The genetics of situs inversus without primary ciliary dyskinesia

Merel C Postema,Clyde Francks,Guy Vingerhoets,Simon E Fisher,Amaia Carrion-Castillo

doi:10.1038/s41598-020-60589-z

Abstract

Situs inversus (SI), a left-right mirror reversal of the visceral organs, can occur with recessive Primary Ciliary Dyskinesia (PCD). However, most people with SI do not have PCD, and the etiology of their condition remains poorly studied. We sequenced the genomes of 15 people with SI, of which six had PCD, as well as 15 controls. Subjects with non-PCD SI in this sample had an elevated rate of left-handedness (five out of nine), which suggested possible developmental mechanisms linking brain and body laterality. The six SI subjects with PCD all had likely recessive mutations in genes already known to cause PCD. Two non-PCD SI cases also had recessive mutations in known PCD genes, suggesting reduced penetrance for PCD in some SI cases. One non-PCD SI case had recessive mutations in PKD1L1, and another in CFAP52 (also known as WDR16). Both of these genes have previously been linked to SI without PCD. However, five of the nine non-PCD SI cases, including three of the left-handers in this dataset, had no obvious monogenic basis for their condition. Environmental influences, or possible random effects in early development, must be considered.

Highlights

Situs inversus (SI), a left-right mirror reversal of the visceral organs, can occur with recessive Primary Ciliary Dyskinesia (PCD)
In this study we aimed to identify rare, highly penetrant genetic mutations that cause SI without PCD, by analysing whole genome sequence data from nine SI subjects without medical histories of PCD, five of whom were left-handed
Monogenic causes were identified in all positive controls, i.e. each of the six PCD subjects had one recessively mutated gene that is already known to cause PCD when mutated

Summary

Introduction

Situs inversus (SI), a left-right mirror reversal of the visceral organs, can occur with recessive Primary Ciliary Dyskinesia (PCD). One non-PCD SI case had recessive mutations in PKD1L1, and another in CFAP52 ( known as WDR16) Both of these genes have previously been linked to SI without PCD. Cilia are hair-like organelles that protrude from the cell surface into the extracellular space[3] They are expressed in various tissues including the respiratory epithelium[4], so that a disruption of ciliary motility can cause symptoms such as chronic bronchitis, inflamed or infected sinuses[5], which are often present in PCD. When leftward nodal flow is absent due to recessive PCD-causing mutations, many of which affect component proteins of the ciliary cytoskeleton, it becomes a matter of chance whether the viscera will take up the normal or mirror-reversed positioning[9]. That was the largest previous study, of which we are aware, that screened the exome for mutations in people with non-PCD SI

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