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In biology and biomedicine, relating phenotypic outcomes with genetic variation and environmental factors remains a challenge: patient phenotypes may not match known diseases, candidate variants may be in genes that haven't been characterized, research organisms may not recapitulate human or veterinary diseases, environmental factors affecting disease outcomes are unknown or undocumented, and many resources must be queried to find potentially significant phenotypic associations. The Monarch Initiative (https://monarchinitiative.org) integrates information on genes, variants, genotypes, phenotypes and diseases in a variety of species, and allows powerful ontology-based search. We develop many widely adopted ontologies that together enable sophisticated computational analysis, mechanistic discovery and diagnostics of Mendelian diseases. Our algorithms and tools are widely used to identify animal models of human disease through phenotypic similarity, for differential diagnostics and to facilitate translational research. Launched in 2015, Monarch has grown with regards to data (new organisms, more sources, better modeling); new API and standards; ontologies (new Mondo unified disease ontology, improvements to ontologies such as HPO and uPheno); user interface (a redesigned website); and community development. Monarch data, algorithms and tools are being used and extended by resources such as GA4GH and NCATS Translator, among others, to aid mechanistic discovery and diagnostics., (© The Author(s) 2019. Published by Oxford University Press on behalf of Nucleic Acids Research.)

The Human Phenotype Ontology (HPO)-a standardized vocabulary of phenotypic abnormalities associated with 7000+ diseases-is used by thousands of researchers, clinicians, informaticians and electronic health record systems around the world. Its detailed descriptions of clinical abnormalities and computable disease definitions have made HPO the de facto standard for deep phenotyping in the field of rare disease. The HPO's interoperability with other ontologies has enabled it to be used to improve diagnostic accuracy by incorporating model organism data. It also plays a key role in the popular Exomiser tool, which identifies potential disease-causing variants from whole-exome or whole-genome sequencing data. Since the HPO was first introduced in 2008, its users have become both more numerous and more diverse. To meet these emerging needs, the project has added new content, language translations, mappings and computational tooling, as well as integrations with external community data. The HPO continues to collaborate with clinical adopters to improve specific areas of the ontology and extend standardized disease descriptions. The newly redesigned HPO website (www.human-phenotype-ontology.org) simplifies browsing terms and exploring clinical features, diseases, and human genes.

Mowat-Wilson syndrome (MWS) is a relatively newly described multiple congenital anomaly/mental retardation syndrome. Haploinsufficiency of a gene termed ZFHX1B (also known as SIP1) on chromosome 2 is responsible for this condition, and clinical genetic testing for MWS recently became available. The majority of reports in the literature originate from Northern Europe and Australia. Here we report our clinical experience with 12 patients diagnosed with MWS within a 2-year period of time in the United States, with particular emphasis on clinical characteristics and management strategies. Individuals with this condition have characteristic facial features, including microcephaly, hypertelorism, medially flared and broad eyebrows, prominent columella, pointed chin, and uplifted earlobes, which typically prompt the clinician to consider the diagnosis. Medical issues in our cohort of patients included seizures (75%) with no predeliction for any particular seizure type; agenesis of the corpus callosum (60% of our patients studied); congenital heart defects (75%), particularly involving the pulmonary arteries and/or valves; hypospadias (55% of males); severely impaired or absent speech (100% of individuals over 1 year of age) with relatively spared receptive language; and Hirschsprung disease (50%) or chronic constipation (25%). The incidence of MWS is unknown, but based on the number of patients identified in a short period of time within the US, it is likely greatly under recognized. MWS should be considered in any individual with severely impaired or absent speech, especially in the presence of seizures and anomalies involving the pulmonary arteries (particularly pulmonary artery sling) or pulmonary valves., ((c) 2006 Wiley-Liss, Inc.)

We report on 20 individuals in 4 kindreds with auriculo-condylar syndrome (ACS), an autosomal dominant disorder characterized by congenital auricular clefts, mandibular condyle hypoplasia, temporomandibular joint (TMJ) abnormalities, micrognathia, microstomia, and a round facial appearance with prominent cheeks. Affected individuals have varying degrees of glossoptosis, respiratory distress, masticatory abnormalities, and malocclusion. Data from these families and those previously described suggest that this is a unique disorder with widely variable expression, including lack of obvious external anomalies in some individuals and severe ear malformations, condyle agenesis, and characteristic facial features in others. Early recognition of this condition should permit appropriate counseling and anticipatory guidance, including evaluation for reconstructive surgery and orthodontia and intervention for upper airway obstruction and sleep apnea., ((c) 2005 Wiley-Liss, Inc.)

