Identification of a Novel Founder Variant in Cause Primary Ciliary Dyskinesia in Five Consanguineous Families Derived from a Single Tribe Descendant of Arabian Peninsula

Overview

Journal Front Genet

Date 2022 Oct 28

PMID 36303540

Authors

Dalal A Al-Mutairi

Basel H Alsabah

Bashar A Alkhaledi

Petra Pennekamp

Heymut Omran

Affiliations

Soon will be listed here.

Abstract

Primary ciliary dyskinesia (PCD) is caused by dysfunction of motile cilia resulting in insufficient mucociliary clearance of the lungs. The overall aim of this study is to identify disease causing genetic variants for PCD patients in the Kuwaiti population. A cohort of multiple consanguineous PCD families was identified from Kuwaiti patients and genomic DNA from the family members was analysed for variant screening. Transmission electron microscopy (TEM) and immunofluorescent (IF) analyses were performed on nasal brushings to detect specific structural abnormalities within ciliated cells. All the patients inherited the same founder variant in and exhibited PCD symptoms. TEM analysis demonstrated lack of outer dynein arms (ODA) in all analysed samples. IF analysis confirmed absence of DNAI1, DNAI2, and DNAH5 from the ciliary axoneme. Whole exome sequencing, autozygosity mapping and segregation analysis confirmed that seven patients carry the same homozygous missense variant (:c.740G>A; p.Arg247Gln; rs755060592). :c.740G>A is the founder variant causing PCD in patients belonging to a particular Arabian tribe which practices consanguineous marriages.

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References

Shapiro A, Davis S, Polineni D, Manion M, Rosenfeld M, Dell S . Diagnosis of Primary Ciliary Dyskinesia. An Official American Thoracic Society Clinical Practice Guideline. Am J Respir Crit Care Med. 2018; 197(12):e24-e39. PMC: 6006411. DOI: 10.1164/rccm.201805-0819ST. View

Pazour G, Agrin N, Walker B, Witman G . Identification of predicted human outer dynein arm genes: candidates for primary ciliary dyskinesia genes. J Med Genet. 2005; 43(1):62-73. PMC: 2593024. DOI: 10.1136/jmg.2005.033001. View

Carr I, Camm N, Taylor G, Charlton R, Ellard S, Sheridan E . GeneScreen: a program for high-throughput mutation detection in DNA sequence electropherograms. J Med Genet. 2010; 48(2):123-30. DOI: 10.1136/jmg.2010.082081. View

Watson C, Crinnion L, Gurgel-Gianetti J, Harrison S, Daly C, Antanavicuite A . Rapid Detection of Rare Deleterious Variants by Next Generation Sequencing with Optional Microarray SNP Genotype Data. Hum Mutat. 2015; 36(9):823-30. PMC: 4744743. DOI: 10.1002/humu.22818. View

Wallmeier J, Al-Mutairi D, Chen C, Loges N, Pennekamp P, Menchen T . Mutations in CCNO result in congenital mucociliary clearance disorder with reduced generation of multiple motile cilia. Nat Genet. 2014; 46(6):646-51. DOI: 10.1038/ng.2961. View

Williams E, Hegde M . Implementing genomic medicine in pathology. Adv Anat Pathol. 2013; 20(4):238-44. DOI: 10.1097/PAP.0b013e3182977199. View

Johansen Taber K, Dickinson B, Wilson M . The promise and challenges of next-generation genome sequencing for clinical care. JAMA Intern Med. 2013; 174(2):275-80. DOI: 10.1001/jamainternmed.2013.12048. View

Lander E, Botstein D . Homozygosity mapping: a way to map human recessive traits with the DNA of inbred children. Science. 1987; 236(4808):1567-70. DOI: 10.1126/science.2884728. View

Mazor M, Alkrinawi S, Chalifa-Caspi V, Manor E, Sheffield V, Aviram M . Primary ciliary dyskinesia caused by homozygous mutation in DNAL1, encoding dynein light chain 1. Am J Hum Genet. 2011; 88(5):599-607. PMC: 3146731. DOI: 10.1016/j.ajhg.2011.03.018. View

10.

Mitchell D, Rosenbaum J . A motile Chlamydomonas flagellar mutant that lacks outer dynein arms. J Cell Biol. 1985; 100(4):1228-34. PMC: 2113766. DOI: 10.1083/jcb.100.4.1228. View

11.

Magnin M, Cros P, Beydon N, Mahloul M, Tamalet A, Escudier E . Longitudinal lung function and structural changes in children with primary ciliary dyskinesia. Pediatr Pulmonol. 2012; 47(8):816-25. DOI: 10.1002/ppul.22577. View

12.

Adzhubei I, Jordan D, Sunyaev S . Predicting functional effect of human missense mutations using PolyPhen-2. Curr Protoc Hum Genet. 2013; Chapter 7:Unit7.20. PMC: 4480630. DOI: 10.1002/0471142905.hg0720s76. View

13.

OCallaghan C, Chetcuti P, Moya E . High prevalence of primary ciliary dyskinesia in a British Asian population. Arch Dis Child. 2009; 95(1):51-2. DOI: 10.1136/adc.2009.158493. View

14.

Zariwala M, Knowles M, Omran H . Genetic defects in ciliary structure and function. Annu Rev Physiol. 2006; 69:423-50. DOI: 10.1146/annurev.physiol.69.040705.141301. View

15.

Pennarun G, Chapelin C, Escudier E, Bridoux A, Dastot F, Cacheux V . The human dynein intermediate chain 2 gene (DNAI2): cloning, mapping, expression pattern, and evaluation as a candidate for primary ciliary dyskinesia. Hum Genet. 2001; 107(6):642-9. DOI: 10.1007/s004390000427. View

16.

Fowkes M, Mitchell D . The role of preassembled cytoplasmic complexes in assembly of flagellar dynein subunits. Mol Biol Cell. 1998; 9(9):2337-47. PMC: 25499. DOI: 10.1091/mbc.9.9.2337. View

17.

Olbrich H, Haffner K, Kispert A, Volkel A, Volz A, Sasmaz G . Mutations in DNAH5 cause primary ciliary dyskinesia and randomization of left-right asymmetry. Nat Genet. 2002; 30(2):143-4. DOI: 10.1038/ng817. View

18.

Leigh M, Pittman J, Carson J, Ferkol T, Dell S, Davis S . Clinical and genetic aspects of primary ciliary dyskinesia/Kartagener syndrome. Genet Med. 2009; 11(7):473-87. PMC: 3739704. DOI: 10.1097/GIM.0b013e3181a53562. View

19.

Carr I, Markham S, Pena S . Estimating the degree of identity by descent in consanguineous couples. Hum Mutat. 2011; 32(12):1350-8. DOI: 10.1002/humu.21584. View

20.

Ratjen F, Waters V, Klingel M, McDonald N, Dell S, Leahy T . Changes in airway inflammation during pulmonary exacerbations in patients with cystic fibrosis and primary ciliary dyskinesia. Eur Respir J. 2015; 47(3):829-36. DOI: 10.1183/13993003.01390-2015. View