Categories: Vision / eye phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 615984 (trait) , 607590 (gene)

Links to relevant human diseases in MONDO:

• MONDO:0014433: Bardet-Biedl syndrome 4

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2019

Species-specific description: Peterson et al. (2019): "This finding represents the first identification of a naturally-occurring nonhuman primate model of BBS, and more broadly the first such model of retinitis pigmentosa and a ciliopathy with an associated genetic mutation".

Markers: Initially, Peterson et al. (2019) "leveraged the mGAP database of sequence variants identified in 293 ONPRC rhesus macaques, including primary relatives of the two cases, to identify candidate variants [including] . . . a single basepair deletion in exon 3 of BBS7: c.160delG (p.Ala54fs) as a strong candidate variant based on the function of the BBS7 gene and the predicted damaging impact of the resulting translational frame shift and premature termination". Peterson et al. (2019) then reported that "Subsequent whole genome sequencing of the initial affected monkey confirmed it to be homozygous for the BBS7 c.160delG (p.Ala54fs) variant. Sanger re-sequencing of both affected cases also confirmed them each to be homozygous for the BBS7 allele, while the sire and dam of affected siblings were heterozygous."

Molecular basis: Peterson et al. (2019) "identified a lineage of rhesus macaques with a frameshift mutation in exon 3 of the BBS7 gene c.160delG (p.Ala54fs) that is predicted to produce a non-functional protein."

Clinical features: Peterson et al. (2019): "Three full- or half-sibling monkeys homozygous for the BBS7 c.160delG variant, at ages 3.5, 4 and 6 years old, displayed a combination of severe photoreceptor degeneration and progressive kidney disease. In vivo retinal imaging revealed features of severe macular degeneration, including absence of photoreceptor layers, degeneration of the retinal pigment epithelium, and retinal vasculature atrophy."

Pathology: Peterson et al. (2019): "Electroretinography in the 3.5-year-old case demonstrated loss of scotopic and photopic a-waves and markedly reduced and delayed b-waves. Histological assessments in the 4- and 6-year-old cases confirmed profound loss of photoreceptors and inner retinal neurons across the posterior retina, with dramatic thinning and disorganization of all cell layers, abundant microglia, absent or displaced RPE cells, and significant gliosis in the subretinal space. Retinal structure, including presence of photoreceptors, was preserved only in the far periphery. Ultrasound imaging of the kidneys revealed deranged architecture, and renal histopathology identified distorted contours with depressed, fibrotic foci and firmly adhered renal capsules; renal failure occurred in the 6-year-old case."

Prevalence: Peterson et al. (2019): "A genotyping screen of the extended macaque pedigree using a custom-design TaqMan assay confirmed an autosomal recessive inheritance pattern, identifying 61 carriers (39 living) and one additional homozygous individual".

Associated gene: