title: Whole-exome sequencing and digital PCR identified a novel compound heterozygous mutation in the NPHP1 gene in a case of Joubert syndrome and related disorders.
abstract: BACKGROUND
  Joubert syndrome and related disorders (JSRD) is a clinically and genetically heterogeneous condition with autosomal recessive or X-linked inheritance, which share a distinctive neuroradiological hallmark, the so-called molar tooth sign. JSRD is classified into six clinical subtypes based on associated variable multiorgan involvement. To date, 21 causative genes have been identified in JSRD, which makes genetic diagnosis difficult.
  
  
  METHODS
  We report here a case of a 28-year-old Japanese woman diagnosed with JS with oculorenal defects with a novel compound heterozygous mutation (p.Ser219*/deletion) in the NPHP1 gene. Whole-exome sequencing (WES) of the patient identified the novel nonsense mutation in an apparently homozygous state. However, it was absent in her mother and heterozygous in her father. A read depth-based copy number variation (CNV) detection algorithm using WES data of the family predicted a large heterozygous deletion mutation in the patient and her mother, which was validated by digital polymerase chain reaction, indicating that the patient was compound heterozygous for the paternal nonsense mutation and the maternal deletion mutation spanning the site of the single nucleotide change.
  
  
  CONCLUSIONS
  It should be noted that analytical pipelines that focus purely on sequence information cannot distinguish homozygosity from hemizygosity because of its inability to detect large deletions. The ability to detect CNVs in addition to single nucleotide variants and small insertion/deletions makes WES an attractive diagnostic tool for genetically heterogeneous disorders.
authors.affiliation: Department of Neurology, Hematology, Metabolism, Endocrinology, and Diabetology, Yamagata University Faculty of Medicine, 2-2-2 Iida-nishi, Yamagata, 990-9585, Japan. skoyama@med.id.yamagata-u.ac.jp.
authors.forename: Shingo
authors.initials: S
authors.lastname: Koyama
authors.affiliation: Department of Neurology, Hematology, Metabolism, Endocrinology, and Diabetology, Yamagata University Faculty of Medicine, 2-2-2 Iida-nishi, Yamagata, 990-9585, Japan.
authors.forename: Hidenori
authors.initials: H
authors.lastname: Sato
authors.affiliation: Department of Neurology, Hematology, Metabolism, Endocrinology, and Diabetology, Yamagata University Faculty of Medicine, 2-2-2 Iida-nishi, Yamagata, 990-9585, Japan.
authors.forename: Manabu
authors.initials: M
authors.lastname: Wada
authors.affiliation: Department of Neurology, Hematology, Metabolism, Endocrinology, and Diabetology, Yamagata University Faculty of Medicine, 2-2-2 Iida-nishi, Yamagata, 990-9585, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Kawanami
authors.affiliation: Thoracic Oncology Program, University of Hawaii, Cancer Center, 701 Ilalo Street, Honolulu, HI, 96813, USA.
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Emi
authors.affiliation: Department of Neurology, Hematology, Metabolism, Endocrinology, and Diabetology, Yamagata University Faculty of Medicine, 2-2-2 Iida-nishi, Yamagata, 990-9585, Japan.
authors.forename: Takeo
authors.initials: T
authors.lastname: Kato
mesh_terms: D000015:Abnormalities, Multiple / Q000175:diagnosis / Q000235:genetics*; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000328:Adult; D044466:Asian People / Q000235:genetics; D001483:Base Sequence; D001921:Brain / Q000000981:diagnostic imaging; D002531:Cerebellum / Q000002:abnormalities*; D003598:Cytoskeletal Proteins; D004247:DNA / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism; D004252:DNA Mutational Analysis; D005124:Eye Abnormalities / Q000175:diagnosis / Q000235:genetics*; D005260:Female; D017353:Gene Deletion; D006579:Heterozygote; D006801:Humans; D007564:Japan; D052177:Kidney Diseases, Cystic / Q000175:diagnosis / Q000235:genetics*; D008279:Magnetic Resonance Imaging; D008565:Membrane Proteins / Q000235:genetics*; D010375:Pedigree; D016133:Polymerase Chain Reaction; D012160:Retina / Q000002:abnormalities*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D003598:Cytoskeletal Proteins; D008565:Membrane Proteins; C108725:NPHP1 protein, human; D004247:DNA
keywords: Case report; Deletion; Digital PCR; Hidden Markov model; Joubert syndrome; NPHP1; Whole exome sequencing