EXPLAINING RARE MENDELIAN PHENOTYPES: EXOME SEQUENCING AND FUNCTIONAL ANALYSIS OF SPONDYLOMETAPHYSEAL DYSPLASIA WITH CONE-ROD DYSTROPHY

Mendelian phenotype;phospholipid;PCYT1A;lipid metabolism;exome sequencing;bone dysplasia;not listed

Jurgens, JulieRaben, Daniel M. ;

Johns Hopkins University

关键词: Mendelian phenotype;    phospholipid;    PCYT1A;    lipid metabolism;    exome sequencing;    bone dysplasia;    not listed;   

Others  :  https://jscholarship.library.jhu.edu/bitstream/handle/1774.2/59136/JURGENS-DISSERTATION-2018.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: JOHNS HOPKINS DSpace Repository

【 摘 要 】

Mendelian disorders are a set of heritable phenotypes that come at a significant cost for patients, their families, and the healthcare system.Here we describe and implement strategies to determine the genetic basis of unexplained Mendelian disorders through next-generation sequencing. Using whole-exome sequencing, we found that a novel heterozygous variant in COL2A1 underlies Stanescu dysplasia, and that biallelic variants in PCYT1A cause spondylometaphyseal dysplasia with cone-rod dystrophy (SMD-CRD). In addition to detecting causal variants for phenotypes of interest, next-generation sequencing has the potential to reveal incidental findings in genes unrelated to a patient’s primary phenotype.We find that incidental findings arise frequently in clinically actionable genes, yet our ability to interpret them is extremely limited, highlighting the need for improved and standardized variant classification methods. Finally, we generated and characterized various cellular models for the characterization of SMD-CRD alleles in PCYT1A. Our studies suggest that full or partial loss of PCYT1A expression has variable and cell-type specific consequences, resulting in altered lipid metabolism and lipid droplet formation, accelerated chondrocyte differentiation, and varying degrees of PCYT1A loss-of-function.We conclude that concerted efforts are required to fully elucidate the genetic and mechanistic bases of Mendelian phenotypes, and that sustained efforts are required for the accurate interpretation of human genetic variation detected by next-generation sequencing studies.