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

BackgroundJoubert 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 presentationWe 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.ConclusionIt 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12881-017-0399-2) contains supplementary material, which is available to authorized users.

Results of next-generation sequencing gene panel diagnostics including copy-number variation analysis in 810 patients suspected of heritable thoracic aortic disorders

“…The eXome hidden Markov model (XHMM) is one of several algorithms developed for the detection of CNVs through NGS data (Fromer & Purcell, 2014;Fromer et al, 2012). XHMM has identified (potential) causative CNVs in, for example, patients with Parkinson's disease, autism spectrum disorders, and rare diseases like Joubert syndrome and very early onset inflammatory bowel disease (Kelsen et al, 2015;Koyama et al, 2017;Poultney et al, 2013;Spataro et al, 2017). The aim of this study was to assess both the diagnostic yield of our panel of H-TAD-associated genes and the prevalence of CNVs in these genes.…”

NPHP1‐Related ciliopathies: A new case and major review of the ophthalmic manifestations of 147 reported cases

“…There were 646 NPHP cases, 23 Joubert Syndrome cases, and nine Senior Loken cases. 125 NPHP cases, 13 Joubert syndrome cases, and all nine Senior Loken cases had ophthalmic abnormalities with a total of 147 cases overall with eye manifestations 9‐56 . Most common eye manifestations include retinal abnormalities ( n = 70) including retinitis pigmentosa and retinal dystrophies as well as nystagmus ( n = 19) and strabismus ( n = 14).…”

Exome sequencing and RNA analysis identify two novel CPLANE1 variants causing Joubert syndrome

“…Since 2012, more and more variants of CPLANE1 have been identified in JS families (Liu et al, 2020 ; Zhu et al, 2021 ). WES has proved to be a powerful tool for the identification of novel variants in JS (Koyama et al, 2017 ). In our study, the JS family had undergone expanded carrier screening for recessive diseases, the result was negative, and routine WES also could not explain the cause of JS.…”