Dataset Information

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

ABSTRACT:

Background

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.

Methods

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 forced expiratory volume in 1 s (FEV₁) Global Lung Index z-scores and body mass index z-scores.

Results

68 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. 45 individuals from 40 families had 17 clinically actionable variants and four had variants of unknown significance in 14 PCD genes. CCDC39, DNAH11 and DNAAF11 were the most commonly mutated genes. 100% of variants were homozygous. Patients had a median age of 10.0 years at diagnosis, were highly consanguineous (93%) and 100% were 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 (FEV₁ z-score median -1.90 (-5.0-1.32)) and growth was mostly within the normal range (z-score mean -0.36 (-3.03-2.57). 19% individuals had finger clubbing.

Conclusions

Despite limited local resources in Palestine, 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.

SUBMITTER: Rumman N

PROVIDER: S-EPMC10107064 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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Publications

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

Rumman Nisreen N Fassad Mahmoud R MR Driessens Corine C Goggin Patricia P Abdelrahman Nader N Adwan Adel A Albakri Mutaz M Chopra Jagrati J Doherty Regan R Fashho Bishara B Freke Grace M GM Hasaballah Abdallah A Jackson Claire L CL Mohamed Mai A MA Abu Nema Reda R Patel Mitali P MP Pengelly Reuben J RJ Qaaqour Ahmad A Rubbo Bruna B Thomas N Simon NS Thompson James J Walker Woolf T WT Wheway Gabrielle G Mitchison Hannah M HM Lucas Jane S JS

ERJ open research 20230301 2

<h4>Background</h4>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.<h4>Methods</h4>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 ...[more]

PMID: 37077557

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Project description:BACKGROUND: Mutations in the DNAI1 gene, encoding a component of outer dynein arms of the ciliary apparatus, are the second most important genetic cause of primary ciliary dyskinesia (PCD), the genetically heterogeneous recessive disorder with the prevalence of ~1/20,000. The estimates of the DNAI1 involvement in PCD pathogenesis differ among the reported studies, ranging from 4% to 10%. METHODS: The coding sequence of DNAI1 was screened (SSCP analysis and direct sequencing) in a group of PCD patients (157 families, 185 affected individuals), the first ever studied large cohort of PCD patients of Slavic origin (mostly Polish); multiplex ligation-dependent probe amplification (MLPA) analysis was performed in a subset of ~80 families. RESULTS: Three previously reported mutations (IVS1+2-3insT, L513P and A538T) and two novel missense substitutions (C388Y and G515S) were identified in 12 families (i.e. ~8% of non-related Polish PCD patients). The structure of background SNP haplotypes indicated common origin of each of the two most frequent mutations, IVS1+2-3insT and A538T. MLPA analysis did not reveal any significant differences between patients and control samples. The Polish cohort was compared with all the previously studied PCD groups (a total of 487 families): IVS1+2-3insT remained the most prevalent pathogenetic change in DNAI1 (54% of the mutations identified worldwide), and the increased global prevalence of A538T (14%) was due to the contribution of the Polish cohort. CONCLUSIONS: The worldwide involvement of DNAI1 mutations in PCD pathogenesis in families not preselected for ODA defects ranges from 7 to 10%; this global estimate as well as the mutation profile differs in specific populations. Analysis of the background SNP haplotypes suggests that the increased frequency of chromosomes carrying A538T mutations in Polish patients may reflects local (Polish or Slavic) founder effect. Results of the MLPA analysis indicate that no large exonic deletions are involved in PCD pathogenesis.

Project description:BackgroundPrimary ciliary dyskinesia (PCD), a rare ciliopathy disorder, is caused by variants in multiple genes, with DNAH5 being one of the most frequently implicated. However, the precise relationship between variant type or location in the DNAH5 gene and the clinical heterogeneity remains elusive. The present systematic review aims to provide critical insights into the impact of the molecular nature of DNAH5 variants on PCD phenotypes.MethodsWe enrolled all reported cases of PCD with biallelic pathogenic variants in the DNAH5 gene to date, and evaluated genotype-phenotype correlations in these patients, employing truncating (TV) and missense (MV) variant-carrying as grouping criteria.ResultsA total of 323 PCD patients with the DNAH5 variants were included, with 14.55% of these patients were diagnosed as Kartagener syndrome. Pediatric and adult patients exhibited distinct clinical features, including varying incidences of bronchiectasis, infertility, neonatal respiratory distress (NRD), ciliary ultrastructural defects distributions, and lung function (all p < 0.05). With regard to mutational patterns, truncating variants in DNAH5 were clustered in the 1200-3200 amino acid region, and were more prevalent in children compared to adult (p < 0.0001). Most missense variants are clustering in the linker, AAA + ATPase and AAA-lid domains. The most frequently observed mutation, c.10815delT, was prevalent in Europe and America, whereas c.8030G > A was more common in China and Asia. In terms of genotype-phenotype correlations, individuals with the TV/TV genotype exhibited a higher proportion of NRD and earlier onset compared to those with MV-carrying genotypes, both in overall population and in pediatric patients (all p < 0.05). Patients with the TV/TV genotype exhibited worse lung function compared to those with MV-carrying genotypes.ConclusionThe study underscores the broad mutational spectrum and high phenotypic heterogenicity in DNAH5-related PCD patients. The presence of biallelic truncating variants may predispose patients to earlier disease onset and poorer lung function.

Dataset Information

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

Background

Methods

Results

Conclusions

Publications

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

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