Primary ciliary dyskinesia-causing mutations in Amish and Mennonite communities

Abstract

Objective: To determine whether individuals with primary ciliary dyskinesia (PCD) from unrelated Amish and Mennonite families harbor a single and unique founder mutation.

Study design: Subjects from Amish and Mennonite communities in several states were enrolled in the study. All subjects were clinically characterized, and nasal nitric oxide levels were measured. Nasal epithelial scrapings were collected from several subjects for ciliary ultrastructural analyses. DNA was isolated from patients with PCD and their unaffected first- and second-degree relatives. Genome-wide homozygosity mapping, linkage analyses, targeted mutation analyses, and exome sequencing were performed.

Results: All subjects from Old-Order Amish communities from Pennsylvania were homozygous for a nonsense mutant DNAH5 allele, c.4348C>T (p.Q1450X). Two affected siblings from an unrelated Mennonite family in Arkansas were homozygous for the same nonsense DNAH5 mutation. Children with PCD from an Amish family from Wisconsin had biallelic DNAH5 mutations, c.4348C>T (p.Q1450X) and c.10815delT (p.P3606HfsX23), and mutations in other genes associated with PCD were also identified in this community.

Conclusion: The Amish and Mennonite subjects from geographically dispersed and socially isolated communities had the same founder DNAH5 mutation, owing to the common heritage of these populations. However, disease-causing mutations in other PCD-associated genes were also found in affected individuals in these communities, illustrating the genetic heterogeneity in this consanguineous population.

Keywords: NO; Nitric oxide; PCD; Primary ciliary dyskinesia.

Figure

Family pedigrees and genetic analyses. A, Consanguineous kindred with related nuclear families in Amish communities from Pennsylvania. B, Mennonite family from Arkansas. C, Amish-Mennonite family with children with PCD from several midwestern states, in which affected individuals had 2 heteroallelic DNAH5 mutations. Solid symbols indicate affected individuals; central dots, heterozygous individuals; dark-blue symbols, c.4348C>T (p.Q1450X) DNAH5 mutation; light-blue symbols, c.10815delT (p.P3606HfsX23) DNAH5 mutation; yellow symbols, DNAI1 (g.IVS1+2_3insT) mutation; red symbols, HEATR2 (p.L795P) mutation. Arrows specify the probands. Asterisks indicate subjects who underwent genetic testing. si, situs inversus totalis; sa, situs ambiguus