A 65 kilobase deletion of the upstream TYR gene region in a family with oculocutaneous albinism type 1

Oculocutaneous albinism type 1 is caused by variants in the TYR (tyrosinase) gene. We describe a family with two affected sibs who inherited the pathogenic missense TYR variant c.1146C > A;p.(Asn382Lys) from their mother and a deletion encompassing 65 kilobase pairs of the upstream region of the gene between hg38 coordinates chr11:89110944 and chr11:89175770, from their father. The deletion likely arose by non-homologous recombination since the regions including the two deletion breakpoints share no sequence homology. The deletion contains a single enhancer element that is homologous to a 5' Tyr core regulatory element in the mouse. A luciferase reporter assay showed that this element had a positive regulatory activity. This represents to our knowledge the first deletion solely restricted to non-coding upstream sequences of the TYR gene. It is assumed that the deletion down-regulates expression of the TYR gene and is therefore pathogenic, allowing to establish the diagnosis of OCA 1 in the patients. This study underscores the need to extend the search for pathogenic variants to regulatory regions either by whole genome sequencing or by targeted next generation sequencing of a panel including entire genes (exons, introns, flanking sequences) in order to improve the diagnostic rate in patients with albinism.