify CYP2D6*36 and characterize CYP2D6 duplications. METHODS: Genotyping of 16 CYP2D6 alleles, multiplex ligation-dependent probe amplification (MLPA) and CYP2D6*36 and duplication allele-specific genotyping were performed on 427 African-American, Asian, Caucasian, Hispanic, and Ashkenazi Jewish individuals. RESULTS: A novel PCR strategy determined that almost half of all CYP2D6*10 (100C>T) alleles are actually *36 (isolated or in tandem with *10) and all identified duplication alleles were characterized. Integrated results from all testing platforms enabled the refinement of genotype frequencies across all studied populations. CONCLUSION: The polymorphic CYP2D6 gene requires comprehensive interrogation to characterize allelic variation across ethnicities, which was enabled in this study by integrating multiplexed genotyping, MLPA copy number analysis, novel PCR strategies and duplication allele-specific genotyping.

Robust identification of mosaic variants in congenital heart disease.

Mosaicism due to somatic mutations can cause multiple diseases including cancer, developmental and overgrowth syndromes, neurodevelopmental disorders, autoinflammatory diseases, and atrial fibrillation. With the increased use of next generation sequencing technology, multiple tools have been developed to identify low-frequency variants, specifically from matched tumor-normal tissues in cancer studies. To investigate whether mosaic variants are implicated in congenital heart disease (CHD), we developed a pipeline using the cancer somatic variant caller MuTect to identify mosaic variants in whole-exome sequencing (WES) data from a cohort of parent/affected child trios (n = 715) and a cohort of healthy individuals (n = 416). This is a novel application of the somatic variant caller designed for cancer to WES trio data. We identified two cases with mosaic KMT2D mutations that are likely pathogenic for CHD, but conclude that, overall, mosaicism detectable in peripheral blood or saliva does not account for a significant portion of CHD etiology.

Cytogenomic identification and long-read single molecule real-time (SMRT) sequencing of a Bardet-Biedl Syndrome 9 (BBS9) deletion.

Bardet-Biedl syndrome (BBS) is a recessive disorder characterized by heterogeneous clinical manifestations, including truncal obesity, rod-cone dystrophy, renal anomalies, postaxial polydactyly, and variable developmental delays. At least 20 genes have been implicated in BBS, and all are involved in primary cilia function. We report a 1-year-old male child from Guyana with obesity, postaxial polydactyly on his right foot, hypotonia, ophthalmologic abnormalities, and developmental delay, which together indicated a clinical diagnosis of BBS. Clinical chromosomal microarray (CMA) testing and high-throughput BBS gene panel sequencing detected a homozygous 7p14.3 deletion of exons 1-4 of BBS9 that was encompassed by a 17.5 Mb region of homozygosity at chromosome 7p14.2-p21.1. The precise breakpoints of the deletion were delineated to a 72.8 kb region in the proband and carrier parents by third-generation long-read single molecule real-time (SMRT) sequencing (Pacific Biosciences), which suggested non-homologous end joining as a likely mechanism of formation. Long-read SMRT sequencing of the deletion breakpoints also determined that the aberration included the neighboring RP9 gene implicated in retinitis pigmentosa; however, the clinical significance of this was considered uncertain given the paucity of reported cases with unambiguous RP9 mutations. Taken together, our study characterized a BBS9 deletion, and the identification of this shared haplotype in the parents suggests that this pathogenic aberration may be a BBS founder mutation in the Guyanese population. Importantly, this informative case also highlights the utility of long-read SMRT sequencing to map nucleotide breakpoints of clinically relevant structural variants.

Dual Diagnosis of Ellis-van Creveld Syndrome and Hearing Loss in a Consanguineous Family.

Multilocus analysis of rare or genetically heterogeneous diseases is a distinct advantage of next-generation sequencing (NGS) over conventional single-gene investigations. Recent studies have begun to uncover an under-recognized prevalence of dual molecular diagnoses in patients with a "blended" phenotype that is the result of 2 clinical diagnoses involving 2 separate genetic loci. This blended phenotype could be mistakenly interpreted as a novel clinical extension of a single-gene disorder. In this study, we ascertained a proband from a large consanguineous Iranian family who manifests postlingual, progressive, moderate hearing loss in addition to suspected Ellis-van Creveld syndrome phenotype. NGS with a customized skeletal dysplasia panel containing over 370 genes and subsequent bioinformatics analysis disclosed 2 homozygous mutations in EVC2 (c.2653C>T; p.Arg885*) and COL11A2 (c.966dup; p.Thr323Hisfs*19), respectively. This study highlights a dual molecular diagnosis in a patient with a blending of 2 distinct phenotypes and illustrates the advantage and importance of this staple technology to facilitate rapid and comprehensive genetic dissection of a heterogeneous phenotype. The differentiation between phenotypic expansion of a genetic disorder and a blended phenotype that is due to more than one distinct genetic aberration is essential in order to reduce the diagnostic odyssey endured by patients.

