%0 Journal Article %J Nature %D 2020 %T A brief history of human disease genetics. %A Claussnitzer, Melina %A Cho, Judy H %A Collins, Rory %A Cox, Nancy J %A Dermitzakis, Emmanouil T %A Hurles, Matthew E %A Kathiresan, Sekar %A Kenny, Eimear E %A Lindgren, Cecilia M %A MacArthur, Daniel G %A North, Kathryn N %A Plon, Sharon E %A Rehm, Heidi L %A Risch, Neil %A Rotimi, Charles N %A Shendure, Jay %A Soranzo, Nicole %A McCarthy, Mark I %K Animals %K Genetic Testing %K Genetic Variation %K Genomics %K Genotype %K Humans %K Phenotype %K Rare Diseases %X

A primary goal of human genetics is to identify DNA sequence variants that influence biomedical traits, particularly those related to the onset and progression of human disease. Over the past 25 years, progress in realizing this objective has been transformed by advances in technology, foundational genomic resources and analytical tools, and by access to vast amounts of genotype and phenotype data. Genetic discoveries have substantially improved our understanding of the mechanisms responsible for many rare and common diseases and driven development of novel preventative and therapeutic strategies. Medical innovation will increasingly focus on delivering care tailored to individual patterns of genetic predisposition.

%B Nature %V 577 %P 179-189 %8 2020 01 %G eng %N 7789 %1 https://www.ncbi.nlm.nih.gov/pubmed/31915397?dopt=Abstract %R 10.1038/s41586-019-1879-7 %0 Journal Article %J Genome Med %D 2019 %T Exome sequencing reveals a high prevalence of BRCA1 and BRCA2 founder variants in a diverse population-based biobank. %A Abul-Husn, Noura S %A Soper, Emily R %A Odgis, Jacqueline A %A Cullina, Sinead %A Bobo, Dean %A Moscati, Arden %A Rodriguez, Jessica E %A Loos, Ruth J F %A Cho, Judy H %A Belbin, Gillian M %A Suckiel, Sabrina A %A Kenny, Eimear E %X

BACKGROUND: Pathogenic variants in BRCA1 and BRCA2 (BRCA1/2) lead to increased risk of breast, ovarian, and other cancers, but most variant-positive individuals in the general population are unaware of their risk, and little is known about prevalence in non-European populations. We investigated BRCA1/2 prevalence and impact in the electronic health record (EHR)-linked BioMe Biobank in New York City.

METHODS: Exome sequence data from 30,223 adult BioMe participants were evaluated for pathogenic variants in BRCA1/2. Prevalence estimates were made in population groups defined by genetic ancestry and self-report. EHR data were used to evaluate clinical characteristics of variant-positive individuals.

RESULTS: There were 218 (0.7%) individuals harboring expected pathogenic variants, resulting in an overall prevalence of 1 in 139. The highest prevalence was in individuals with Ashkenazi Jewish (AJ; 1 in 49), Filipino and other Southeast Asian (1 in 81), and non-AJ European (1 in 103) ancestry. Among 218 variant-positive individuals, 112 (51.4%) harbored known founder variants: 80 had AJ founder variants (BRCA1 c.5266dupC and c.68_69delAG, and BRCA2 c.5946delT), 8 had a Puerto Rican founder variant (BRCA2 c.3922G>T), and 24 had one of 19 other founder variants. Non-European populations were more likely to harbor BRCA1/2 variants that were not classified in ClinVar or that had uncertain or conflicting evidence for pathogenicity (uncertain/conflicting). Within mixed ancestry populations, such as Hispanic/Latinos with genetic ancestry from Africa, Europe, and the Americas, there was a strong correlation between the proportion of African genetic ancestry and the likelihood of harboring an uncertain/conflicting variant. Approximately 28% of variant-positive individuals had a personal history, and 45% had a personal or family history of BRCA1/2-associated cancers. Approximately 27% of variant-positive individuals had prior clinical genetic testing for BRCA1/2. However, individuals with AJ founder variants were twice as likely to have had a clinical test (39%) than those with other pathogenic variants (20%).

CONCLUSIONS: These findings deepen our knowledge about BRCA1/2 variants and associated cancer risk in diverse populations, indicate a gap in knowledge about potential cancer-related variants in non-European populations, and suggest that genomic screening in diverse patient populations may be an effective tool to identify at-risk individuals.

%B Genome Med %V 12 %P 2 %8 2019 Dec 31 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/31892343?dopt=Abstract %R 10.1186/s13073-019-0691-1 %0 Journal Article %J Elife %D 2017 %T Genetic identification of a common collagen disease in puerto ricans via identity-by-descent mapping in a health system. %A Belbin, Gillian Morven %A Odgis, Jacqueline %A Sorokin, Elena P %A Yee, Muh-Ching %A Kohli, Sumita %A Glicksberg, Benjamin S %A Gignoux, Christopher R %A Wojcik, Genevieve L %A Van Vleck, Tielman %A Jeff, Janina M %A Linderman, Michael %A Schurmann, Claudia %A Ruderfer, Douglas %A Cai, Xiaoqiang %A Merkelson, Amanda %A Justice, Anne E %A Young, Kristin L %A Graff, Misa %A North, Kari E %A Peters, Ulrike %A James, Regina %A Hindorff, Lucia %A Kornreich, Ruth %A Edelmann, Lisa %A Gottesman, Omri %A Stahl, Eli Ea %A Cho, Judy H %A Loos, Ruth Jf %A Bottinger, Erwin P %A Nadkarni, Girish N %A Abul-Husn, Noura S %A Kenny, Eimear E %K Adolescent %K Adult %K Aged %K Child %K Collagen Diseases %K Female %K Fibrillar Collagens %K Genotype %K Heterozygote %K Hispanic Americans %K Homozygote %K Humans %K Male %K Middle Aged %K Molecular Epidemiology %K Multigene Family %K Musculoskeletal Diseases %K New York City %K Pedigree %K Whole Genome Sequencing %K Young Adult %X

Achieving confidence in the causality of a disease locus is a complex task that often requires supporting data from both statistical genetics and clinical genomics. Here we describe a combined approach to identify and characterize a genetic disorder that leverages distantly related patients in a health system and population-scale mapping. We utilize genomic data to uncover components of distant pedigrees, in the absence of recorded pedigree information, in the multi-ethnic Bio biobank in New York City. By linking to medical records, we discover a locus associated with both elevated genetic relatedness and extreme short stature. We link the gene, , with a little-known genetic disease, previously thought to be rare and recessive. We demonstrate that disease manifests in both heterozygotes and homozygotes, indicating a common collagen disorder impacting up to 2% of individuals of Puerto Rican ancestry, leading to a better understanding of the continuum of complex and Mendelian disease.

%B Elife %V 6 %8 2017 09 12 %G eng %1 https://www.ncbi.nlm.nih.gov/pubmed/28895531?dopt=Abstract %R 10.7554/eLife.25060