Landscapes of missense variant impact for human superoxide dismutase 1.

Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease for which important subtypes are caused by variation in the Superoxide Dismutase 1 gene . Diagnosis based on sequencing can not only be definitive but also indicate specific therapies available for -associated ALS (SOD1-ALS). Unfortunately, SOD1-ALS diagnosis is limited by the fact that a substantial fraction (currently 26%) of ClinVar SOD1 missense variants are classified as "variants of uncertain significance" (VUS).

Design of a Randomized, Placebo-Controlled, Phase 3 Trial of Tofersen Initiated in Clinically Presymptomatic SOD1 Variant Carriers: the ATLAS Study.

Despite extensive research, amyotrophic lateral sclerosis (ALS) remains a progressive and invariably fatal neurodegenerative disease. Limited knowledge of the underlying causes of ALS has made it difficult to target upstream biological mechanisms of disease, and therapeutic interventions are usually administered relatively late in the course of disease. Genetic forms of ALS offer a unique opportunity for therapeutic development, as genetic associations may reveal potential insights into disease etiology.

PINES: phenotype-informed tissue weighting improves prediction of pathogenic noncoding variants.

Functional characterization of the noncoding genome is essential for biological understanding of gene regulation and disease. Here, we introduce the computational framework PINES (Phenotype-Informed Noncoding Element Scoring), which predicts the functional impact of noncoding variants by integrating epigenetic annotations in a phenotype-dependent manner. PINES enables analyses to be customized towards genomic annotations from cell types of the highest relevance given the phenotype of interest.

Common Variant Burden Contributes to the Familial Aggregation of Migraine in 1,589 Families.

Complex traits, including migraine, often aggregate in families, but the underlying genetic architecture behind this is not well understood. The aggregation could be explained by rare, penetrant variants that segregate according to Mendelian inheritance or by the sufficient polygenic accumulation of common variants, each with an individually small effect, or a combination of the two hypotheses. In 8,319 individuals across 1,589 migraine families, we calculated migraine polygenic risk scores (PRS) and found a significantly higher common variant burden in familial cases (n = 5,317, OR = 1.

Quantitative Assessment of Facial Asymmetry Using Three-Dimensional Surface Imaging in Adults: Validating the Precision and Repeatability of a Global Approach.

Objective: Comparison of global versus landmark analyses of facial asymmetry using three-dimensional photogrammetry to establish a precise method for evaluating facial asymmetry.

Design: The landmark-based approach utilized anthropometric data points. Our global approach involved registration of mirror images, independent of a midplane, to calculate a root mean square (RMS) value.

Qualitative and quantitative assessment of single fingerprints in forensic DNA analysis.

Fingerprints and touched items are important sources of DNA for STR profiling, since this evidence can be recovered in a wide variety of criminal offenses. However, there are some fundamental difficulties in working with these samples, including variability in quantity and quality of extracted DNA. In this study, we collected and analyzed over 700 fingerprints.

Cardiac channelopathy testing in 274 ethnically diverse sudden unexplained deaths.

Sudden unexplained deaths (SUD) in apparently healthy individuals, for which the causes of deaths remained undetermined after comprehensive forensic investigations and autopsy, present vexing challenges to medical examiners and coroners. Cardiac channelopathies, a group of inheritable diseases that primarily affect heart rhythm by altering the cardiac conduction system, have been known as one of the likely causes of SUD. Adhering to the recommendations of including molecular diagnostics of cardiac channelopathies in SUD investigation, the Molecular Genetics Laboratory of the New York City (NYC) Office of Chief Medical Examiner (OCME) has been routinely testing for six major channelopathy genes (KCNQ1, KCNH2, SCN5A, KCNE1, KCNE2, and RyR2) since 2008.

Reciprocal duplication of the Williams-Beuren syndrome deletion on chromosome 7q11.23 is associated with schizophrenia.

Background: Several copy number variants (CNVs) have been implicated as susceptibility factors for schizophrenia (SZ). Some of these same CNVs also increase risk for autism spectrum disorders, suggesting an etiologic overlap between these conditions. Recently, de novo duplications of a region on chromosome 7q11.

Validation of a DNA mixture statistics tool incorporating allelic drop-out and drop-in.

DNA mixture analysis is a current topic of discussion in the forensics literature. Of particular interest is how to approach mixtures where allelic drop-out and/or drop-in may have occurred. The Office of Chief Medical Examiner (OCME) of The City of New York has developed and validated the Forensic Statistical Tool (FST), a software tool for likelihood ratio analysis of forensic DNA samples, allowing for allelic drop-out and drop-in.

A genome-wide scan of Ashkenazi Jewish Crohn's disease suggests novel susceptibility loci.

Crohn's disease (CD) is a complex disorder resulting from the interaction of intestinal microbiota with the host immune system in genetically susceptible individuals. The largest meta-analysis of genome-wide association to date identified 71 CD-susceptibility loci in individuals of European ancestry. An important epidemiological feature of CD is that it is 2-4 times more prevalent among individuals of Ashkenazi Jewish (AJ) descent compared to non-Jewish Europeans (NJ).

Estimating the number of contributors to two-, three-, and four-person mixtures containing DNA in high template and low template amounts.

Aim: To develop guidelines to estimate the number of contributors to two-, three-, and four-person mixtures containing either high template DNA (HT-DNA) or low template DNA (LT-DNA) amounts.

