Investigation of the Molecular Basis of Primary Ciliary Dyskinesia and Situs Inversus amongst the Amish

Abstract

Cilia are hair-like projections from eukaryotic cells: they are complex organelles that can be split into motile (normal/embryonic nodal) and non-motile types. Primary ciliary dyskinesia (PCD) is genetically heterogeneous, typically autosomal recessive disorder, characterised by oto-sino-pulmonary disease, male infertility and situs abnormalities, due to structural and motion defects of cilia. Early diagnosis and specialist intervention significantly improves clinical outcome. Situs inversus (SI) is a related condition involving, the mirror image rearrangement of the internal organs and has a more complex genetic basis; it can also be a component of a more complex syndrome. Pathogenic variants in >40 genes have been associated with these conditions, accounting for <70% of cases.

This project is part of a long-running clinical-genetic program based amongst the Amish communities in the USA which aims to define the frequencies and genetic causes of PCD/SI. A combination of clinical phenotyping, autozygosity mapping, and whole exome sequencing, were used to investigate Amish families affected by these disorders. This enabled the identification of the novel disease genes in each case. This study determined that both PCD and SI occur more commonly amongst the Amish than in non-Amish families. Genomic studies of affected individuals identified known causes of PCD, as well as two putative novel causes of PCD/SI. Notably, previous studies of knockout mice for one of the new candidate genes identified SI as a key phenotype, overlapping with the human condition. Preliminary genetic studies in other families with PCD and situs abnormalities failed to identify clear genetic causes, so studies are ongoing to investigate more complex pathogenesis. While additional work is required to define the outcome of the sequence variants identified, these studies provide a greatly improved understanding of the frequencies and causes of PCD/SI in the Amish, and define two putative new candidate genetic causes.