A splice site and copy number variant responsible for TTC25-related primary ciliary dyskinesia

K Backman; W E Mears; A Waheeb; M Beaulieu Bergeron; J McClintock; J de Nanassy; J Reisman; M Osmond; T Hartley; A J Mears; K D Kernohan; Care4Rare Canada

doi:10.1016/j.ejmg.2021.104193

A splice site and copy number variant responsible for TTC25-related primary ciliary dyskinesia

Eur J Med Genet. 2021 May;64(5):104193. doi: 10.1016/j.ejmg.2021.104193. Epub 2021 Mar 18.

Authors

K Backman¹, W E Mears², A Waheeb³, M Beaulieu Bergeron⁴, J McClintock⁵, J de Nanassy⁵, J Reisman⁶, M Osmond², T Hartley², A J Mears⁷, K D Kernohan⁸; Care4Rare Canada²

Collaborator

Care4Rare Canada:
D A Dyment⁹

Affiliations

¹ Department of Pediatrics, University of Saskatchewan, Saskatoon, SK, Canada.
² Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON, Canada.
³ Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, ON, Canada.
⁴ Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, ON, Canada; Department of Pathology and Laboratory Medicine, University of Ottawa, Ottawa, ON, Canada.
⁵ Department of Pathology and Laboratory Medicine, Children's Hospital of Eastern Ontario, Ottawa, ON, Canada.
⁶ Department of Pediatrics, Children's Hospital of Eastern Ontario, Ottawa, ON, Canada.
⁷ Newborn Screening Ontario, Children's Hospital of Eastern Ontario, Ottawa, ON, Canada.
⁸ Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON, Canada; Newborn Screening Ontario, Children's Hospital of Eastern Ontario, Ottawa, ON, Canada.
⁹ Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON, Canada; Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, ON, Canada. Electronic address: ddyment@cheo.on.ca.

PMID: 33746037
DOI: 10.1016/j.ejmg.2021.104193

Abstract

Primary ciliary dyskinesia (PCD) is a genetically heterogeneous disorder of motile cilia. With few exceptions, PCD is an autosomal recessive condition, and there are over 40 genes associated with the condition. We present a case of a newborn female with clinical features of PCD, specifically the Kartagener syndrome phenotype, due to variants in TTC25. This gene has been previously associated with PCD in three families. Two multi-gene panels performed as a neonate and at two years of age were uninformative. Exome sequencing was performed by the Care4Rare Canada Consortium on a research basis, and an apparent homozygous intronic variant (TTC25:c.1145+1G > A) was identified that was predicted to abolish the canonical splice donor activity of exon 8. The child's mother was a heterozygous carrier of the variant. The paternal sample did not show the splice variant, and homozygosity was observed across the paternal locus. Microarray analysis showed a 50 kb heterozygous deletion spanning the genes TTC25 and CNP. This is the first example of a pathogenic gross deletion in trans with a splice variant, resulting in TTC25-related PCD.

Keywords: Ciliopathy; Copy number variant; Exome sequencing; Kartagener syndrome; Primary ciliary dyskinesia; TTC25.

Publication types

Case Reports

MeSH terms

Carrier Proteins / genetics*
Carrier Proteins / metabolism
DNA Copy Number Variations
Female
Gene Deletion*
Humans
Infant, Newborn
Kartagener Syndrome / genetics*
Kartagener Syndrome / pathology
RNA Splice Sites

Substances

Carrier Proteins
RNA Splice Sites
TTC25 protein, human