A de novo variant in OTX2 in a lamb with otocephaly.
- Paris JM Institute of Genetics, Vetsuisse Faculty, University of Bern, Bremgartenstr. 109a, 3001, Bern, Switzerland.
- Letko A Institute of Genetics, Vetsuisse Faculty, University of Bern, Bremgartenstr. 109a, 3001, Bern, Switzerland.
- Häfliger IM Institute of Genetics, Vetsuisse Faculty, University of Bern, Bremgartenstr. 109a, 3001, Bern, Switzerland.
- Švara T Institute of Pathology, Forensic and Administrative Veterinary Medicine, Veterinary Faculty, University of Ljubljana, Gerbičeva 60, 1000, Ljubljana, Slovenia.
- Gombač M Institute of Pathology, Forensic and Administrative Veterinary Medicine, Veterinary Faculty, University of Ljubljana, Gerbičeva 60, 1000, Ljubljana, Slovenia.
- Klinc P Clinic for Reproduction and Large Animals, Veterinary Faculty, University of Ljubljana, Cesta v Mestni log 47, 1000, Ljubljana, Slovenia.
- Škibin A Infrastructure Centre for Sustainable Recultivation Vremščica, Veterinary Faculty, University of Ljubljana, Gabrče 30, 6224, Senožeče, Slovenia.
- Pogorevc E Small Animal Clinic, Veterinary Faculty, University of Ljubljana, Cesta v Mestni log 47, 1000, Ljubljana, Slovenia.
- Drögemüller C Institute of Genetics, Vetsuisse Faculty, University of Bern, Bremgartenstr. 109a, 3001, Bern, Switzerland. cord.droegemueller@vetsuisse.unibe.ch.
- 2020-01-24
Published in:
- Acta veterinaria Scandinavica. - 2020
Agnathia
Domestic animal
Microstomia
Precision medicine
Rare disease
Synotia
Whole-genome sequencing
Animals
Craniofacial Abnormalities
Genetic Variation
Mutation
Otx Transcription Factors
Sheep
Sheep Diseases
English
BACKGROUND
Otocephaly is a rare lethal malformation of the first branchial arch. While the knowledge on the causes of otocephaly in animals is limited, different syndromic forms in man are associated with variants of the PRRX1 and OTX2 genes.
CASE PRESENTATION
A stillborn male lamb of the Istrian Pramenka sheep breed showed several congenital craniofacial anomalies including microstomia, agnathia, aglossia, and synotia. In addition, the lamb had a cleft palate, a small opening in the ventral neck region, a cystic oesophagus and two hepatic cysts. The brain was normally developed despite the deformed shape of the head. Taken together the findings led to a diagnosis of otocephaly. Whole-genome sequencing was performed from DNA of the affected lamb and both parents revealing a heterozygous single nucleotide variant in the OTX2 gene (Chr7: 71478714G > A). The variant was absent in both parents and therefore due to a de novo mutation event. It was a nonsense variant, XM_015097088.2:c.265C > T; which leads to an early premature stop codon and is predicted to truncate more than 70% of the OTX2 open reading frame (p.Arg89*).
CONCLUSIONS
The genetic findings were consistent with the diagnosis of the otocephaly and provide strong evidence that the identified loss-of-function variant is pathogenic due to OTX2 haploinsufficiency. The benefits of trio-based whole-genome sequencing as an emerging tool in veterinary pathology to confirm diagnosis are highlighted.
Otocephaly is a rare lethal malformation of the first branchial arch. While the knowledge on the causes of otocephaly in animals is limited, different syndromic forms in man are associated with variants of the PRRX1 and OTX2 genes.
CASE PRESENTATION
A stillborn male lamb of the Istrian Pramenka sheep breed showed several congenital craniofacial anomalies including microstomia, agnathia, aglossia, and synotia. In addition, the lamb had a cleft palate, a small opening in the ventral neck region, a cystic oesophagus and two hepatic cysts. The brain was normally developed despite the deformed shape of the head. Taken together the findings led to a diagnosis of otocephaly. Whole-genome sequencing was performed from DNA of the affected lamb and both parents revealing a heterozygous single nucleotide variant in the OTX2 gene (Chr7: 71478714G > A). The variant was absent in both parents and therefore due to a de novo mutation event. It was a nonsense variant, XM_015097088.2:c.265C > T; which leads to an early premature stop codon and is predicted to truncate more than 70% of the OTX2 open reading frame (p.Arg89*).
CONCLUSIONS
The genetic findings were consistent with the diagnosis of the otocephaly and provide strong evidence that the identified loss-of-function variant is pathogenic due to OTX2 haploinsufficiency. The benefits of trio-based whole-genome sequencing as an emerging tool in veterinary pathology to confirm diagnosis are highlighted.
- Language
-
- English
- Open access status
- gold
- Identifiers
-
- DOI 10.1186/s13028-020-0503-z
- PMID 31969185
- Persistent URL
- https://sonar.ch/global/documents/279179
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