Analysis of 589,306 genomes identifies individuals resilient to severe Mendelian childhood diseases.

Genetic studies of human disease have traditionally focused on the detection of disease-causing mutations in afflicted individuals. Here we describe a complementary approach that seeks to identify healthy individuals resilient to highly penetrant forms of genetic childhood disorders. A comprehensive screen of 874 genes in 589,306 genomes led to the identification of 13 adults harboring mutations for 8 severe Mendelian conditions, with no reported clinical manifestation of the indicated disease. Our findings demonstrate the promise of broadening genetic studies to systematically search for well individuals who are buffering the effects of rare, highly penetrant, deleterious mutations. They also indicate that incomplete penetrance for Mendelian diseases is likely more common than previously believed. The identification of resilient individuals may provide a first step toward uncovering protective genetic variants that could help elucidate the mechanisms of Mendelian diseases and new therapeutic strategies.

Novel mutations in EVC cause aberrant splicing in Ellis-van Creveld syndrome.

Ellis-van Creveld syndrome (EvC) is a rare autosomal recessive disorder characterized by disproportionate chondrodysplasia, postaxial polydactyly, nail dystrophy, dental abnormalities and in a proportion of patients, congenital cardiac malformations. Weyers acrofacial dysostosis (Weyers) is another dominantly inherited disorder allelic to EvC syndrome but with milder phenotypes. Both disorders can result from loss-of-function mutations in either EVC or EVC2 gene, and phenotypes associated with the two gene mutations are clinically indistinguishable. We present here a clinical and molecular analysis of a Chinese family manifested specific features of EvC syndrome. Sequencing of both EVC and EVC2 identified two novel heterozygous splice site mutations c.384+5G>C in intron 3 and c.1465-1G>A in intron 10 in EVC, which were inherited from mother and father, respectively. In vitro minigene expression assay, RT-PCR and sequencing analysis demonstrated that c.384+5G>C mutation abolished normal splice site and created a new cryptic acceptor site within exon 4, whereas c.1465-1G>A mutation affected consensus splice junction site and resulted in full exon 11 skipping. These two aberrant pre-mRNA splicing processes both produced in-frame abnormal transcripts that possibly led to abolishment of important functional domains. To our knowledge, this is the first report of EVC mutations that cause EvC syndrome in Chinese population. Our data revealed that EVC splice site mutations altered splicing pattern and helped elucidate the pathogenesis of EvC syndrome.

Identification of rare variants in TNNI3 with atrial fibrillation in a Chinese GeneID population.

Despite advances by genome-wide association studies (GWAS), much of heritability of common human diseases remains missing, a phenomenon referred to as 'missing heritability'. One potential cause for 'missing heritability' is the rare susceptibility variants overlooked by GWAS. Atrial fibrillation (AF) is the most common arrhythmia seen at hospitals and increases risk of stroke by fivefold and doubles risk of heart failure and sudden death. Here, we studied one large Chinese family with AF and hypertrophic cardiomyopathy (HCM). Whole-exome sequencing analysis identified a mutation in TNNI3, R186Q, that co-segregated with the disease in the family, but did not exist in >1583 controls, suggesting that R186Q causes AF and HCM. High-resolution melting curve analysis and direct DNA sequence analysis were then used to screen mutations in all exons and exon-intron boundaries of TNNI3 in a panel of 1127 unrelated AF patients and 1583 non-AF subjects. Four novel missense variants were identified in TNNI3, including E64G, M154L, E187G and D196G in four independent AF patients, but no variant was found in 1583 non-AF subjects. All variants were not found in public databases, including the ExAC Browser database with 60,706 exomes. These data suggest that rare TNNI3 variants are associated with AF (P = 0.03). TNNI3 encodes troponin I, a key regulator of the contraction-relaxation function of cardiac muscle and was not previously implicated in AF. Thus, this study may identify a new biological pathway for the pathogenesis of AF and provides evidence to support the rare variant hypothesis for missing heritability.

Disease-associated variants in different categories of disease located in distinct regulatory elements.

