The Palestinian primary ciliary dyskinesia population: first results of the diagnostic and genetic spectrum

Abstract

Diagnostic testing for primary ciliary dyskinesia (PCD) started in 2013 in Palestine. We aimed to describe the diagnostic, genetic, and clinical spectrum of the Palestinian PCD population.Individuals with symptoms suggestive of PCD were opportunistically considered for diagnostic testing: nasal nitric oxide (nNO) measurement, transmission electron microscopy (TEM), and/or PCD genetic panel or whole exome testing. Clinical characteristics of those with a positive diagnosis were collected close to testing including FEV1GLI z-scores, and BMI z-scores.Sixty-eight individuals had a definite positive PCD diagnosis, 31 confirmed by genetic and TEM results, 23 by TEM results alone, and 14 by genetic variants alone. Forty-five individuals from 40 families had seventeen clinically actionable variants, and 4 had variants of unknown significance in 14 PCD-genes. CCDC39, DNAH11, andDNAAF11were the most commonly mutated genes. 100% of variants were homozygous. Patients had median age of 11.2 years at diagnosis, were highly consanguineous (93%) and 100% of Arabic descent. Clinical features included persistent wet cough (99%), neonatal respiratory distress (84%), and situs inversus(43%). Lung function at diagnosis was already impaired (FEV1z-score median −1.90 (−5.0 to 1.32)) and growth was mostly within the normal range (z-score mean= −0.36 (−3.03 to 2.57). 19% individuals had finger clubbing.Despite limited local resources, detailed geno- and phenotyping forms the basis of one of the largest national PCD populations globally. There was notable familial homozygosity within the context of significant population heterogeneity.

Defective airway intraflagellar transport underlies a combined motile and primary ciliopathy syndrome caused by IFT74 mutations

“…As part of a project to investigate the genetic and clinical spectrum of PCD in Palestine, individuals admitted to paediatric pulmonology clinic with symptoms suggestive of PCD were subject to diagnostic testing by nasal nitric oxide (nNO) measurement, transmission electron microscopy (TEM), and genetic testing, as recently reported ( 36 ). In this analysis, targeted gene panel sequencing with an established bioinformatics pipeline, coupled to CNV analysis using ExomeDepth software ( 37 ), revealed a homozygous genomic deletion spanning the whole of exon 2 of IFT74 , in one child (II.1) with suspected PCD and syndromic features from a Palestinian Arab family ( Fig.…”

“…Clinical analysis and diagnostics of patients followed the clinical guidelines as described previously ( 36 ). Molecular genetics analysis was done using targeted next-generation sequencing (NGS) as described before ( 36 , 37 ) with filtering using the gene panel listed in Supplementary Material, Table S1 . The impact on splicing was predicted using in silico tools, e.g.…”

“…All antibodies and dilutions used are listed in Supplementary Material, Table S3 . For TEM, nasal brushing biopsies were fixed in 4% glutaraldehyde followed by processing and quantification as previously described ( 36 ).…”

Ultrastructure for the diagnosis of primary ciliary dyskinesia in South Africa, a resource-limited setting

“…Despite being an upper-middle income country, South Africa has a high Gini coefficient of 0.63, and more than 80% of the population depend on state-funded healthcare facilities ( 8 , 9 ). Rumman et al ( 10 , 11 ) evaluated options for PCD diagnoses in resource-limited countries, reporting that any reduction in the technical standard of the equipment/method used resulted in a lack of sensitivity, and that there was still a fundamental reliance on expertise, specialised equipment, and collaboration with suitably equipped groups having this expertise. As would be expected then, nationwide specialised centres for the diagnoses of relatively rare, non-communicable diseases, are not evident in the South African setting.…”

One person can make a difference: identification of people with a rare genetic lung disease

“…In this issue of ERJ Open Research , R umman et al . [ 4 ] describe a cohort of patients with PCD in Palestine, an area with limited resources compounded by decades-long conflict and restrictions. The Palestinian population in the West Bank area cared for by N. Rumman's group, who have been living in this narrow region for many generations, are closely related and some with tribal origins.…”