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Background Thousands of genes have been associated with different Mendelian conditions. One of the valuable sources to track these gene-disease associations (GDAs) is the Online Mendelian Inheritance in Man (OMIM) database. However, most of the information in OMIM is textual, and heterogeneous (e.g. summarized by different experts), which complicates automated reading and understanding of the data. Here, we used Natural Language Processing (NLP) to make a tool (Gene-Phenotype Association Discovery (GPAD)) that could syntactically process OMIM text and extract the data of interest. Results GPAD applies a series of language-based techniques to the text obtained from OMIM API to extract GDA discovery-related information. GPAD can inform when a particular gene was associated with a specific phenotype, as well as the type of validation—whether through model organisms or cohort-based patient-matching approaches—for such an association. GPAD extracted data was validated with published reports and was compared with large language model. Utilizing GPAD's extracted data, we analysed trends in GDA discoveries, noting a significant increase in their rate after the introduction of exome sequencing, rising from an average of about 150–250 discoveries each year. Contrary to hopes of resolving most GDAs for Mendelian disorders by now, our data indicate a substantial decline in discovery rates over the past five years (2017–2022). This decline appears to be linked to the increasing necessity for larger cohorts to substantiate GDAs. The rising use of zebrafish and Drosophila as model organisms in providing evidential support for GDAs is also observed. Conclusions GPAD’s real-time analyzing capacity offers an up-to-date view of GDA discovery and could help in planning and managing the research strategies. In future, this solution can be extended or modified to capture other information in OMIM and scientific literature.

Background Congenital Myasthenic Syndromes (CMS) are rare genetic diseases, which share as a common denominator muscle fatigability due to failure of neuromuscular transmission. A distinctive clinical feature of presynaptic CMS variants caused by defects of the synthesis of acetylcholine is the association with life-threatening episodes of apnea. One of these variants is caused by mutations in the SLC5A7 gene, which encodes the sodium-dependent HC-3 high-affinity choline transporter 1 (CHT1). To our knowledge there are no published cases of this CMS type in Latin America. Case presentation We present two cases of CHT1-CMS. Both patients were males presenting with repeated episodes of apnea, hypotonia, weakness, ptosis, mild ophthalmoparesis, and bulbar deficit. The first case also presented one isolated seizure, while the second case showed global developmental delay. Both cases, exhibited incomplete improvement with treatment with pyridostigmine. Conclusions This report emphasizes the broad incidence of CMS with episodic apnea caused by mutations in the SLC5A7 gene and the frequent association of this condition with serious manifestations of central nervous system involvement.

Discovery of rare or low frequency variants in exome or genome data that are associated with complex traits often will require use of very large sample sizes to achieve adequate statistical power. For a fixed sample size, sequencing of individuals sampled from the tails of a phenotype distribution (i.e., extreme phenotypes design) maximizes power and this approach was recently validated empirically with the discovery of variants in DCTN4 that influence the natural history of P. aeruginosa airway infection in persons with cystic fibrosis (CF; MIM219700). The increasing availability of large exome/genome sequence datasets that serve as proxies for population-based controls affords the opportunity to test an alternative, potentially more powerful and generalizable strategy, in which the frequency of rare variants in a single extreme phenotypic group is compared to a control group (i.e., extreme phenotype vs. control population design). As proof-of-principle, we applied this approach to search for variants associated with risk for age-of-onset of chronic P. aeruginosa airway infection among individuals with CF and identified variants in CAV2 and TMC6 that were significantly associated with group status. These results were validated using a large, prospective, longitudinal CF cohort and confirmed a significant association of a variant in CAV2 with increased age-of-onset of P. aeruginosa airway infection (hazard ratio = 0.48, 95% CI=[0.32, 0.88]) and variants in TMC6 with diminished age-of-onset of P. aeruginosa airway infection (HR = 5.4, 95% CI=[2.2, 13.5]) A strong interaction between CAV2 and TMC6 variants was observed (HR=12.1, 95% CI=[3.8, 39]) for children with the deleterious TMC6 variant and without the CAV2 protective variant. Neither gene showed a significant association using an extreme phenotypes design, and conditions for which the power of an extreme phenotype vs. control population design was greater than that for the extreme phenotypes design were explored.

Host genetic variation modifying HIV-1 acquisition risk can inform development of HIV-1 prevention strategies. However, associations between rare or intermediate-frequency variants and HIV-1 acquisition are not well studied. We tested for the association between variation in genic regions and extreme HIV-1 acquisition phenotypes in 100 sub-Saharan Africans with whole genome sequencing data. Missense variants in immunoglobulin-like regions of CD101 and, among women, one missense/5' UTR variant in UBE2V1, were associated with increased HIV-1 acquisition risk (p = 1.9x10-4 and p = 3.7x10-3, respectively, for replication). Both of these genes are known to impact host inflammatory pathways. Effect sizes increased with exposure to HIV-1 after adjusting for the independent effect of increasing exposure on acquisition risk. ClinicalTrials.gov NCT00194519; NCT00557245.

