De novo retinoic acid receptor beta (RARB) variant associated with microphthalmia and dystonia.

Eur J Med Genet

Institute of Neurogenomics, Helmholtz Zentrum München, Munich, Germany; Institute of Human Genetics, School of Medicine, Technical University of Munich, Munich, Germany. Electronic address:

Published: August 2023

Background: Definition of the individual genotypes that cause a Mendelian phenotype is of great importance both to clinical diagnostics and disease characterization. Heterozygous de novo gain-of-function missense variants in RARB are associated with syndromic microphthalmia 12 (MCOPS12), a developmental disorder characterized by eye malformations and variable involvement of other organs. A subset of patients were described with poorly delineated movement disorders. Additionally, RARB bi-allelic loss-of-function variants, inherited from asymptomatic heterozygous carrier parents, have been found in a recessive family with four MCOPS12-affected members.

Patient/methods: We used trio whole-exome sequencing to explore the molecular basis of disease in an individual with congenital eye abnormality and movement disorder. All patients with reported RARB variants were reviewed.

Results: We report on identification of a heterozygous de novo RARB nonsense variant in a girl with microphthalmia and progressive generalized dystonia. Public database entries indicate that the de novo variant is recurrently present in clinically affected subjects but a literature report has not yet been available.

Conclusions: We provide the first detailed evidence for a role of dominant RARB truncating alterations in congenital eye-brain disease, expanding the spectrum of MCOPS12-associated mutations. Considered together with the published family with bi-allelic variants, the data suggest manifestation and non-manifestation of disease in relation to almost identical RARB loss-of-function variations, an apparent paradox that is seen in a growing number of human genetic conditions associated with both recessive and dominant inheritance patterns.

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http://dx.doi.org/10.1016/j.ejmg.2023.104802DOI Listing

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