An effective combination of whole-exome sequencing and runs of homozygosity for the diagnosis of primary ciliary dyskinesia in consanguineous families

Abstract

Primary ciliary dyskinesia (PCD) is clinically characterized by neonatal respiratory distress, chronic sinusitis, bronchiectasis and infertility, and situs inversus in 50% of the patients. PCD is a result of mutations in genes encoding proteins involved in ciliary function, and is primarily inherited in an autosomal recessive fashion. Diagnosis of PCD is often a challenging task due to its high clinical and genetic heterogeneities. In the present study, we attempted to use whole-exome sequencing (WES) combined with runs of homozygosity (ROH) approaches to identify the genetic defects in four Chinese consanguineous families with clinical PCD. We successfully identified three recently acknowledged PCD genes: DYX1C1, CCNO and ARMC4, and one well-characterized PCD gene, DNAI1. Our study provides compelling evidence that WES in combination with ROH analysis is an efficient diagnostic tool for identifying genetic causes of PCD in consanguineous families. Furthermore, our work expands the genetic mutation spectrum in PCD, and provides the additional tools to better serve the counseling of the families with PCD.

Atypical cyclins: the extended family portrait

“…Cells with impaired CCNO expression display a marked reduction in the number of multiple motile cilia, which is caused by altered generation of centrioles at deuterosomes [73,74]. Therefore, it is not surprising that several studies have assigned CCNO a role in multiciliogenesis and mucociliary disorders [73][74][75][76][77][78] and infertility [79]. CCNO has also been shown to promote apoptosis in lymphoid cells [80].…”

Compound Heterozygous Variants in the Coiled-Coil Domain Containing 40 Gene in a Chinese Family with Primary Ciliary Dyskinesia Cause Extreme Phenotypic Diversity in Cilia Ultrastructure

“…In this study, we applied targeted gene-based NGS that has proven to be reliable, rapid and cost- effective, was capable of identifying the candidate mutation in patients with PCD ( Djakow et al, 2016 ; Guo et al, 2017 ). According to American College of Medical Genetics and Genomics (ACMG) variant interpretation guidelines, these two mutations were identified as “likely pathogenic” mutations ( Richards et al, 2015 ).…”

Genomic profiling supports the diagnosis of primary ciliary dyskinesia and reveals novel candidate genes and genetic variants

“…The clinical features of PCD are nowadays well recognized, but the diagnosis is still challenging, especially when patients represent non-specific signs and symptoms, and when necessary equipment and screening tests including nasal nitric oxide (nNO) measurements, nasal mucociliary transport tests, and saccharine test, are not available to physicians. Even transmission electron microscopy, which is considered as “gold standard” for PCD, cannot resolve 30% of PCD patients with normal cilia ultrastructure [ 10 – 15 ]. Therefore, implementation of genetic and molecular diagnosis of PCD is rather a necessity, regardless of whether it is a confirmation of a clinical diagnosis or suspicion of PCD.…”

“…The identification of PCD genes has been based on linkage studies, candidate gene approaches and proteomic analyses, combined with sequencing of potentially causative genes [ 16 – 19 ]. Recently, the availability of high-throughput sequencing techniques contributed to the swift identification of new PCD-causative genes, resulting in more than 40 genes to be identified so far, which allowed 65% of cases to be genetically described [ 15 , 20 – 23 ].…”