A 73,128 bp de novo deletion encompassing the OPN1LW/OPN1MW gene cluster in sporadic Blue Cone Monochromacy: a case report

Abstract

BackgroundBlue Cone Monochromacy (BCM) is a rare congenital cone dysfunction disorder with X-linked recessive mode of inheritance. BCM is caused by mutations at the OPN1LW/MW cone opsin gene cluster including deletions of the locus control region (LCR) and/or parts of the gene cluster. We aimed at investigating the clinical presentation, genetic cause and inheritance underlying a sporadic case of BCM.Case presentationWe report a 24-year-old male presenting with congenital photophobia, nystagmus and colour vision abnormalities. There was no history of retinal dystrophy in the family. Clinical diagnosis of BCM was supported by genetic investigations of the patient and his family members. Molecular genetic analysis of the OPN1LW/OPN1MW gene cluster revealed a novel deletion of about 73 kb in the patient encompassing the LCR. The deletion was absent in the X-chromosomes of both the mother and transmitting grandfather.ConclusionsThe present report provides the clinical findings and the genetic basis underlying a sporadic BCM case which is caused by a de novo deletion within the OPN1LW/MW gene cluster originating from the mother’s germline due to Alu-repeat mediated recombination. This is the first report of a de novo deletion resulting in BCM, highlighting the importance to consider BCM and perform genetic testing for this condition in male patients with cone dysfunction also in the absence of a positive family history.

Pitfalls in the genetic testing of the OPN1LW-OPN1MW gene cluster in human subjects

“…The deletion in proband #4664 is a de novo mutation in the maternal grandfather’s germline as reported previously 8 . In order to rule out a loss of the SDIns due to a more complex rearrangement in this de novo event, we investigated the OPN1LW-OPN1MW gene cluster in the maternal grandfather (#5762) from whom the chromosomal segment was inherited (Fig.…”

Next-Generation Sequencing Applications for Inherited Retinal Diseases

“…Gross deletions have previously been detected in many genes, including BEST1 , EYS , MERTK , USH2A and many more from the aforementioned study alone [ 119 ]. Large deletions have also been reported in RPGR [ 122 ], CHM [ 58 ], OPN1LW / OPN1MW [ 123 ] and USH1C [ 1 ], to name but a few. Deletions are likely to be the most detectable CNV type given that most studies employ WES or TS to detect mutations.…”

“…Short-read sequencing is generally preferred to ensure that high-quality data are produced [ 137 ]. However, this technology is greatly hindered by features of the genome, such as repetitive elements, which are not only abundant in our genomes, but also known to increase the likelihood of an SV event occurring in IRD genes [ 123 , 138 ]. Long-read sequencing offers superior sequencing of such regions and offers a chance to more accurately recapitulate patients’ true genomic sequences through the use of de novo assembly [ 139 , 140 , 141 ].…”

The landscape of submicroscopic structural variants at the OPN1LW/OPN1MW gene cluster on Xq28 underlying blue cone monochromacy

“…The cosegregation of the SV with the disease was tested and confirmed where affected family members were available. We only observed a single case for which we could establish a de novo event in the lineage of an individual family (BCM 17/SVar10, Table 1 ) ( 19 ).…”