BACKGROUND: The invention of high throughput sequencing technologies has led to the discoveries of hundreds of thousands of genetic variants associated with thousands of human diseases. Many of these genetic variants are located outside the protein coding regions, and as such, it is challenging to interpret the function of these genetic variants by traditional genetic approaches. Recent genome-wide functional genomics studies, such as FANTOM5 and ENCODE have uncovered a large number of regulatory elements across hundreds of different tissues or cell lines in the human genome. These findings provide an opportunity to study the interaction between regulatory elements and disease-associated genetic variants. Identifying these diseased-related regulatory elements will shed light on understanding the mechanisms of how these variants regulate gene expression and ultimately result in disease formation and progression. RESULTS: In this study, we curated and categorized 27,558 Mendelian disease variants, 20,964 complex disease variants, 5,809 cancer predisposing germline variants, and 43,364 recurrent cancer somatic mutations. Compared against nine different types of regulatory regions from FANTOM5 and ENCODE projects, we found that different types of disease variants show distinctive propensity for particular regulatory elements. Mendelian disease variants and recurrent cancer somatic mutations are 22-fold and 10- fold significantly enriched in promoter regions respectively (q<0.001), compared with allele-frequency-matched genomic background. Separate from these two categories, cancer predisposing germline variants are 27-fold enriched in histone modification regions (q<0.001), 10-fold enriched in chromatin physical interaction regions (q<0.001), and 6-fold enriched in transcription promoters (q<0.001). Furthermore, Mendelian disease variants and recurrent cancer somatic mutations share very similar distribution across types of functional effects. We further found that regulatory regions are located within over 50% coding exon regions. Transcription promoters, methylation regions, and transcription insulators have the highest density of disease variants, with 472, 239, and 72 disease variants per one million base pairs, respectively. CONCLUSIONS: Disease-associated variants in different disease categories are preferentially located in particular regulatory elements. These results will be useful for an overall understanding about the differences among the pathogenic mechanisms of various disease-associated variants.

An integrative pipeline for multi-modal discovery of disease relationships.

In the past decade there has been an explosion in genetic research that has resulted in the generation of enormous quantities of disease-related data. In the current study, we have compiled disease risk gene variant information and Electronic Medical Record (EMR) classification codes from various repositories for 305 diseases. Using such data, we developed a pipeline to test for clinical prevalence, gene-variant overlap, and literature presence for all 46,360 unique diseases pairs. To determine whether disease pairs were enriched we systematically employed both Fishers' Exact (medical and literature) and Term Frequency-Inverse Document Frequency (genetics) methodologies to test for enrichment, defining statistical significance at a Bonferonni adjusted threshold of (p < 1 × 10(-6)) and weighted q < 0.05 accordingly. We hypothesize that disease pairs that are statistically enriched in medical and genetic spheres, but not so in the literature have the potential to reveal non-obvious connections between clinically disparate phenotypes. Using this pipeline, we identified 2,316 disease pairs that were significantly enriched within an EMR and 213 enriched genetically. Of these, 65 disease pairs were statistically enriched in both, 19 of which are believed to be novel. These identified non-obvious relationships between disease pairs are suggestive of a shared underlying etiology with clinical presentation. Further investigation of uncovered disease-pair relationships has the potential to provide insights into the architecture of complex diseases, and update existing knowledge of risk factors.

A PTPN11 allele encoding a catalytically impaired SHP2 protein in a patient with a Noonan syndrome phenotype.

The RASopathies are a relatively common group of phenotypically similar and genetically related autosomal dominant genetic syndromes caused by missense mutations affecting genes participating in the RAS/mitogen-activated protein kinase (MAPK) pathway that include Noonan syndrome (NS) and Noonan syndrome with multiple lentigines (NSML, formerly LEOPARD syndrome). NS and NSML can be difficult to differentiate during infancy, but the presence of multiple lentigines, café au lait spots, and specific cardiac defects facilitate the diagnosis. Furthermore, individual PTPN11 missense mutations are highly specific to each syndrome and engender opposite biochemical alterations on the function of SHP-2, the protein product of that gene. Here, we report on a 5-year-old male with two de novo PTPN11 mutations in cis, c.1471C>T (p.Pro491Ser), and c.1492C>T (p.Arg498Trp), which are associated with NS and NSML, respectively. This boy's phenotype is intermediate between NS and NSML with facial dysmorphism, short stature, mild global developmental delay, pulmonic stenosis, and deafness but absence of café au lait spots or lentigines. The double-mutant SHP-2 was found to be catalytically impaired. This raises the question of whether clinical differences between NS and NSML can be ascribed solely to the relative SHP-2 catalytic activity.

