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Hanno Joern Bolz, Anja Kron, Tobias Eisenberger, Christian Decker, Barbara Seipel, Cornelia Kraus, Carsten Bergmann, Christine Neuhaus; Targeted NGS Incidentally Reveals Klinefelter Syndrome in a Patient with X-Linked Recessive Retinitis Pigmentosa and Skewed X Inactivation. Invest. Ophthalmol. Vis. Sci. 2014;55(13):3263.
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© ARVO (1962-2015); The Authors (2016-present)
Retinitis pigmentosa (RP) is genetically extremely heterogeneous, a challenge for comprehensive genetic testing. Here, we aimed at identifying the causative mutation in a male with simplex RP of early onset and rapid progression.
We have established targeted next-generation sequencing (NGS) of more than 120 genes associated with non-syndromic retinal dystrophies. Besides mere sequence analysis, we quantify NGS reads to additionally detect deletions and duplications comprising one to multiple exons, enabling us to identify the causative mutations in most patients with RP and related conditions. X chromosome inactivation pattern was determined in the lymphocytes by the androgen receptor methylation-based assay.
We identified a 4 bp deletion in an X-linked recessive RP gene, RP2, predicted to result in loss-of-function, in our male simplex RP patient. Surprisingly, the wildtype sequence was also present in about half of the reads, and the heterozygous state of the mutation was confirmed by Sanger sequencing. Read quantification for other X-chromosomal genes in our panel consistently indicated the presence of additional X-chromosomal material in the patient compared to male and female controls. Chromosome analysis revealed a 47,XXY karyotype in all analyzed cells, consistent with Klinefelter syndrome. X chromosome inactivation assay revealed a skewed X inactivation pattern.
Combined sequence analysis and quantification of NGS data as well as X inactivation studies were instrumental in identifying the complex cause of RP in this patient. His RP likely results from preferential expression of the mutant RP2 copy. We suggest that patients should be informed that NGS aimed at identifying Mendelian mutations may incidentally reveal sex chromosome aneuploidies that would have remained undiagnosed otherwise. To our knowledge, this is the first description of X-linked recessive RP in a patient with Klinefelter syndrome: The probability of both disorders to occur simultaneously is extremely low.
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