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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.
BMC Med Genet. 2017 Mar 27; 18(1):37.BM

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.

CASE PRESENTATION

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.

CONCLUSION

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+Show Affiliations

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.Department of Neurology, Hematology, Metabolism, Endocrinology, and Diabetology, Yamagata University Faculty of Medicine, 2-2-2 Iida-nishi, Yamagata, 990-9585, Japan.Department of Neurology, Hematology, Metabolism, Endocrinology, and Diabetology, Yamagata University Faculty of Medicine, 2-2-2 Iida-nishi, Yamagata, 990-9585, Japan.Department of Neurology, Hematology, Metabolism, Endocrinology, and Diabetology, Yamagata University Faculty of Medicine, 2-2-2 Iida-nishi, Yamagata, 990-9585, Japan.Thoracic Oncology Program, University of Hawaii, Cancer Center, 701 Ilalo Street, Honolulu, HI, 96813, USA.Department of Neurology, Hematology, Metabolism, Endocrinology, and Diabetology, Yamagata University Faculty of Medicine, 2-2-2 Iida-nishi, Yamagata, 990-9585, Japan.

Pub Type(s)

Case Reports
Journal Article

Language

eng

PubMed ID

28347285

Citation

Koyama, Shingo, et al. "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." BMC Medical Genetics, vol. 18, no. 1, 2017, p. 37.
Koyama S, Sato H, Wada M, et al. 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. BMC Med Genet. 2017;18(1):37.
Koyama, S., Sato, H., Wada, M., Kawanami, T., Emi, M., & Kato, T. (2017). 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. BMC Medical Genetics, 18(1), 37. https://doi.org/10.1186/s12881-017-0399-2
Koyama S, et al. 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. BMC Med Genet. 2017 Mar 27;18(1):37. PubMed PMID: 28347285.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Koyama,Shingo, AU - Sato,Hidenori, AU - Wada,Manabu, AU - Kawanami,Toru, AU - Emi,Mitsuru, AU - Kato,Takeo, Y1 - 2017/03/27/ PY - 2016/06/21/received PY - 2017/03/14/accepted PY - 2017/3/29/entrez PY - 2017/3/30/pubmed PY - 2017/5/16/medline KW - Case report KW - Deletion KW - Digital PCR KW - Hidden Markov model KW - Joubert syndrome KW - NPHP1 KW - Whole exome sequencing SP - 37 EP - 37 JF - BMC medical genetics JO - BMC Med. Genet. VL - 18 IS - 1 N2 - 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. CASE PRESENTATION: 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. CONCLUSION: 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. SN - 1471-2350 UR - https://www.unboundmedicine.com/medline/citation/28347285/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_ L2 - https://bmcmedgenet.biomedcentral.com/articles/10.1186/s12881-017-0399-2 DB - PRIME DP - Unbound Medicine ER -