Mapping the Most Common Founder Variant in That Causes Primary Ciliary Dyskinesia in Multiple Consanguineous Families of Bedouin Arabs

Overview

Journal J Clin Med

Specialty General Medicine

Date 2023 Oct 28

PMID 37892643

Authors

Dalal A Al-Mutairi

Basel H Alsabah

Petra Pennekamp

Heymut Omran

Affiliations

Soon will be listed here.

Abstract

Introduction: Primary ciliary dyskinesia (PCD) is a congenital thoracic disorder caused by dysfunction of motile cilia, resulting in insufficient mucociliary clearance of the lungs. The overall aim of this study is to identify causative defective genes in PCD-affected individuals in the Kuwaiti population.

Methods: A cohort of multiple consanguineous PCD families was identified from Kuwaiti patients and genomic DNA from the family members was isolated using standard procedures. The DNA samples from all affected individuals were analyzed by whole exome sequencing (WES). Transmission electron microscopy (TEM) and immunofluorescent analysis (IF) were performed on samples obtained by nasal brushings to identify specific structural abnormalities within ciliated cells.

Results: Here, we present six multiplex families with 11 patients who all presented with typical PCD symptoms. Ten out of eleven patients inherited a 3 bp homozygous deletion of GAA in , whereas the eleventh patients inherited this variant in trans with a frameshift deletion in . Genetic results were confirmed by segregation analysis. The in-frame deletion of GAA in has previously been published as pathogenic in both annotated transcript variants (1 and 2). In contrast, the previously unpublished frameshift deletion identified in KU-15.IV2 impacts only transcript variant two. Regarding all 11 PCD individuals analyzed, IF results demonstrated absence of RSPH9 protein and TEM analysis showed the typical findings in mutant individuals.

Conclusions: We present the largest cohort of PCD individuals affected by the founder in-frame deletion GAA in . This founder variant is the most common PCD-causing variant in Bedouin Arabs in Kuwait.

Citing Articles

Novel pathogenic variants of associated with clinical and genetic spectra of primary ciliary dyskinesia in an Arab population.

Al-Mutairi D, Alsabah B, Pennekamp P, Omran H Front Genet. 2024; 15:1396797.

PMID: 39045318 PMC: 11264286. DOI: 10.3389/fgene.2024.1396797.

A homozygous mutation causes osteogenesis and dentinogenesis imperfecta with craniofacial anomalies.

Al-Mutairi D, Jarragh A, Alsabah B, Wein M, Mohammed W, Alkharafi L JBMR Plus. 2024; 8(5):ziae026.

PMID: 38562913 PMC: 10984723. DOI: 10.1093/jbmrpl/ziae026.

References

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

Cho E, Huh H, Jeong I, Lee N, Koh W, Park H . A nonsense variant in NME5 causes human primary ciliary dyskinesia with radial spoke defects. Clin Genet. 2020; 98(1):64-68. DOI: 10.1111/cge.13742. View

Al-Mutairi D, Alsabah B, Alkhaledi B, Pennekamp P, Omran H . Identification of a novel founder variant in cause primary ciliary dyskinesia in five consanguineous families derived from a single tribe descendant of Arabian Peninsula. Front Genet. 2022; 13:1017280. PMC: 9596166. DOI: 10.3389/fgene.2022.1017280. View

Carr I, Morgan J, Watson C, Melnik S, Diggle C, Logan C . Simple and efficient identification of rare recessive pathologically important sequence variants from next generation exome sequence data. Hum Mutat. 2013; 34(7):945-52. DOI: 10.1002/humu.22322. 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

Frommer A, Hjeij R, Loges N, Edelbusch C, Jahnke C, Raidt J . Immunofluorescence Analysis and Diagnosis of Primary Ciliary Dyskinesia with Radial Spoke Defects. Am J Respir Cell Mol Biol. 2015; 53(4):563-73. PMC: 5306451. DOI: 10.1165/rcmb.2014-0483OC. View