Individuals with heritable thoracic aortic disease (HTAD) face a high risk of deadly aortic dissections, but genetic testing identifies causative variants in only a minority of cases. We explored the contribution of non-canonical splice variants (NCVAS) to thoracic aortic disease (TAD) using SpliceAI and sequencing data from diverse cohorts, including 551 early-onset sporadic dissection cases and 437 HTAD probands with exome sequencing, 57 HTAD pedigrees with whole genome sequencing, and select sporadic cases with clinical panel testing. NCVAS were identified in syndromic HTAD genes such as FBN1 , SMAD3 , and COL3A1 , including intronic variants in FBN1 in two Marfan syndrome (MFS) families. Validation in the Penn Medicine BioBank and UK Biobank showed enrichment of NCVAS in HTAD-associated genes among dissections. These findings suggest NCVAS are an underrecognized contributor to TAD, particularly in sporadic dissection and unsolved MFS cases, highlighting the potential of advanced splice prediction tools in genetic diagnostics.

While efforts proceed to better understand the mechanism by which Ig-like variants alter CD101 function, our results suggest that development of methods to target CD101 activity could provide a novel approach to host-directed, HIV-1 prevention. The CD101 carrier group includes 58 individuals with serum cytokine measurements who have at least one alternative allele at chr1:117554421 or chr1:117560058 or chr1:117568500, which are the three variants in the Ig-like Primary Replication Variants (PRV) group that had individual FDRs < 0.05 in the replication stage. Shown are the distributions of log(IL1RN) after adjustment for panel/batch for individuals in the cytokine analyses with and without these Ig-like primary replication missense variants. https://doi.org/10.1371/journal.ppat.1007588.s002 (PNG) 1.

Identifying genes and variants contributing to rare disease phenotypes and Mendelian conditions informs biology and medicine, yet potential phenotypic consequences for variation of >75% of the ~20,000 annotated genes in the human genome are lacking. Technical advances to assess rare variation genome-wide, particularly exome sequencing (ES), enabled establishment in the United States of the National Institutes of Health (NIH)-supported Centers for Mendelian Genomics (CMGs) and have facilitated collaborative studies resulting in novel “disease gene” discoveries. Pedigree-based genomic studies and rare variant analyses in families with suspected Mendelian conditions have led to the elucidation of hundreds of novel disease genes and highlighted the impact of de novo mutational events, somatic variation underlying nononcologic traits, incompletely penetrant alleles, phenotypes with high locus heterogeneity, and multilocus pathogenic variation. Herein, we highlight CMG collaborative discoveries that have contributed to understanding both rare and common diseases and discuss opportunities for future discovery in single-locus Mendelian disorder genomics. Phenotypic annotation of all human genes; development of bioinformatic tools and analytic methods; exploration of non-Mendelian modes of inheritance including reduced penetrance, multilocus variation, and oligogenic inheritance; construction of allelic series at a locus; enhanced data sharing worldwide; and integration with clinical genomics are explored. Realizing the full contribution of rare disease research to functional annotation of the human genome, and further illuminating human biology and health, will lay the foundation for the Precision Medicine Initiative.

Thyrotropin (TSH) is the master regulator of thyroid gland growth and function. Resistance to TSH (RTSH) describes conditions with reduced sensitivity to TSH. Dominantly inherited RTSH has been linked to a locus on chromosome 15q, but its genetic basis has remained elusive. Here we show that non-coding mutations in a (TTTG) 4 short tandem repeat (STR) underlie dominantly inherited RTSH in all 82 affected participants from 12 unrelated families. The STR is contained in a primate-specific Alu retrotransposon with thyroid-specific cis -regulatory chromatin features. Fiber-seq and RNA-seq studies revealed that the mutant STR activates a thyroid-specific enhancer cluster, leading to haplotype-specific upregulation of the bicistronic MIR7-2 / MIR1179 locus 35 kb downstream and overexpression of its microRNA products in the participants’ thyrocytes. An imbalance in signaling pathways targeted by these micro-RNAs provides a working model for this cause of RTSH. This finding broadens our current knowledge of genetic defects altering pituitary–thyroid feedback regulation. Short tandem repeat mutations in a primate Alu element on chromosome 15q cause activation of a thyroid-specific enhancer, upregulating MIR7-2 / MIR1179 . This results in defective thyroid proliferation and thyrotropin resistance.

Evan Eichler and colleagues report an estimate of the mutation rate in humans that is based on the whole-genome sequences of five parent-offspring trios from a Hutterite population and genotyping data from an extended pedigree. They use a new approach for estimating the mutation rate over multiple generations that takes into account the extensive autozygosity in this founder population. Knowledge of the rate and pattern of new mutation is critical to the understanding of human disease and evolution. We used extensive autozygosity in a genealogically well-defined population of Hutterites to estimate the human sequence mutation rate over multiple generations. We sequenced whole genomes from 5 parent-offspring trios and identified 44 segments of autozygosity. Using the number of meioses separating each pair of autozygous alleles and the 72 validated heterozygous single-nucleotide variants (SNVs) from 512 Mb of autozygous DNA, we obtained an SNV mutation rate of 1.20 × 10 −8 (95% confidence interval 0.89–1.43 × 10 −8 ) mutations per base pair per generation. The mutation rate for bases within CpG dinucleotides (9.72 × 10 −8 ) was 9.5-fold that of non-CpG bases, and there was strong evidence ( P = 2.67 × 10 −4 ) for a paternal bias in the origin of new mutations (85% paternal). We observed a non-uniform distribution of heterozygous SNVs (both newly identified and known) in the autozygous segments ( P = 0.001), which is suggestive of mutational hotspots or sites of long-range gene conversion.