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Multi-Omic Investigations of a 17-19 Translocation Links MINK1 Disruption to Autism, Epilepsy and Osteoporosis

Eisfeldt, Jesper ; Schuy, Jakob ; Stattin, Eva-Lena ; Kvarnung, Malin ; Falk, Anna LU ; Feuk, Lars and Lindstrand, Anna (2022) In International Journal of Molecular Sciences 23(16).
Abstract

Balanced structural variants, such as reciprocal translocations, are sometimes hard to detect with sequencing, especially when the breakpoints are located in repetitive or insufficiently mapped regions of the genome. In such cases, long-range information is required to resolve the rearrangement, identify disrupted genes and, in symptomatic carriers, pinpoint the disease-causing mechanisms. Here, we report an individual with autism, epilepsy and osteoporosis and a de novo balanced reciprocal translocation: t(17;19) (p13;p11). The genomic DNA was analyzed by short-, linked- and long-read genome sequencing, as well as optical mapping. Transcriptional consequences were assessed by transcriptome sequencing of patient-specific neuroepithelial... (More)

Balanced structural variants, such as reciprocal translocations, are sometimes hard to detect with sequencing, especially when the breakpoints are located in repetitive or insufficiently mapped regions of the genome. In such cases, long-range information is required to resolve the rearrangement, identify disrupted genes and, in symptomatic carriers, pinpoint the disease-causing mechanisms. Here, we report an individual with autism, epilepsy and osteoporosis and a de novo balanced reciprocal translocation: t(17;19) (p13;p11). The genomic DNA was analyzed by short-, linked- and long-read genome sequencing, as well as optical mapping. Transcriptional consequences were assessed by transcriptome sequencing of patient-specific neuroepithelial stem cells derived from induced pluripotent stem cells (iPSC). The translocation breakpoints were only detected by long-read sequencing, the first on 17p13, located between exon 1 and exon 2 of MINK1 (Misshapen-like kinase 1), and the second in the chromosome 19 centromere. Functional validation in induced neural cells showed that MINK1 expression was reduced by >50% in the patient's cells compared to healthy control cells. Furthermore, pathway analysis revealed an enrichment of changed neural pathways in the patient's cells. Altogether, our multi-omics experiments highlight MINK1 as a candidate monogenic disease gene and show the advantages of long-read genome sequencing in capturing centromeric translocations.

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author
; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Autistic Disorder/genetics, Chromosome Mapping, Epilepsy/genetics, Humans, Osteoporosis/genetics, Protein Serine-Threonine Kinases/genetics, Translocation, Genetic
in
International Journal of Molecular Sciences
volume
23
issue
16
publisher
MDPI AG
external identifiers
  • pmid:36012658
  • scopus:85137736512
ISSN
1422-0067
DOI
10.3390/ijms23169392
language
English
LU publication?
yes
id
1f0fa34b-aa3b-4959-b96a-97c9305cbc38
date added to LUP
2022-09-20 14:03:28
date last changed
2024-06-13 14:34:14
@article{1f0fa34b-aa3b-4959-b96a-97c9305cbc38,
  abstract     = {{<p>Balanced structural variants, such as reciprocal translocations, are sometimes hard to detect with sequencing, especially when the breakpoints are located in repetitive or insufficiently mapped regions of the genome. In such cases, long-range information is required to resolve the rearrangement, identify disrupted genes and, in symptomatic carriers, pinpoint the disease-causing mechanisms. Here, we report an individual with autism, epilepsy and osteoporosis and a de novo balanced reciprocal translocation: t(17;19) (p13;p11). The genomic DNA was analyzed by short-, linked- and long-read genome sequencing, as well as optical mapping. Transcriptional consequences were assessed by transcriptome sequencing of patient-specific neuroepithelial stem cells derived from induced pluripotent stem cells (iPSC). The translocation breakpoints were only detected by long-read sequencing, the first on 17p13, located between exon 1 and exon 2 of MINK1 (Misshapen-like kinase 1), and the second in the chromosome 19 centromere. Functional validation in induced neural cells showed that MINK1 expression was reduced by &amp;gt;50% in the patient's cells compared to healthy control cells. Furthermore, pathway analysis revealed an enrichment of changed neural pathways in the patient's cells. Altogether, our multi-omics experiments highlight MINK1 as a candidate monogenic disease gene and show the advantages of long-read genome sequencing in capturing centromeric translocations.</p>}},
  author       = {{Eisfeldt, Jesper and Schuy, Jakob and Stattin, Eva-Lena and Kvarnung, Malin and Falk, Anna and Feuk, Lars and Lindstrand, Anna}},
  issn         = {{1422-0067}},
  keywords     = {{Autistic Disorder/genetics; Chromosome Mapping; Epilepsy/genetics; Humans; Osteoporosis/genetics; Protein Serine-Threonine Kinases/genetics; Translocation, Genetic}},
  language     = {{eng}},
  month        = {{08}},
  number       = {{16}},
  publisher    = {{MDPI AG}},
  series       = {{International Journal of Molecular Sciences}},
  title        = {{Multi-Omic Investigations of a 17-19 Translocation Links MINK1 Disruption to Autism, Epilepsy and Osteoporosis}},
  url          = {{http://dx.doi.org/10.3390/ijms23169392}},
  doi          = {{10.3390/ijms23169392}},
  volume       = {{23}},
  year         = {{2022}},
}