A genome-wide association study identifies susceptibility loci for nonsyndromic sagittal craniosynostosis near BMP2 and within BBS9.

Sagittal craniosynostosis is the most common form of craniosynostosis, affecting approximately one in 5,000 newborns. We conducted, to our knowledge, the first genome-wide association study for nonsyndromic sagittal craniosynostosis (sNSC) using 130 non-Hispanic case-parent trios of European ancestry (NHW). We found robust associations in a 120-kb region downstream of BMP2 flanked by rs1884302 (P = 1.13 × 10(-14), odds ratio (OR) = 4.58) and rs6140226 (P = 3.40 × 10(-11), OR = 0.24) and within a 167-kb region of BBS9 between rs10262453 (P = 1.61 × 10(-10), OR = 0.19) and rs17724206 (P = 1.50 × 10(-8), OR = 0.22). We replicated the associations to both loci (rs1884302, P = 4.39 × 10(-31) and rs10262453, P = 3.50 × 10(-14)) in an independent NHW population of 172 unrelated probands with sNSC and 548 controls. Both BMP2 and BBS9 are genes with roles in skeletal development that warrant functional studies to further understand the etiology of sNSC.

The same chromosome 9p21.3 locus is associated with type 2 diabetes and coronary artery disease in a Chinese Han population.

OBJECTIVE: Recent genome-wide association studies (GWAS) revealed that a 9p21.3 locus was associated with type 2 diabetes. In this study, we carried out a large-scale case-control study in the GeneID Chinese Han population to 1) further replicate the association of 9p21.3 type 2 diabetes GWAS single nucleotide polymorphisms (SNPs) and 2) assess the association of these SNPs with coronary artery disease. RESEARCH DESIGN AND METHODS: Three SNPs (rs2383208, rs10811661, and rs10757283) were genotyped in two GeneID cohorts of 3,167 Chinese Han individuals. Case-control association design was used to determine the association of the SNPs with type 2 diabetes and coronary artery disease. Gensini scores were calculated in the coronary artery disease subjects and were tested for association with the variants. Multivariate logistic regressions were performed on association studies. RESULTS: The association between two of the three SNPs and type 2 diabetes was replicated in the GeneID population (rs2383208, P = 0.936; rs10811661-T, P = 0.02, odds ratio [OR] = 1.23; rs10757283-C, P = 0.003, OR = 1.30). The same two SNPs also contributed to the risk of coronary artery disease (CAD) (rs10811661-T, P = 0.002, OR = 1.19; rs10757283-C, P = 0.003, OR = 1.18). In addition, rs10757283 was associated with severity of coronary atherosclerosis estimated by the Gensini scoring system (risk allele C, quantitative-trait regression adjusted P = 0.002). CONCLUSIONS: For the first time to our knowledge, our results indicated that the same 9p21.3 locus, represented by SNPs rs10811661 and rs10757283, contributed to the risk of type 2 diabetes and coronary artery disease in our GeneID Chinese Han population.

Slow cardiac myosin regulatory light chain 2 (MYL2) was down-expressed in chronic heart failure patients.

BACKGROUND: Genetic studies have shown that many slow cardiac myosin regulatory light chain 2 (MYL2) gene mutations can cause hypertrophic cardiomyopathy, which is one of the most common causes of heart failure (HF). But until now there has been no pathological or histological evidence that MYL2 may be associated with HF development. Recent microarray studies indicated that myosin heavy chain expression changed in the pathological process of HF. Because MYL2 is a regulatory component of myosin heavy polypeptide, the role of MYL2 protein in HF needs to be studied. HYPOTHESIS: The level of expression of MYL2 may change in the heart tissue of patients with chronic HF. METHODS: We collected 28 human right auricle samples, 16 from chronic HF patients and 12 from healthy control subjects. Immunohistochemistry was carried out to observe the tissue-expression pattern of the MYL2 protein and Western blot methods were performed to quantify the relative MYL2 expression level. RESULTS: In chronic HF patients, the MYL2 protein level decreased significantly compared with normal controls (t test P < 0.05). Among the 16 HF patients, MYL2 expression in the severe HF group (New York Heart Association [NYHA] class III or IV) was even lower than that of the moderate HF group (NYHA class II) (t test P < 0.05). CONCLUSIONS: MYL2 was down-expressed in HF tissues, and our findings suggested that MYL2 may play a role in the development and progression of chronic HF.