Purpose: To report on the use of fluorescence in situ hybridization (FISH) and dosage-sensitive Southern blot analysis in the molecular diagnosis of patients with Saethre-Chotzen syndrome., Methods: FISH and dosage-sensitive Southern blot analysis utilizing TWIST gene probes were performed on patients with Saethre-Chotzen syndrome but without an identifiable TWIST sequence variation., Results: Four unrelated patients with a deletion of the TWIST gene were identified by Southern blot; one of them had a complex chromosomal rearrangement involving 7p21 and no apparent deletion by FISH, suggesting a smaller deletion in the region including the TWIST gene. A fifth patient had an abnormal TWIST gene fragment on Southern blot analysis that segregated with the disease in the family; FISH was normal in this patient, suggesting a partial deletion or rearrangement in or near the gene., Conclusion: FISH and dosage-sensitive Southern blot analysis are useful diagnostic tools in Saethre-Chotzen syndrome without TWIST sequence variation.

Van der Woude syndrome (VWS) is an autosomal dominant craniofacial disorder with high penetrance and variable expression. Its clinical features are variably expressed, but include cleft lip and/or cleft palate, lip pits and hypodontia. All VWS families studied to date map the disease gene to a < 2 cM region of chromosome 1q32, with no evidence of locus heterogeneity. The aim of this study is to refine the localization of the VWS gene and to further assess possible heterogeneity. We analyzed four multiplex VWS families. All available members were clinically assessed and genotyped for 19 short tandem repeat markers on chromosome 1 in the VWS candidate gene region. We performed two-point and multipoint limit of detection (LOD) score analyses using a high penetrance autosomal dominant model. All families showed positive LOD scores without any recombination in the candidate region. The largest two-point LOD score was 5.87. Our assay method for short tandem repeat (STR) markers provided highly accurate size estimation of marker allele fragment sizes, and therefore enabled us to determine the specific alleles segregating with the VWS gene in each of our four families. We observed a striking pattern of STR allele sharing at several closely linked loci among our four Caucasian VWS families recruited at three different locations in the US. These results suggest the possibility of a unique origin for a mutation responsible for many or most cases of VWS.

Two regions were chosen for linkage studies to cleft lip with or without cleft palate (CL[P]) because they are break points of a balanced translocation in a patient with severe bilateral facial clefting. We used dinucleotide repeats to test chromosomal regions 1q21 and 22q11.2 for such linkage. We studied three families with apparently dominantly inherited CL(P). Families #1 and #2 are local Caucasian families that have not been previously reported; family #3 is a Belgian family that has been previously published [DePaepe, 1989]. Significant evidence against close linkage of the dinucleotide repeats (D1S104, D22S156, D22S264) with CL(P) using a dominant model was obtained. Three other candidate regions were tested (2q37,4q31, and 8p) with the dinucleotide repeats PAX3, D4S175, and LPL respectively. The LOD scores generated at these three loci are not statistically significant for demonstrating negative linkage at these regions. However, they may be used with other informative families in the future, since LOD scores for the same model of inheritance may be added together. Negative or neutral LOD scores were generated at all informative loci using an autosomal dominant model with decreased penetrance.

Plasmid isolation was used to refine the epidemiologic analysis for 168 shigellosis cases in Pima County, Ariz. Plasmids of less than 20 kb were used for comparison of plasmid profiles. Plasmid patterns for each species were distinct. A total of 57 of 74 (77%) Shigella flexneri strains could be placed into seven plasmid patterns, 70 of 79 (89%) Shigella sonnei strains could be placed into seven patterns, 12 Shigella boydii strains could be placed into six patterns, and each of 3 Shigella dysenteriae strains differed. There was a correlation between plasmid patterns and serotypes for S. flexneri, and multiple plasmid patterns were found in serotypes 1, 2, and 6, offering a refinement beyond serotyping. In previous studies we found an association between Mexican travel and an S. sonnei 5.1-kb plasmid. When this plasmid was used as a probe, strong homology was seen with numerous small plasmids in all Shigella species: restriction endonuclease analysis revealed a 1.1-kb AvaI-AvaII fragment common to various plasmids of S. sonnei. S. flexneri, and S. boydii independent of species. Of 34 Pima County Shigella isolates from the mid-1970s. 8 showed plasmid patterns similar to those of the recent isolates. Some plasmids from S. sonnei, S. flexneri, and S. boydii strains isolated in the 1970s also contained the AvaI-AvaII fragment. The conservation of this specific fragment in our population for more than 12 years suggests that it may contain genes important in virulence or survival.