Alsaadi M, Gaunt T, Boustred C, Guthrie P, Liu X, Lenzi L . From a single whole exome read to notions of clinical screening: primary ciliary dyskinesia and RSPH9 p.Lys268del in the Arabian Peninsula. Ann Hum Genet. 2012; 76(3):211-20. PMC: 3575730. DOI: 10.1111/j.1469-1809.2012.00704.x. View

El Khouri E, Thomas L, Jeanson L, Bequignon E, Vallette B, Duquesnoy P . Mutations in DNAJB13, Encoding an HSP40 Family Member, Cause Primary Ciliary Dyskinesia and Male Infertility. Am J Hum Genet. 2016; 99(2):489-500. PMC: 4974111. DOI: 10.1016/j.ajhg.2016.06.022. View

Fassad M, Shoman W, Morsy H, Patel M, Radwan N, Jenkins L . Clinical and genetic spectrum in 33 Egyptian families with suspected primary ciliary dyskinesia. Clin Genet. 2019; 97(3):509-515. DOI: 10.1111/cge.13661. View

10.

Knowles M, Daniels L, Davis S, Zariwala M, Leigh M . Primary ciliary dyskinesia. Recent advances in diagnostics, genetics, and characterization of clinical disease. Am J Respir Crit Care Med. 2013; 188(8):913-22. PMC: 3826280. DOI: 10.1164/rccm.201301-0059CI. View

11.

Monies D, Abouelhoda M, Assoum M, Moghrabi N, Rafiullah R, Almontashiri N . Lessons Learned from Large-Scale, First-Tier Clinical Exome Sequencing in a Highly Consanguineous Population. Am J Hum Genet. 2019; 104(6):1182-1201. PMC: 6562004. DOI: 10.1016/j.ajhg.2019.04.011. View

12.

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

13.

Knowles M, Ostrowski L, Leigh M, Sears P, Davis S, Wolf W . Mutations in RSPH1 cause primary ciliary dyskinesia with a unique clinical and ciliary phenotype. Am J Respir Crit Care Med. 2014; 189(6):707-17. PMC: 3983840. DOI: 10.1164/rccm.201311-2047OC. View

14.

Kopanos C, Tsiolkas V, Kouris A, Chapple C, Albarca Aguilera M, Meyer R . VarSome: the human genomic variant search engine. Bioinformatics. 2018; 35(11):1978-1980. PMC: 6546127. DOI: 10.1093/bioinformatics/bty897. View

15.

Anderegg L, Im Hof Gut M, Hetzel U, Howerth E, Leuthard F, Kyostila K . NME5 frameshift variant in Alaskan Malamutes with primary ciliary dyskinesia. PLoS Genet. 2019; 15(9):e1008378. PMC: 6743793. DOI: 10.1371/journal.pgen.1008378. View

16.

Leigh M, Horani A, Kinghorn B, OConnor M, Zariwala M, Knowles M . Primary Ciliary Dyskinesia (PCD): A genetic disorder of motile cilia. Transl Sci Rare Dis. 2019; 4(1-2):51-75. PMC: 6768089. DOI: 10.3233/TRD-190036. View

17.

Horani A, Ferkol T, Dutcher S, Brody S . Genetics and biology of primary ciliary dyskinesia. Paediatr Respir Rev. 2015; 18:18-24. PMC: 4864047. DOI: 10.1016/j.prrv.2015.09.001. View

18.

Kott E, Legendre M, Copin B, Papon J, Dastot-Le Moal F, Montantin G . Loss-of-function mutations in RSPH1 cause primary ciliary dyskinesia with central-complex and radial-spoke defects. Am J Hum Genet. 2013; 93(3):561-70. PMC: 3769924. DOI: 10.1016/j.ajhg.2013.07.013. View

19.

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

20.

Ibanez-Tallon I, Heintz N, Omran H . To beat or not to beat: roles of cilia in development and disease. Hum Mol Genet. 2003; 12 Spec No 1:R27-35. DOI: 10.1093/hmg/ddg061. View