The first case of Branchio-oto-renal (BOR) syndrome caused by a deep intronic variant in EYA1

Marie Lorans; Kristian Alsbjerg Skipper; Trine Østergaard Nielsen; Simon Opstrup Drue; Christine Kroer Nielsen; Christian Vinberg Thorup; Sven Erik Nørholt; Lisbeth Marianne Thøstesen; Pernille Axél Gregersen

doi:10.1007/s00438-025-02336-5

The first case of Branchio-oto-renal (BOR) syndrome caused by a deep intronic variant in EYA1

Marie Lorans^*
, Kristian Alsbjerg Skipper
, Trine Østergaard Nielsen
, Simon Opstrup Drue
, Christine Kroer Nielsen
, Christian Vinberg Thorup
, Sven Erik Nørholt
, Lisbeth Marianne Thøstesen
, Pernille Axél Gregersen

^*Corresponding author for this work

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

Abstract

The aim of this study was to identify the genetic cause of Branchio-oto-renal (BOR) syndrome using whole genome sequencing (WGS) in a previously unsolved case. We describe a novel, deep intronic variant in EYA1 that segregates with BOR syndrome in three generations in a Danish family. According to the prediction algorithm, SpliceAI, the variant creates a cryptic splice donor site in intron 7, resulting in inclusion of a pseudo-exon. We functionally assessed the intronic variant using an in-vitro splicing assay confirming a spliceogenic effect. The abnormally spliced EYA1 transcript is expected to undergo nonsense mediated decay resulting in haploinsufficiency. In conclusion, we identified the genetic cause of BOR syndrome in the family. To the best of our knowledge, this is the first report of a causative deep intronic variant in BOR syndrome. Our results demonstrate the clinical utility of WGS in cases with highly specific phenotypes.

Original language	English
Journal	Molecular Genetics and Genomics
Volume	301
Issue	1
Pages (from-to)	12
ISSN	1617-4615
DOIs	https://doi.org/10.1007/s00438-025-02336-5
Publication status	Published - 2026

Keywords

Humans
Branchio-Oto-Renal Syndrome/genetics
Intracellular Signaling Peptides and Proteins/genetics
Introns/genetics
Nuclear Proteins/genetics
Pedigree
Protein Tyrosine Phosphatases/genetics
Whole Genome Sequencing

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title = "The first case of Branchio-oto-renal (BOR) syndrome caused by a deep intronic variant in EYA1",

abstract = "The aim of this study was to identify the genetic cause of Branchio-oto-renal (BOR) syndrome using whole genome sequencing (WGS) in a previously unsolved case. We describe a novel, deep intronic variant in EYA1 that segregates with BOR syndrome in three generations in a Danish family. According to the prediction algorithm, SpliceAI, the variant creates a cryptic splice donor site in intron 7, resulting in inclusion of a pseudo-exon. We functionally assessed the intronic variant using an in-vitro splicing assay confirming a spliceogenic effect. The abnormally spliced EYA1 transcript is expected to undergo nonsense mediated decay resulting in haploinsufficiency. In conclusion, we identified the genetic cause of BOR syndrome in the family. To the best of our knowledge, this is the first report of a causative deep intronic variant in BOR syndrome. Our results demonstrate the clinical utility of WGS in cases with highly specific phenotypes.",

keywords = "Humans, Branchio-Oto-Renal Syndrome/genetics, Intracellular Signaling Peptides and Proteins/genetics, Introns/genetics, Nuclear Proteins/genetics, Pedigree, Protein Tyrosine Phosphatases/genetics, Whole Genome Sequencing",

author = "Marie Lorans and Skipper, \{Kristian Alsbjerg\} and Nielsen, \{Trine {\O}stergaard\} and Drue, \{Simon Opstrup\} and Nielsen, \{Christine Kroer\} and Thorup, \{Christian Vinberg\} and N{\o}rholt, \{Sven Erik\} and Th{\o}stesen, \{Lisbeth Marianne\} and Gregersen, \{Pernille Ax{\'e}l\}",

year = "2026",

doi = "10.1007/s00438-025-02336-5",

language = "English",

volume = "301",

pages = "12",

journal = "Molecular Genetics and Genomics",

issn = "1617-4615",

publisher = "Springer Science and Business Media Deutschland GmbH",

number = "1",

}

The first case of Branchio-oto-renal (BOR) syndrome caused by a deep intronic variant in EYA1. / Lorans, Marie ; Skipper, Kristian Alsbjerg; Nielsen, Trine Østergaard et al.
In: Molecular Genetics and Genomics, Vol. 301, No. 1, 2026, p. 12.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

TY - JOUR

T1 - The first case of Branchio-oto-renal (BOR) syndrome caused by a deep intronic variant in EYA1

AU - Lorans, Marie

AU - Skipper, Kristian Alsbjerg

AU - Nielsen, Trine Østergaard

AU - Drue, Simon Opstrup

AU - Nielsen, Christine Kroer

AU - Thorup, Christian Vinberg

AU - Nørholt, Sven Erik

AU - Thøstesen, Lisbeth Marianne

AU - Gregersen, Pernille Axél

PY - 2026

Y1 - 2026

N2 - The aim of this study was to identify the genetic cause of Branchio-oto-renal (BOR) syndrome using whole genome sequencing (WGS) in a previously unsolved case. We describe a novel, deep intronic variant in EYA1 that segregates with BOR syndrome in three generations in a Danish family. According to the prediction algorithm, SpliceAI, the variant creates a cryptic splice donor site in intron 7, resulting in inclusion of a pseudo-exon. We functionally assessed the intronic variant using an in-vitro splicing assay confirming a spliceogenic effect. The abnormally spliced EYA1 transcript is expected to undergo nonsense mediated decay resulting in haploinsufficiency. In conclusion, we identified the genetic cause of BOR syndrome in the family. To the best of our knowledge, this is the first report of a causative deep intronic variant in BOR syndrome. Our results demonstrate the clinical utility of WGS in cases with highly specific phenotypes.

AB - The aim of this study was to identify the genetic cause of Branchio-oto-renal (BOR) syndrome using whole genome sequencing (WGS) in a previously unsolved case. We describe a novel, deep intronic variant in EYA1 that segregates with BOR syndrome in three generations in a Danish family. According to the prediction algorithm, SpliceAI, the variant creates a cryptic splice donor site in intron 7, resulting in inclusion of a pseudo-exon. We functionally assessed the intronic variant using an in-vitro splicing assay confirming a spliceogenic effect. The abnormally spliced EYA1 transcript is expected to undergo nonsense mediated decay resulting in haploinsufficiency. In conclusion, we identified the genetic cause of BOR syndrome in the family. To the best of our knowledge, this is the first report of a causative deep intronic variant in BOR syndrome. Our results demonstrate the clinical utility of WGS in cases with highly specific phenotypes.

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KW - Intracellular Signaling Peptides and Proteins/genetics

KW - Introns/genetics

KW - Nuclear Proteins/genetics

KW - Pedigree

KW - Protein Tyrosine Phosphatases/genetics

KW - Whole Genome Sequencing

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DO - 10.1007/s00438-025-02336-5

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SN - 1617-4615

VL - 301

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JO - Molecular Genetics and Genomics

JF - Molecular Genetics and Genomics

IS - 1

ER -

The first case of Branchio-oto-renal (BOR) syndrome caused by a deep intronic variant in EYA1

Abstract

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