Dataset Information

Founder mutation(s) in the RSPH9 gene leading to primary ciliary dyskinesia in two inbred Bedouin families.

ABSTRACT: A rare mutation in the RSPH9 gene leading to primary ciliary dyskinesia was previously identified in two Bedouin families, one from Israel and one from the United Arab Emirates (UAE). Herein we analyse mutation segregation in the Israeli family, present the clinical disease spectrum, and estimate mutation age in the two families. Mutation segregation was studied by restriction fragment length analysis. Mutation ages were estimated using a model of the decrease in the length of ancestral haplotypes. The mutations in each of the two families had a common ancestor less than 95 and less than 17 generations in the past. If the mutations in the two families are descended from a common ancestor, that mutation would have to have arisen at least 150 generations ago. If the Bedouin population has been roughly constant in size for at least 6000 years, it is possible that the mutations in the two families are identical by descent. If there were substantial fluctuations in the size of the Bedouin population, it is more likely that there were two independent mutations. Based on the available data, the population genetic analysis does not strongly favour one conclusion over the other.

SUBMITTER: Reish O

PROVIDER: S-EPMC2853723 | biostudies-literature | 2010 Mar

REPOSITORIES: biostudies-literature

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Founder mutation(s) in the RSPH9 gene leading to primary ciliary dyskinesia in two inbred Bedouin families.

Reish Orit O Slatkin Montgomery M Chapman-Shimshoni Daphne D Elizur Arnon A Chioza Barry B Castleman Victoria V Mitchison Hannah M HM

Annals of human genetics 20100108 2

A rare mutation in the RSPH9 gene leading to primary ciliary dyskinesia was previously identified in two Bedouin families, one from Israel and one from the United Arab Emirates (UAE). Herein we analyse mutation segregation in the Israeli family, present the clinical disease spectrum, and estimate mutation age in the two families. Mutation segregation was studied by restriction fragment length analysis. Mutation ages were estimated using a model of the decrease in the length of ancestral haplotyp ...[more]

PMID: 20070851

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Project description:BackgroundPrimary ciliary dyskinesia (PCD) is an inherited ciliary motility disorder caused by mutations in at least 40 genes. RSPH9 gene mutations encoding aberrant radial spoke head proteins have been linked with PCD. The clinical spectrum extent of RSPH9 gene mutations remains to date largely unknown. We aimed to describe the diagnostic and clinical phenotype in a case-series of RSPH9-associated PCD.MethodsWe performed whole exome sequencing in suspect patients from Cyprus who on repeated cilia biopsies demonstrated loss of the central pair apparatus on Transmission Electron Microscopy (TEM) and rotary beating patterns on High Speed Video Microscopy (HSVM), compatible to findings described previously in PCD patients bearing pathogenic RSPH9 mutations. In cases confirmed by genetic testing, we reviewed diagnostic, demographic and clinical data, as well as anthropometric and spirometric measurements.ResultsWe diagnosed 7 individuals (5 females) homozygous for the novel RSPH9 splice site mutation c.670+2T>C in intron 4, who originated from two families. Despite bearing the same genetic variant, patients presented a highly variable age (median 47.9 years; range, 6.6 to 51.4 years) and with a diverse clinical picture, all reporting a history of chronic or recurrent wet cough (100%), and at varying frequencies neonatal respiratory distress (43%), chronic rhinosinusitis (71%), and wheezing (43%). Complications such as bronchiectasis (71%), history of pneumonia(s) (57%) and surgical interventions (43%) clustered in some patients displaying typical PCD, but not in others with milder phenotypes. BMI-z scores (median: 0.53; range, -0.69 to 1.52), FEV1-z scores (median: -0.37; range: -1.79 to 0.22) and FVC z-scores (median: -0.80; range: -2.01 to 0.36) were on average within the normal range, although slightly reduced.ConclusionsIn conclusion, RSPH9-associated PCD disease demonstrates wide phenotypic variability. In some cases, mild clinical presentation is difficult to justify diagnostic work-up, highlighting the importance of wider adoption of genetic diagnostics. Larger studies are needed to assess variability of clinical spectrum associated to alterations of PCD genes.

Dataset Information

Founder mutation(s) in the RSPH9 gene leading to primary ciliary dyskinesia in two inbred Bedouin families.

Publications

Founder mutation(s) in the RSPH9 gene leading to primary ciliary dyskinesia in two inbred Bedouin families.

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