A de novo variant in OTX2 in a lamb with otocephaly

Paris, Julia Maria (author), Letko, Anna (author), Häflinger, Irene Monika (author), Švara, Tanja (author), Gombač, Mitja (author), Klinc, Primož (author), Škibin, Andrej (author), Pogorevc, Estera (author), Drögemüller, Cord (author)

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 OT X2 genes.Case presentation:A stillborn male lamb of the Istrian Pramenka sheep breed showed several congenital crani-ofacial 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 heterozy-gous single nucleotide variant in the OT X2 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 OT X2 open reading frame (p.Arg89*).Conclusions:The genetic findings were consistent with the diagnosis of the otocephaly and provide strong evi-dence that the identified loss-of-function variant is pathogenic due to OT X2 haploinsufficiency. The benefits of trio-based whole-genome sequencing as an emerging tool in veterinary pathology to confirm diagnosis are highlighted.

• Language: English
• Keywords: Agnathia, microstomia, precision medicine, rare disease, synotia, whole-genome sequencing, sheep
• Work type: Article
• Typology: 1.03 - Short Scientific Article
• Organization: VF - Veterinary Faculty
• Publication status: Published
• Publication version: Version of Record
• Year: 2020
• Number of pages: Str. 1-6
• Numbering: Vol. 62, no. e5
• PID: 20.500.12556/RUL-116670
• UDC: 636.09:616
• ISSN on article: 1751-0147
• DOI: 10.1186/s13028-020-0503-z
• COBISS.SI-ID: 4930682
• Publication date in RUL: 02.06.2020

Record is a part of a journal

• Title: Acta veterinaria Scandinavica
• Shortened title: Acta vet. Scand.
• Publisher: BioMed Central
• ISSN: 1751-0147
• COBISS.SI-ID: 515671577

Licences

• License: CC BY 4.0, Creative Commons Attribution 4.0 International
• Link: http://creativecommons.org/licenses/by/4.0/
• Description: This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.
• Licensing start date: 02.06.2020