title: Diagnosis of an imprinted-gene syndrome by a novel bioinformatics analysis of whole-genome sequences from a family trio.
abstract: Whole-genome sequencing and whole-exome sequencing are becoming more widely applied in clinical medicine to help diagnose rare genetic diseases. Identification of the underlying causative mutations by genome-wide sequencing is greatly facilitated by concurrent analysis of multiple family members, most often the mother-father-proband trio, using bioinformatics pipelines that filter genetic variants by mode of inheritance. However, current pipelines are limited to Mendelian inheritance patterns and do not specifically address disorders caused by mutations in imprinted genes, such as forms of Angelman syndrome and Beckwith-Wiedemann syndrome. Using publicly available tools, we implemented a genetic inheritance search mode to identify imprinted-gene mutations. Application of this search mode to whole-genome sequences from a family trio led to a diagnosis for a proband for whom extensive clinical testing and Mendelian inheritance-based sequence analysis were nondiagnostic. The condition in this patient, IMAGe syndrome, is likely caused by the heterozygous mutation c.832A>G (p.Lys278Glu) in the imprinted gene CDKN1C. The genotypes and disease status of six members of the family are consistent with maternal expression of the gene, and allele-biased expression was confirmed by RNA-Seq for the heterozygotes. This analysis demonstrates that an imprinted-gene search mode is a valuable addition to genome sequence analysis pipelines for identifying disease-causative variants.
authors.affiliation: Inova Translational Medicine Institute, Inova Health System Falls Church, Virginia.
authors.forename: Dale L
authors.initials: DL
authors.lastname: Bodian
authors.affiliation: Inova Translational Medicine Institute, Inova Health System Falls Church, Virginia.
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Solomon
authors.affiliation: Inova Translational Medicine Institute, Inova Health System Falls Church, Virginia.
authors.forename: Alina
authors.initials: A
authors.lastname: Khromykh
authors.affiliation: Inova Translational Medicine Institute, Inova Health System Falls Church, Virginia.
authors.forename: Dzung C
authors.initials: DC
authors.lastname: Thach
authors.affiliation: Inova Translational Medicine Institute, Inova Health System Falls Church, Virginia.
authors.forename: Ramaswamy K
authors.initials: RK
authors.lastname: Iyer
authors.affiliation: Department of Pediatric Endocrinology, Inova Children's Hospital Falls Church, Virginia.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Link
authors.affiliation: Fairfax Neonatal Associates PC, Inova Children's Hospital Falls Church, Virginia.
authors.forename: Robin L
authors.initials: RL
authors.lastname: Baker
authors.affiliation: Fairfax Neonatal Associates PC, Inova Children's Hospital Falls Church, Virginia.
authors.forename: Rajiv
authors.initials: R
authors.lastname: Baveja
authors.affiliation: Inova Translational Medicine Institute, Inova Health System Falls Church, Virginia.
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Vockley
authors.affiliation: Inova Translational Medicine Institute, Inova Health System Falls Church, Virginia.
authors.forename: John E
authors.initials: JE
authors.lastname: Niederhuber
keywords: Bioinformatics; CDKN1C; IMAGe syndrome; diagnosis; exome sequencing; family trio; genomic imprinting; mutation; rare disease; whole-genome sequencing