Identification of a recessive PCDH15 nonsense variant in purebred goats with vestibular dysfunction

TL;DR

A genetic variant in PCDH15 causes vestibular dysfunction in a breed of goats, resembling Usher syndrome in humans.

Contribution

First report of a naturally occurring Usher-like syndrome in goats caused by a PCDH15 nonsense variant.

Findings

A nonsense variant in PCDH15 is linked to vestibular dysfunction in Bunte Deutsche Edelziege goats.

The variant is homologous to a pathogenic mutation causing Usher syndrome type 1F in humans.

Genomic diagnostics can prevent further cases through molecular diagnosis and genetic testing.

Abstract

•Nonsense PCDH15 variant causes vestibular impairment in Bunte Deutsche Edelziege.•Affected goats show head excursions, wide-based stance, and poor postural control.•Pedigree information suggests autosomal recessive inheritance.•First report of naturally occurring Usher-like syndrome in goats.•Pathogenic variant corresponds to Usher syndrome type 1F-related variant in humans.

Nonsense PCDH15 variant causes vestibular impairment in Bunte Deutsche Edelziege.

Affected goats show head excursions, wide-based stance, and poor postural control.

Pedigree information suggests autosomal recessive inheritance.

First report of naturally occurring Usher-like syndrome in goats.

Pathogenic variant corresponds to Usher syndrome type 1F-related variant in humans.

Genetic diseases in goats are less well characterized than in other livestock species. This study reports a previously unrecognized congenital neurological disorder in Bunte Deutsche Edelziege goats and identifies its likely genetic cause. Between 2019 and 2023, a dairy goat farm observed 21 kids with congenital vestibular disease. The affected kids displayed pronounced, sometimes exuberant, wide bilateral excursions of the head and neck, delayed standing, wide-based stance, and poor postural control, while remaining alert and physically strong. Motor coordination improved with age. One retained female displayed mild persistent deficits and suspected hearing impairment in adulthood. Postmortem examinations were unremarkable, and infectious or nutritional causes were excluded. The repeated occurrence and pedigree structure suggested an inherited autosomal recessive disorder. Whole-genome sequencing of two affected kids, compared with large control cohorts, revealed a single rare nonsense variant in exon 5 of the PCDH15 gene encoding protocadherin-15. This variant truncates approximately 93% of the protein and is homologous to a pathogenic variant that causes Usher syndrome type 1F in humans. Sanger sequencing confirmed homozygosity in affected animals and heterozygosity in obligate carriers. The variant was absent from 90 unrelated goats of the same breed and over 1600 global controls. These findings indicate a naturally occurring Usher syndrome-like disorder in goats, representing the first such report, and highlight the value of genomic diagnostics for disease prevention and comparative research. The study provides a basis for the molecular diagnosis of similarly affected animals, as well as for genetic testing to prevent further cases.

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