Methods: Seven hundred and twenty-eight purposeful two-, three-, and four-person mixtures composed of 85 individuals of various ethnicities with template amounts ranging from 10 to 500 pg were examined. The number of alleles labeled at each locus and the number of labeled different and repeating alleles at each locus as well over all loci for 2 HT-DNA or 3 LT-DNA replicates were determined.

Evaluation of 22 genetic variants with Crohn's disease risk in the Ashkenazi Jewish population: a case-control study.

Background: Crohn's disease (CD) has the highest prevalence among individuals of Ashkenazi Jewish (AJ) descent compared to non-Jewish Caucasian populations (NJ). We evaluated a set of well-established CD-susceptibility variants to determine if they can explain the increased CD risk in the AJ population.

Methods: We recruited 369 AJ CD patients and 503 AJ controls, genotyped 22 single nucleotide polymorphisms (SNPs) at or near 10 CD-associated genes, NOD2, IL23R, IRGM, ATG16L1, PTGER4, NKX2-3, IL12B, PTPN2, TNFSF15 and STAT3, and assessed their association with CD status.

Microdeletions of 3q29 confer high risk for schizophrenia.

Schizophrenia (SZ) is a severe psychiatric illness that affects approximately 1% of the population and has a strong genetic underpinning. Recently, genome-wide analysis of copy-number variation (CNV) has implicated rare and de novo events as important in SZ. Here, we report a genome-wide analysis of 245 SZ cases and 490 controls, all of Ashkenazi Jewish descent.

Genetic evidence for an association of the TOR1A locus with segmental/focal dystonia.

Polymorphisms in the TOR1A/TOR1B region have been implicated as being associated with primary focal and segmental dystonia. In a cohort of subjects with either focal or segmental dystonia affecting the face, larynx, neck, or arm, we report a strong association of a single nucleotide polymorphism (SNP), the deletion allele at the Mtdel SNP (rs3842225), and protection from focal dystonia. In contrast, we did not find an association of either allele at the D216H SNP (rs1801968) with focal or segmental dystonia in the same cohort.

Increased postpartum thyroxine replacement in Hashimoto's thyroiditis.

Background: The thyroidal response of pregnant patients with established Hashimoto's thyroiditis remains poorly described. The aim of this study was to determine the impact of pregnancy on Hashimoto's thyroiditis as revealed by changes in postpregnancy levothyroxine requirements.

Methods: We performed a retrospective study of 799 hypothyroid patients in a university hospital.

Isolation and characterization of 23 polymorphic microsatellite loci for a West Indian iguana (Cyclura pinguis) from the British Virgin Islands.

Twenty-three polymorphic microsatellite markers were identified and characterized for Cyclura pinguis, a critically endangered species of lizard (Sauria: Iguanidae) native to Anegada Island in the British Virgin Islands. We examined variation at these loci for 39 C. pinguis, finding up to five alleles per locus and an average expected heterozygosity of 0.

FcRL3 gene promoter variant is associated with peripheral arthritis in Crohn's disease.

Background: The mechanisms responsible for the pathogenesis of peripheral arthropathies (PA) in Crohn's disease (CD) are largely unknown, although many studies indicate that genetic and environmental factors are likely to contribute to risk.

Methods: Because variants in the Fc receptor-like 3 (FcRL3) gene have recently been associated with rheumatoid arthritis and several other autoimmune diseases, we tested 2 FcRL3 promoter variants (-169 C>T and -110 G>A) for association with PA in Spanish CD patients that were recruited from a single center and followed for at least 4 years (mean follow-up time, 11 years).

Results: Among the 342 CD patients evaluated, there were 88 cases of peripheral arthropathy; 31 were classified as arthritis and 57 were classified as arthralgia.

On the probability that a novel variant is a disease-causing mutation.

When a novel variant is found in a patient and not in a group of controls, it becomes a candidate for the disease-causing mutation in that patient. At present, no sampling theory exists for assessing the probability that the novel SNP might actually be a neutral variant. We have developed a population genetics-based method for calculating a P-value for a mutation-detection effort.

Discrepancies in dbSNP confirmation rates and allele frequency distributions from varying genotyping error rates and patterns.

Three recent publications have examined the quality and completeness of public database single nucleotide polymorphism (dbSNP) and have come to dramatically different conclusions regarding dbSNPs false positive rate and the proportion of dbSNPs that are expected to be common. These studies employed different genotyping technologies and different protocols in determining minimum acceptable genotyping quality thresholds. Because heterozygous sites typically have lower quality scores than homozygous sites, a higher minimum quality threshold reduces the number of false positive SNPs, but yields fewer heterozygotes and leads to fewer confirmed SNPs.

Undetected genotyping errors cause apparent overtransmission of common alleles in the transmission/disequilibrium test.

The transmission/disequilibrium test (TDT), a family-based test of linkage and association, is a popular and intuitive statistical test for studies of complex inheritance, as it is nonparametric and robust to population stratification. We carried out a literature search and located 79 significant TDT-derived associations between a microsatellite marker allele and a disease. Among these, there were 31 (39%) in which the most common allele was found to exhibit distorted transmission to affected offspring, implying that the allele may be associated with either susceptibility to or protection from a disease.

Association between the tumor necrosis factor locus and the clinical outcome of Leishmania chagasi infection.

A periurban outbreak of visceral leishmaniasis (VL) caused by the protozoan Leishmania chagasi is ongoing outside Natal, northeast Brazil. Manifestations range from asymptomatic infection to disseminated visceral disease. Literature reports suggest that both genetic and environmental factors influence the outcome of infection.