Abstract
The clinical evaluation of a genetic syndrome relies upon recognition of a characteristic pattern of signs or symptoms to guide targeted genetic testing for confirmation of the diagnosis. However, individuals displaying a single phenotype of a complex syndrome may not meet criteria for clinical diagnosis or genetic testing. Here, we present a phenome-wide association study (PheWAS) approach to systematically explore the phenotypic expressivity of common and rare alleles in genes associated with four well-described syndromic diseases (Alagille (AS), Marfan (MS), DiGeorge (DS), and Noonan (NS) syndromes) in the general population. Using human phenotype ontology (HPO) terms, we systematically mapped 60 phenotypes related to AS, MS, DS and NS in 337,198 unrelated white British from the UK Biobank (UKBB) based on their hospital admission records, self-administrated questionnaires, and physiological measurements. We performed logistic regression adjusting for age, sex, and the first 5 genetic principal components, for each phenotype and each variant in the target genes (JAG1, NOTCH2 FBN1, PTPN1 and RAS-opathy genes, and genes in the 22q11.2 locus) and performed a gene burden test. Overall, we observed multiple phenotype-genotype correlations, such as the association between variation in JAG1, FBN1, PTPN11 and SOS2 with diastolic and systolic blood pressure; and pleiotropy among multiple variants in syndromic genes. For example, rs11066309 in PTPN11 was significantly associated with a lower body mass index, an increased risk of hypothyroidism and a smaller size for gestational age, all in concordance with NS-related phenotypes. Similarly, rs589668 in FBN1 was associated with an increase in body height and blood pressure, and a reduced body fat percentage as observed in Marfan syndrome. Our findings suggest that the spectrum of associations of common and rare variants in genes involved in syndromic diseases can be extended to individual phenotypes within the general population.
Highlights
Genetic syndromes are rare diseases defined by a specific and clinically recognizable set of phenotypes across multiple organ systems
Standard medical evaluation of genetic syndromes relies upon recognizing a characteristic pattern of signs or symptoms to guide targeted genetic testing for confirmation of the diagnosis
We take advantage of a rich electronic health record, various phenotypic measurements, and genetic information in 337,198 unrelated white British from the UK Biobank (UKBB), to study the relation between single syndromic disease phenotypes and genes related to syndromic disease
Summary
Genetic syndromes are rare diseases defined by a specific and clinically recognizable set of phenotypes across multiple organ systems. The era of next-generation sequencing has enabled substantial progress in linking syndromic disease to specific genetic loci, coupled with public databases of genotype-phenotype relationships to facilitate the classification of genetic variants from “benign” to “pathogenic” for use in clinical decision making. The diagnosis or classification of an individual with genetic syndrome relies upon expert recognition of a characteristic pattern of signs or symptoms or a set of defined diagnostic criteria. Individuals displaying single phenotypes of a complex syndrome may not meet criteria for clinical diagnosis or genetic testing; expanding a binary definition of syndromic phenotypes to phenotype scores can identify more individuals with Mendelian disease patterns [4]. The descriptions of allelic heterogeneity, penetrance, and expressivity in syndromic disease genes have focused almost exclusively upon rare or familial alleles [7, 8]
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